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MegaEl-Dena

MegaEl-Dena®

FOR DIGESTIVE SYSTEM HEALTH SUPPORT

  • Provides a full spectrum of probiotic strains for proper digestive system function
  • Helps the growth of beneficial microorganisms in the intestinal tract
  • Strengthens the immune system and helps alleviate side effects of anitiotics
  • Made of 100% natural non-dairy microorganisms and contains NO sugar
  • Produced in the USA in accordance with GMP standards

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WHO NEEDS MEGAEL-DENA?

Anyone with disturbances of microbial balance, especially if:

  • You take antibiotics
  • You have diarrhea 
  • You have gastric and duodenal ulcers associated with Helicobacter pylori 
  • You need to enhance your immune system
  • You are a smoker

 

WHY MEGAEL DENA?

  • MegaEl-Dena contains scientifically and clinically proven ingredients and is made of non-diary products.
  • MegaEl-Dena is a synbiotic combining both probiotics and prebiotics.
  • MegaEl-Dena contains eight probiotic species, which provide a full spectrum of probiotic strains for proper digestive system health & function and immune system support.
  • MegaEl-Dena contains prebiotics that selectively stimulate the growth, reproduction and functional activity of Lactobacillus and Bifidobacterium, which means that the positive impact of MegaEl-Dena will continue to support your bacterial balance even after you stop taking it.
  • MegaEl-Dena is made in the USA according to GMP standards from environmentally friendly animal and plant sources, and constitutes a natural product free of chemical agents.

SERVING SIZE: 2 Capsules

SERVINGS PER CONTAINER: 30

Ingredients

Amount Per Serving  CFU /mg 

% Daily value

Probiotic Bacteria Complex containing:

5   billion

*

Lactobacillus acidophilus

1.25 billion

*

Lactobacillus rhamnosus

1 billion

*

Bifidobacterium lactis

750 million

*

Lactobacillus casei

500 million

*

Bifidobacterium breve

500 million

*

Bifidobacterium longum

500 million

*

Bifidobacterium bifidum

250 million

*

Streptococcus thermophilus

250 million

*

Fructooligosaccharides (FOS)

520 mg

*

* Daily Value not established.

Other ingredients: gelatin, magnesium stearate,  titanium dioxide, FD&C Blue No 1

PROPERTIES OF INGREDIENTS

MegaEl-Dena contains 8 species of bacteria that are present in the normal intestinal microbiota of all age groups. Of these, two large genera, Lactobacillus and Bifidobacterium, are the dominant components of the natural intestinal microbiota and are found in all parts of the gastrointestinal tract, but most often in the large intestine. Living lactic acid bacteria, Bifidobacterium, and Streptococcus thermophilus perform several functions in the gut that support and regulate the physiological balance in the intestinal microbiota. The strains of lactic acid bacteria included in Megael-Dena are resistant to antibiotics. These microbial strains are highly acid-resistant, which allows use of the product if it is dissolved in advance. MegaEl-Dena promotes a marked increase in the content of other components of the normal microbiota. MegaEl-Dena contains prebiotic that selectively stimulate the growth, propagation, and functional activity of Lactobacillus and Bifidobacterium. 

RECOMMENDED USE

For preservation and regulation of the normal balance of intestinal microbiota in cases of:

  • dysbacteriosis
  • diarrhea
  • flatulence
  • constipation
  • nausea, vomiting, and abdominal pain caused by digestive problems due to antibiotic and chemotherapy treatments
  • atopic allergies
  • impaired immunity
  • candidiasis
  • stomatitis
  • lesions and ulcers of the stomach and duodenum
  • in the postoperative period, to adjust the balance of intestinal microbiota and reduce the likelihood of complications

DIRECTIONS FOR USE

As a dietary supplement, follow these recommendations.

Age

Initial serving

Maintenance

Children aged 4 and older

1 capsule twice a day

1 capsule once a day

Adults

2 capsules twice a day

2 capsules once a day

Aged 65+

3 capsules twice a day

3 capsules once a day


Capsules should be taken immediately after a meal with a small amount of liquid. The contents of the capsules can be dissolved in a liquid (such as water or juice) before use.

CONTRAINDICATIONS

Hypersensitivity to one of the components of MegaEl-Dena.

WARNINGS

  • If pregnant or nursing, consult your healthcare practitioner before taking this product.
  • The color of the product can vary depending on the color changes of natural components.

STORAGE AND PACKAGING

Store in a cool, dry place. Keep out of reach of children.

One bottle contains 60 capsules.

WHAT IS PROBIOTIC?

When ingested in appropriate amounts, probiotics are microorganisms that have a favorable influence on human health through improving the indigenous microbiota.

It is estimated that the number of bacteria inhabiting the human body (most of them reside in the gastrointestinal tract) is about ten times the number of our own cells. Complex interactions between these bacteria and our digestive system present well-documented health benefits. In particular, these microorganisms protect the human body from the invasion of pathogenic microorganisms, either by directly competing with them or by modulating the immune response.

The beneficial effects of Bifidobacterium and Lactobacillus bacteria have been reported at least since the late 1980s and confirmed by multiple clinical trials. Whereas species from several bacterial genera and at least one yeast species have been used as probiotics, Bifidobacterium and Lactobacillus remain the best-studied and most widely used ones. Seven out of the eight species of viable beneficial bacteria included in MegaEl-Dena belong to these genera: four species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), and three species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus).

 

WHAT IS PREBIOTIC?

Prebiotics are substances that cannot be digested by humans but stimulate the growth of beneficial bacteria. Since beneficial bacteria are already present in the intestines (even if their number is reduced), taking prebiotics stimulates the growth of these beneficial bacteria and helps normalize the microbiota. The most widely known prebiotics are nondigestible oligosaccharides, in particular fructooligosaccharides (FOS), which are included in the MegaEl-Dena formulation.

 

WHAT IS SYNBIOTIC?

Supplements that contain both probiotics and prebiotics, are called synbiotics and are assumed to have synergistic effects on the growth of beneficial bacteria. Synbiotics are expected to be more efficient than probiotics or prebiotics taken separately. In addition, some species of probiotic bacteria, such as Streptococcus thermophilus (present in MegaEl-Dena) supply other bacteria with nutrients that stimulate their growth, similar to the effects of prebiotics.

The two approaches of regulating indigenous microbiota through the intake of probiotics or prebiotics are not mutually exclusive; moreover, they can be used as complementary, leading to the concept of synbiotics. MegaEl-Dena is a synbiotic, as it combines viable beneficial bacteria and FOS.

 

WHAT FOOD CAN COMPENSATE THE LACK OF PROBIOTICS IN MY BODY?  

Probiotics are almost exclusively consumed as fermented dairy products such as yogurt, soft cheeses (like Gouda) or freeze-dried cultures.

 

WHAT ARE THE NATURAL SOURCES OF PROBIOTICS? 

The most widely known prebiotics are nondigestible oligosaccharides, in particular fructooligosaccharides (FOS), also called oligofructose (which is included in the MegaEl-Dena formulation), as well as galactooligosaccharides and lactulose. Prebiotics are found naturally in many foods, and can also be isolated from plants. Natural sources of prebiotics include: bananas, whole grains, garlic, onions, honey, leeks, artichokes, fortified foods and beverages.

  

CAN CHILDREN TAKE PROBIOTICS? 

Yes, children can take MegaEl-Dena. For appropriate information about ages and dosages (for US) please see the Leaflet section. Capsules should be taken immediately after a meal with a small amount of liquid. The contents of the capsules can be dissolved in a liquid (such as water or juice) before use.

Various commensal microorganisms are present even in the gastrointestinal tract of newborn babies.  This colonization is largely complete at one week of life; the first exposure to commensal microorganisms occurs during the infant's passage through the birth canal and continues as the baby is breastfed, because breast milk also contains commensal microorganisms.

Colonization of the newborn’s gastrointestinal tract by “incorrect” sets of microorganisms (known as dysbiosis) is associated with several immunological disorders, including atopic allergy (defined as allergic reactions in people with genetic predisposition to hypersensitivity to certain allergens); the gut microbiota differs in healthy and allergic babies. Dysbiosis occurs not only in infants but also in pregnant women and is a risk factor for the development of atopic allergies, probably because the composition of the vaginal microflora and that of breast milk affects the composition of the baby’s microbiota.  

 

SHOULD I TAKE PROBIOTICS OR PREBIOTICS WHILE TAKING ANTIBIOTICS AND WHY? 

A number of clinical studies have shown beneficial effects of probiotics and/or prebiotics in patients undergoing antibiotic therapy. Here is why:

  1. Disruption in the intestinal microflora caused by the use of broad-spectrum antibiotics may promote excessive colonization of intestinal mucosa by fungi, in particular Candida species. This colonization is a risk factor for invasive candidiasis, which is a systemic life-threatening infection. Since probiotics help to restore endogenous microflora, they can be expected to help prevent Candida infections.
  2. Sometimes antibiotic-induced dysbiosis (a collective name for disturbances in the composition of the intestinal microbiota that lead to an imbalance between beneficial and harmful bacteria) leads to the prevalence of harmful bacteria, such as Clostridium difficile. Taking probiotics and/or prebiotics may have beneficial effects in patients with these disturbances. For example, taking L. rhamnosus or a combination of B. lactis and S.thermophilus (all three bacterial species are components of MegaEl-Dena) during antibiotic therapy has been found to reduce the risk of antibiotic-associated diarrhea.
  3. Taking prebiotics (FOS) is associated with fewer relapses in patients with C. difficile infection, whereas synbiotics have been found to help reduce the presence of C. difficile in the gastrointestinal tract. Overall, several components of MegaEl-Dena (both probiotics and prebiotics) have been found to be associated with beneficial effects in patients with acute diarrhea caused by antibiotic therapy, whereas no adverse effects of probiotics have been observed.

 

WHAT IS DYSBIOSIS? 

Dysbiosis (dysbacteriosis) is a collective name for disturbances in the composition of the intestinal microbiota that lead to an imbalance between beneficial and harmful bacteria. Potential causes of dysbiosis include the use (and overuse) of antibiotics and vaccinations, general antimicrobial strategies, exposure of newborns to “incorrect” sets of microorganisms in hospitals, psychological stress, and diet components; in particular, the microbiota composition is affected by the content of sulfates, sugars, proteins, and the ratio between dietary intake of proteins and fibers/indigestible starch. Smoking also increases the risk of dysbiosis.

Chronic dysbiosis is associated with a number of pathological conditions, such as gastrointestinal disturbances, Helicobacter pylori infection, inflammatory bowel disease, ankylosing spondylitis, colorectal cancer, chronic fatigue syndrome, non-alcoholic fatty liver disease, and obesity. Genetic predisposition may also play a role in the development of dysbiosis. In many cases, dysbiosis is asymptomatic, or its consequences may be difficult to detect without special studies.

 

HOW CAN PROBIOTICS ENHANCE MY IMMUNE SYSTEM?

Disturbances in the composition of the intestinal microbiota (a collective name for bacteria that inhabit the gastrointestinal tract) lead to an imbalance between beneficial and harmful bacteria and are associated with several immunological disorders.

Taking supplements that contain probiotics (beneficial bacteria) may help correct alterations in the composition of intestinal microbiota.

Communication between intestinal microbiota and the human body is mediated by multiple regulatory mechanisms.

  1. Bacteria may directly interact with intestinal epithelial or immune cells and can also produce bioactive compounds that act as immune modulators.
  2. Notably, approximately 70% of immune system cells are located in the gastrointestinal tract.
  3. Probiotics are known to have beneficial effects on immunity, both at the molecular and cellular levels. For example, two studies, one conducted in Canada and the other in New Zealand, found that probiotics increase the production of interferon-α (which plays a role in protection against viral infections) in healthy elderly people but reduce the production of a proinflammatory cytokine tumor necrosis factor (TNF)-α in the gastrointestinal tract.
  4. The ability of microbiota to regulate human immunity is illustrated by a study that involved healthy volunteers and found that intake of several species of bacteria that normally live in the intestines and are considered beneficial resulted in changes in the expression of genes involved in the control of immunity.
  5. Some probiotics increase the serum level of the anti-inflammatory cytokine IL-10. Thus, probiotics would be expected to boost the innate immune response against viral infections and at the same time have an anti-inflammatory effect.
  6. A number of studies have also documented the ability of probiotics to stimulate the production of immunoglobulin A (IgA), which plays a critical role in mucosal immunity.
  7. Probiotics were also reported to enhance the bactericidal activity of leukocytes and to affect the Th1/Th2 balance. Th1 cells produce proinflammatory cytokines (including TNF-α mentioned above) involved in responses to bacterial and protozoan pathogens, and are also involved in inflammatory autoimmune disorders, whereas Th2 cells stimulate production of antibodies against parasites such as worms, and are also involved in allergies. Different probiotics have been shown to selectively shift the balance towards Th1 or Th2 responses, and may sometimes stimulate both.

 

CAN I TAKE MEGAEL-DENA IF I HAVE GASTIC AND DUODENAL ULCERS ASSOCIATED WITH HELICOBACTER PYLORI INFECTION? 

There are no contraindications for taking MegaEl-Dena if you have gastric and duodenal ulcers.

Major risk factor for such diseases as gastric ulcer, duodenal ulcer, and some cancers is H. pylori infection. Antibiotic therapy is used to eradicate this infection. Although antibiotics are intended to kill pathogenic bacteria, they also kill beneficial bacteria and cause changes in the species composition of microorganisms that inhabit the gastrointestinal tract.

The evidence available from a number of clinical studies suggests that intake of probioticsƒ has positive effect on H. pylori eradication and significantly reduces the risk of side effects of antibiotic therapy.

 

IS IT SAFE TO TAKE PRODUCTS CONTAINING MICROORGANISMS?

Soon after birth, different microorganisms colonize the sterile gastrointestinal tract of a newborn baby; colonization is complete after about one week, but the numbers and species of intestinal bacteria continue to change in the first several months of life. Many microorganisms that inhabit our intestines (called collectively commensal microbiota) can be considered as our symbionts and beneficial for the human body; their important function is to protect our bodies from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract. There are multiple regulatory mechanisms that mediate the communication between the commensal microbiota and host.

However, early colonization of the gastrointestinal tract by microbes may be disturbed, among other factors, by antibiotics, sterile food, overuse of antimicrobials, or exposure of newborns to “incorrect” sets of microorganisms in hospitals. This may result in an imbalance between beneficial and harmful bacteria (called dysbiosis or dysbacteriosis).

 

CAN I TAKE MEGAEL-DENA IF I HAVE LACTOSE INTOLERANCE? 

MegaEl-Dena contains eight species of microorganisms from non-dairy sources.  It contains no lactose, so it is allowed for people on a dairy-free diet.

 

CAN I TAKE MEGAEL IF I AM VEGAN? 

Megael-Dena contains novel non-dairy probiotic microorganisms. But it comes in gelatine capsules. Gelatin capsules are made through a process that involves boiling down certain parts of animals. If vegan, remove the capsule shell before taking Megael-Dena. 

 

HOW LONG CAN I TAKE PROBIOTICS?

As probiotics assure healthy gut microbiota, there are no limits in duration of taking probiotics. Living lactic acid bacteria, Bifidobacteria, and Streptococcus thermophilus perform several functions in the gut that support and regulate the physiological balance in the intestinal microbiota. If the body does not get enough prebiotics through food, supplementation with probiotics can help to maintain the right bacterial balance in the organism and improve the immune system. MegaEl-Dena contains 8 species of bacteria that are present in the normal intestinal microbiota of all age groups.

[more]

BENEFITS OF TAKING MEGAEL-DENA AS A SOURCE OF PROBIOTICS AND FRUCTOOLIGOSACCHARIDES

It is generally believed that taking supplements containing beneficial bacteria, compounds that stimulate their growth, or both (like MegaEl-Dena), is beneficial for health, especially for people with disturbances in the composition of endogenous microflora. It should be noted that clinical guidelines for the use of probiotics differ in different countries: in the US, they are considered as dietary supplements and thus cannot be formally considered to cure or treat any diseases (even if this is supported by clinical trials), whereas in European countries such claims are allowed and have to be substantiated by properly conducted human trials in the targeted population or in healthy volunteers [1].

[endshort]

BENEFITS OF TAKING MEGAEL-DENA AS A SOURCE OF PROBIOTICS AND FRUCTOOLIGOSACCHARIDES

It is generally believed that taking supplements containing beneficial bacteria, compounds that stimulate their growth, or both (like MegaEl-Dena), is beneficial for health, especially for people with disturbances in the composition of endogenous microflora. It should be noted that clinical guidelines for the use of probiotics differ in different countries: in the US, they are considered as dietary supplements and thus cannot be formally considered to cure or treat any diseases (even if this is supported by clinical trials), whereas in European countries such claims are allowed and have to be substantiated by properly conducted human trials in the targeted population or in healthy volunteers [1].

 

Probiotics

One way to help normalize microbiota composition is to use supplements containing probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora”[2]. The beneficial effects of Bifidobacterium and Lactobacillus bacteria have been reported at least since the late 1980s [3], and multiple clinical trials have been conducted to ascertain the usefulness of probiotics in patients with different conditions accompanied by disturbances in microbiota composition. Whereas species from several bacterial genera and at least one yeast species have been used as probiotics, Bifidobacterium and Lactobacillus remain the best studied (recently reviewed by McFarland [1]).

 

In this respect, MegaEl-Dena is largely a mainstream formulation because seven out of the eight species of viable beneficial bacteria that it contains belong to these genera: four species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), three species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus.

 

A recent analysis of the results of 63 trials conducted in different countries has found that 56%–83% of probiotic products helped improve the intestinal microbiota in patients with dysbiosis but almost 80% of such products had no effect on the microbiota in healthy individuals [1]. Thus, probiotic supplements would be most helpful after the events that disrupt the endogenous microbiota and until restoration of the normal microbiota, but would have little or no effect on the microbiota in healthy people. Below we mention specific use cases of the probiotic bacterial species included in MegaEl-Dena.

 

A large double-blind placebo-controlled study conducted in Cambridge (UK) involved 162 patients who had been treated with antibiotics for H. pylori infection [4]. This study found that supplementation with a combination of two strains of L. acidophilus and two strains of Bifidobacterium during and after antibiotic therapy helped to alleviate the antibiotic-induced disruption of the intestinal microbiota. Supplementation with probiotics was also found to be associated with a lower increase in the incidence of antibiotic resistance of enterococci after antibiotic therapy [4], although the probiotic strains used were antibiotic-sensitive.

 

A study conducted in Finland found that Lactobacillus rhamnosus ingestion for five days to four weeks was associated with alleviation of clinical symptoms of gastrointestinal inflammation and atopic dermatitis in children, possibly via enhanced production of the anti-inflammatory cytokine interleukin-10 [5].

 

Prebiotics

Improvement in the composition of gut microbiota may be transient if the conditions remain unfavorable for beneficial bacteria. Another concept, which is aimed at overcoming these problems, is that of prebiotics. This term was coined in 1995 to describe “a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improves host health” [3]. Since beneficial bacteria are already present in the intestines (even if their numbers may be reduced), the concept of prebiotics postulates that taking these compounds would stimulate the growth of these bacteria and help normalize the microbiota.

 

The most widely known prebiotics are nondigestible oligosaccharides, in particular fructooligosaccharides (FOS) [3], also called oligofructose (which is included in the MegaEl-Dena formulation), as well as galactooligosaccharides and lactulose. Although FOS are non-digestible, bacteria in the colon metabolize them into short-chain fatty acids, which can be absorbed [6].

 

A specific case of the use of FOS was described by Whelan and colleagues [7]. Using healthy volunteers, they simulated enteral tube feeding, which is known to disturb the intestinal microbiota and increase the risk of Clostridium difficile colonization. The authors found that supplementation of the enteric formula with FOS/fiber was associated with increased bifidobacteria counts and reduced clostridia in comparison with the standard formula [7].

 

Synbiotics

The two approaches, probiotics and prebiotics, are not mutually exclusive; moreover, they can be used as complementary, leading to the concept of synbiotics, i.e. supplements containing both probiotics and prebiotics that are assumed to have synergistic effects on the growth of beneficial bacteria, both endogenous and those introduced with the supplement [3,8]. Since MegaEl-Dena combines 8 species of viable beneficial bacteria and FOS, it is a synbiotic.

 

Finally, it should be noted that some studies have addressed the safety of the use of probiotics. For example, a study conducted in Finland [9] examined a hypothesis that a wide use of probiotics might increase the probability of bacteremia, i.e. the presence of bacteria in the blood that may cause sepsis. However, this study failed to find any link between bacteremia and the use of L. rhamnosus (one of the species used in MegaEl-Dena), thus confirming the safety of the probiotic use. Another species used in MegaEl-Dena, S. thermophilus, is related to such human pathogens as Streptococcus pyogenes (which causes a range of localized or systemic infections) and Streptococcus pneumoniae (the causative agent of pneumonia as its Latin name indicates). However, S. thermophilus is generally recognized as safe, which has been recently explained by a comparative study of its genome and genomes of pathogenic streptococci, which found that S. thermophilus has lost all genes necessary for virulence in related species; this confirms that “massive consumption of this bacterium by humans likely entails no health risk” [10]. Moreover, the use of S. thermophilus as a probiotic is well documented. For example, supplementation with a mixture of S. thermophilus and Bifidobacterium was found to be effective in prevention of rotavirus-induced diarrhea [11] and antibiotic-associated diarrhea [12] and in reducing severity of acute diarrhea in infants [13].

 

Another beneficial effect of S. thermophilus is that it stimulates the growth of lactobacilli by providing them with specific nutrients, such as formic acid, folic acid, and fatty acids [14]. Thus, the inclusion of S. thermophilus in a probiotic formulation can be expected to have an effect similar to that of the inclusion of prebiotics.

 

References

  1. McFarland, L.V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open 4, e005047 (2014).
  2. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  3. Gibson, G.R. & Roberfroid, M.B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125, 1401-1412 (1995).
  4. Plummer, S.F. et al. Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy. Int J Antimicrob Agents 26, 69-74 (2005).
  5. Pessi, T., Sutas, Y., Hurme, M. & Isolauri, E. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin Exp Allergy 30, 1804-1808 (2000).
  6. Tokunaga, T. Novel physiological function of fructooligosaccharides. Biofactors 21, 89-94 (2004).
  7. Whelan, K. et al. Fructooligosaccharides and fiber partially prevent the alterations in fecal microbiota and short-chain fatty acid concentrations caused by standard enteral formula in healthy humans. J Nutr 135, 1896-1902 (2005).
  8. Roberfroid, M.B. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr 80, S197-202 (1998).
  9. Salminen, M.K. et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 35, 1155-1160 (2002).
  10. Bolotin, A. et al. Complete sequence and comparative genome analysis of the dairy bacterium Streptococcus thermophilus. Nat Biotechnol 22, 1554-1558 (2004).
  11. Saavedra, J.M., Bauman, N.A., Oung, I., Perman, J.A. & Yolken, R.H. Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 344, 1046-1049 (1994).
  12. Corrêa, N.B., Péret Filho, L.A., Penna, F.J., Lima, F.M. & Nicoli, J.R. A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for prevention of antibiotic-associated diarrhea in infants. J Clin Gastroenterol 39, 385-389 (2005).
  13. Thibault, H., Aubert-Jacquin, C. & Goulet, O. Effects of long-term consumption of a fermented infant formula (with Bifidobacterium breve c50 and Streptococcus thermophilus 065) on acute diarrhea in healthy infants. J Pediatr Gastroenterol Nutr 39, 147-152 (2004).
  14. Sieuwerts, S. et al. Mixed-culture transcriptome analysis reveals the molecular basis of mixed-culture growth in Streptococcus thermophilus and Lactobacillus bulgaricus. Appl Environ Microbiol 76, 7775-7784 (2010).

[endmore]

[more]

BENEFITS OF TAKING MEGAEL-DENA AS AN IMMUNOMODULATOR

Beneficial microorganisms, predominantly bacteria, which inhabit the gastrointestinal tract (collectively called commensal microbiota, or commensal microflora), protect our bodies from invasion by pathogenic microorganisms, either by direct competition with pathogens or via immunomodulation [1,2]. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract [3]. Beneficial bacteria are also thought to enhance the epithelial barrier, which separates the content of the gastrointestinal tract with a multitude of microorganisms from the cells of the immune system located underneath the intestinal epithelium [4].

[endshort]

BENEFITS OF TAKING MEGAEL-DENA AS AN IMMUNOMODULATOR

Beneficial microorganisms, predominantly bacteria, which inhabit the gastrointestinal tract (collectively called commensal microbiota, or commensal microflora), protect our bodies from invasion by pathogenic microorganisms, either by direct competition with pathogens or via immunomodulation [1,2]. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract [3]. Beneficial bacteria are also thought to enhance the epithelial barrier, which separates the content of the gastrointestinal tract with a multitude of microorganisms from the cells of the immune system located underneath the intestinal epithelium [4].

 

Disturbances in the composition of the intestinal microbiota that lead to an imbalance between beneficial and harmful bacteria, which are called dysbiosis (or dysbacteriosis), are associated with several immunological disorders, including inflammatory bowel disease, a group of inflammatory conditions mainly affecting the colon and small intestine [5-7]. One of the major types of inflammatory bowel disease is ulcerative colitis, continuous mucosal inflammation limited to the colon with common symptoms such as bloody diarrhea and abdominal pain [8,9].

 

Multiple regulatory mechanisms mediate the communication between the commensal microbiota and host. Bacteria may directly interact with intestinal epithelial or immune cells through specific receptors and can also produce bioactive compounds that act as immune modulators [1,2,10]. One of the mechanisms of immunomodulatory activities of beneficial bacteria appears to involve Toll-like receptors, the same receptors that are involved in recognition of danger signals from potential pathogens and initiating the inflammatory response [11]. The mechanism of action of bioactive compounds produced by the commensal microbiota may involve regulation of cytokine secretion through the NFκB and MAPK signaling pathways, which in its turn regulates proliferation and differentiation of immune cells. The ability of the microbiota to regulate human immunity is illustrated by a study that involved healthy volunteers, which found that supplementation with lactic bacteria (Lactobacillus acidophilus, L. casei, and L. rhamnosus) for 7 weeks resulted in changes in the expression of genes involved in regulatory networks that control immunity and mucosal homeostasis [12]. Host epithelial cells, in their turn, produce compounds and signals (such as fucosylated cell surface proteins) that are recognized and metabolized by commensal bacteria [13]. Normally, the commensal microbiota is tolerated by the host and does not provoke an immune response. Altered microbiota composition and function is thought to provoke increased immune stimulation, and abnormal immune responses to the commensal microbiota may be one of the mechanisms that underlie the development of inflammatory bowel disease [14].

 

One way to help correct disturbances in the intestinal microbiota is to use supplements containing probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [15]. Another way to modulate the intestinal microbiota is supplementation with so-called prebiotics, i.e. food ingredients that are non-digestible for humans but stimulate the growth of beneficial bacteria [16]. Formulations that contain both probiotics and prebiotics are called synbiotics. MegaEl-Dena is a synbiotic: it contains prebiotics (FOS) and probiotics, i.e. 8 species of viable beneficial bacteria, including 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus. Probiotics are known to have beneficial effects on immunity, both at the molecular and cellular levels. Thus, they can be used to help correct immunological disorders such as ulcerative colitis. These aspects are described below.

 

Effect of probiotics on cytokine and immunoglobulin production

A Japanese study that used 60 healthy volunteers found that administration of a Lactobacillus species resulted in a statistically significant increase in interferon-α in 2–4 weeks depending on the dose [17]. The authors also compared viable and heat-killed bacteria and found that this effect required viable bacteria [17]. Similarly, a later study by Arunachalam and colleagues [18] conducted in Canada used B. lactis administration in elderly healthy volunteers and found a significant increase (in comparison with the placebo group) in the levels of interferon-α after 6 weeks of taking the probiotic. Intake of L. rhamnosus was reported to reduce the production of intestinal tumor necrosis factor (TNF)-α, which is a proinflammatory cytokine [19].

 

A number of studies have documented the ability of probiotics to stimulate the production of immunoglobulin A (IgA), which plays a critical role in mucosal immunity [20,21]. Intake of B. bifidum and L. acidophilus was reported to increase the IgA levels in subjects receiving attenuated Salmonella typhi to mimic an enteropathogenic infection; the increase was observed both in IgA specific to the pathogen and in total serum IgA [22]. Similarly, in children, the intake of L. casei in parallel with rotavirus vaccination [23] or intake of L. rhamnosus or L. casei during rotavirus-induced diarrhea [24,25] stimulated IgA production. Similar observations have been reported for bifidobacteria: Fukushima and coworkers found that the intake of B. lactis increased the levels of both total and pathogen-specific IgA upon anti-poliovirus vaccination in healthy children [26]. In a more recent study, consumption of Bifidobacterium-containing yogurt was found to be associated with an increase in the levels of serum IgA and reduction of those of the pro-inflammatory cytokine interleukin (IL)-6, suggesting immunostimulatory and anti-inflammatory effects [27]. An anti-inflammatory effect of probiotics was also documented by Pessi and coworkers [28], who found that L. rhamnosus administration in children with atopic allergy increased the serum level of the anti-inflammatory cytokine IL-10 but did not affect the levels of several pro-inflammatory cytokines, and by Hart and coworkers who found that bifidobacteria inhibit production of interferon-γ [29]. Thus, these studies indicate that different combinations of probiotic species may stimulate immune responses and/or suppress inflammation.

 

Effect of probiotics on immune cells

An enhanced ex vivo phagocytosis-mediated bactericidal activity of polymorphonuclear leukocytes was observed in healthy elderly volunteers after 6 weeks of supplementation with B. lactis in a Canadian study [18]. A similar study conducted in New Zealand, which also used B. lactis supplementation in healthy elderly volunteers, confirmed this finding for polymorphonuclear leukocytes and extended it to monocytes [30]. Furthermore, the authors noted an increase in the total, helper (CD4+), and activated (CD25+) T lymphocytes and natural killer cells in the probiotic group in comparison with the placebo group as well as increased ex vivo tumoricidal activity of natural killer cells [30]. To what extent these ex vivo findings reflect the in vivo situation remains unclear [31].

 

The effects of probiotics on T helper cells, in particular on the balance between Th1 and Th2 cells, are well documented (reviewed by Delcenserie and colleagues [31]). Th1 cells produce pro-inflammatory cytokines (including interferon-γ and TNFα mentioned above) involved in responses to bacterial and protozoan pathogens, and are also involved in inflammatory autoimmune disorders, whereas Th2 cells stimulate production of antibodies against parasites such as worms, and are also involved in allergies [32]. The balance between Th1 and Th2 cells is influenced by dendritic cells. Using an ex vivo approach, Hart and colleagues found that exposure of human dendritic cells to a probiotic containing a mixture of several species (similar to MegaEl-Dena) reduced LPS-induced production of the pro-inflammatory cytokine IL-12, whereas production of anti-inflammatory IL-10 remained unaffected, suggesting that probiotics would shift the Th1/Th2 balance towards Th2 [29]. However, Mohamadzadeh and coworkers [33] found that exposure of LPS-challenged human dendritic cells to a mixture of several Lactobacillus strains induced high level of secretion of IL-12 and IL-18, but not IL-10, indicating a shift towards Th1. These contrasting results suggest that the effects of probiotics on fine tuning of the Th1/Th2 balance is likely to be species-specific. In some cases, probiotic stimulate both Th1 and Th2 responses [31].

 

Ulcerative colitis

Several studies that used either probiotics or synbiotics (some similar in composition to MegaEl-Dena) found that the intake of these supplements was associated with positive effects on the induction and/or maintenance of remission in ulcerative colitis (reviewed by Isaacs and Herfarth [34] and Haller and colleagues [35]). A more recent review of the published studies concluded that probiotics have beneficial effects in patients with mild to moderate ulcerative colitis and help to induce and maintain remission and to prevent pouchitis [36].

 

References

  1. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  2. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  3. Bengmark, S. Gut microbial ecology in critical illness: is there a role for prebiotics, probiotics, and synbiotics? Curr Opin Crit Care 8, 145-151 (2002).
  4. Ohland, C.L. & Macnaughton, W.K. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol 298, G807-819 (2010).
  5. Marteau, P. Bacterial flora in inflammatory bowel disease. Dig Dis 27 Suppl 1, 99-103 (2009).
  6. Seksik, P. [Gut microbiota and IBD]. Gastroenterol Clin Biol 34 Suppl 1, S44-51 (2010).
  7. Tamboli, C.P., Neut, C., Desreumaux, P. & Colombel, J.F. Dysbiosis in inflammatory bowel disease. Gut 53, 1-4 (2004).
  8. Benjamin, J.L. et al. Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. Inflamm Bowel Dis 18, 1092-1100 (2012).
  9. Mulder, D.J., Noble, A.J., Justinich, C.J. & Duffin, J.M. A tale of two diseases: the history of inflammatory bowel disease. J Crohns Colitis 8, 341-348 (2014).
  10. Hemarajata, P. & Versalovic, J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 6, 39-51 (2013).
  11. Ezendam, J. & van Loveren, H. Probiotics: immunomodulation and evaluation of safety and efficacy. Nutr Rev 64, 1-14 (2006).
  12. van Baarlen, P. et al. Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci U S A 108 Suppl 1, 4562-4569 (2011).
  13. Pickard, J.M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638-641 (2014).
  14. Sartor, R.B. Microbial influences in inflammatory bowel diseases. Gastroenterology 134, 577-594 (2008).
  15. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  16. Gibson, G.R. & Roberfroid, M.B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125, 1401-1412 (1995).
  17. Kishi, A., Uno, K., Matsubara, Y., Okuda, C. & Kishida, T. Effect of the oral administration of Lactobacillus brevis subsp. coagulans on interferon-alpha producing capacity in humans. J Am Coll Nutr 15, 408-412 (1996).
  18. Arunachalam, K., Gill, H.S. & Chandra, R.K. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019). Eur J Clin Nutr 54, 263-267 (2000).
  19. Majamaa, H. & Isolauri, E. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol 99, 179-185 (1997).
  20. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nat Rev Immunol 3, 63-72 (2003).
  21. Macpherson, A.J. & Slack, E. The functional interactions of commensal bacteria with intestinal secretory IgA. Curr Opin Gastroenterol 23, 673-678 (2007).
  22. Link-Amster, H., Rochat, F., Saudan, K.Y., Mignot, O. & Aeschlimann, J.M. Modulation of a specific humoral immune response and changes in intestinal flora mediated through fermented milk intake. FEMS Immunol Med Microbiol 10, 55-63 (1994).
  23. Isolauri, E., Joensuu, J., Suomalainen, H., Luomala, M. & Vesikari, T. Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine 13, 310-312 (1995).
  24. Kaila, M., Isolauri, E., Saxelin, M., Arvilommi, H. & Vesikari, T. Viable versus inactivated lactobacillus strain GG in acute rotavirus diarrhoea. Arch Dis Child 72, 51-53 (1995).
  25. Majamaa, H., Isolauri, E., Saxelin, M. & Vesikari, T. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 20, 333-338 (1995).
  26. Fukushima, Y., Kawata, Y., Hara, H., Terada, A. & Mitsuoka, T. Effect of a probiotic formula on intestinal immunoglobulin A production in healthy children. Int J Food Microbiol 42, 39-44 (1998).
  27. Yang, Y.J. & Sheu, B.S. Probiotics-containing yogurts suppress Helicobacter pylori load and modify immune response and intestinal microbiota in the Helicobacter pylori-infected children. Helicobacter 17, 297-304 (2012).
  28. Pessi, T., Sutas, Y., Hurme, M. & Isolauri, E. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin Exp Allergy 30, 1804-1808 (2000).
  29. Hart, A.L. et al. Modulation of human dendritic cell phenotype and function by probiotic bacteria. Gut 53, 1602-1609 (2004).
  30. Gill, H.S., Rutherfurd, K.J., Cross, M.L. & Gopal, P.K. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 74, 833-839 (2001).
  31. Delcenserie, V. et al. Immunomodulatory effects of probiotics in the intestinal tract. Curr Issues Mol Biol 10, 37-54 (2008).
  32. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat Rev Immunol 2, 933-944 (2002).
  33. Mohamadzadeh, M. et al. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci U S A 102, 2880-2885 (2005).
  34. Isaacs, K. & Herfarth, H. Role of probiotic therapy in IBD. Inflamm Bowel Dis 14, 1597-1605 (2008).
  35. Haller, D. et al. Guidance for substantiating the evidence for beneficial effects of probiotics: probiotics in chronic inflammatory bowel disease and the functional disorder irritable bowel syndrome. J Nutr 140, 690S-697S (2010).
  36. Mullner, K., Miheller, P., Herszenyi, L. & Tulassay, Z. Probiotics in the management of Crohn's disease and ulcerative colitis. Curr Pharm Des 20, 4556-4560 (2014).

[endmore]

[more]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH GASTRIC AND DUODENAL ULCERS ASSOCIATED WITH HELICOBACTER PYLORI INFECTION

Many bacteria inhabiting the gastrointestinal tract are beneficial [1]; their important function is to protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [2,3]. However, some of these bacteria may be harmful. Helicobacter pylori is a Gram-negative bacterium of the Proteobacteria phylum that predominantly colonizes the stomach and induces inflammation. Overall, H. pylori is considered a harmful bacterium because its presence is a major risk factor for such diseases as gastric ulcer, duodenal ulcer, some cancers, and some cardiovascular and autoimmune diseases although at least some H. pylori strains protect from gastroesophageal reflux disease and esophageal adenocarcinoma and may also indirectly protect from asthma [4,5]. H. pylori infection often occurs in early childhood from infected mothers [6].

[endshort]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH GASTRIC AND DUODENAL ULCERS ASSOCIATED WITH HELICOBACTER PYLORI INFECTION

Many bacteria inhabiting the gastrointestinal tract are beneficial [1]; their important function is to protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [2,3]. However, some of these bacteria may be harmful. Helicobacter pylori is a Gram-negative bacterium of the Proteobacteria phylum that predominantly colonizes the stomach and induces inflammation. Overall, H. pylori is considered a harmful bacterium because its presence is a major risk factor for such diseases as gastric ulcer, duodenal ulcer, some cancers, and some cardiovascular and autoimmune diseases although at least some H. pylori strains protect from gastroesophageal reflux disease and esophageal adenocarcinoma and may also indirectly protect from asthma [4,5]. H. pylori infection often occurs in early childhood from infected mothers [6].

 

The prevalence of H. pylori infection increases with age and eventually reaches 70–90%; this increase is more rapid in developing than in developed countries [7]. Antibiotic therapy (usually a combination of different antibiotics) is used to eradicate H. pylori [5]. Although antibiotics are intended to kill pathogenic bacteria, they reduce the total number of bacteria and cause changes in microbiota composition [8]. These changes can be counteracted by taking probiotics, beneficial bacteria that normally inhabit the gastrointestinal tract and, when taken in adequate amounts, may help to restore normal microbiota [9]. MegaEl-Dena contains 8 species of viable beneficial bacteria: 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus.

 

A number of studies on the use of probiotics in subjects infected with H. pylori have addressed two major aspects: [1] the effect of probiotics on H. pylori bacterial load (with or without antibiotic therapy) and [2] the efficiency of probiotics in reducing the side effects of antibiotic therapy.

 

A study conducted in Taiwan, which included 70 H. pylori-positive volunteers, found that the group that consumed yogurt containing L. acidophilus and B. lactis for 6 weeks had reduced H. pylori bacterial loads (without any antibiotic therapy) in comparison with the placebo group [10]. Moreover, the authors demonstrated that B. lactis but not L. acidophilus inhibited the growth of H. pylori in vitro. The results of some clinical studies corroborate these in vitro data and are consistent with a higher efficiency of Bifidobacterium species than Lactobacillus species in helping to eradicate H. pylori. A later Taiwanese study, which involved 38 children with H. pylori infection and 38 age- and sex-matched non-infected control subjects, found that infected children had reduced Bifidobacterium spp. counts, whereas consumption of Bifidobacterium spp.–containing yogurt for 4 weeks helped to reduce the H. pylori load and increase the Bifidobacterium spp./Escherichia coli ratio [11]. Furthermore, consumption of Bifidobacterium-containing yogurt was associated with an increase in the levels of serum IgA and reduction of those of the pro-inflammatory cytokine interleukin (IL)-6, [11] suggesting immunostimulatory and anti-inflammatory effects [11]. Conversely, a Polish study that involved 83 children with H. pylori infection undergoing eradication therapy with antibiotics amoxicillin and clarithromycin concluded that supplementation with L. rhamnosus had no significant effect on the eradication rate or therapy-related adverse effects [12]. However, a meta-analysis of 33 clinical studies (4,459 patients in total) on the association between the intake of probiotics and the success of eradication of H. pylori infection concluded that four species (two of which, L. acidophilus and L. casei, are MegaEl-Dena components) are associated with a higher success rate [13].

 

A Brazilian study that enrolled 107 H. pylori-infected patients with peptic ulcer or functional dyspepsia who underwent antibiotic therapy (furazolidone, tetracycline, and lansoprazole) found no difference in the H. pylori eradication rate between the group receiving placebo and the group receiving a probiotic (L. acidophilus, L. rhamnosus, B. bifidum, and Streptococcus faecium) [14]. Although the probiotic tended to reduce the rate of therapy-related adverse effects, the difference between the probiotic and placebo groups did not reach statistical significance [14]. As the rate of H. pylori eradication in this study reached 80–90%, the apparent absence of the effect of probiotics might be due to a masking effect of efficient antibiotic therapy.

 

A double-blind placebo-controlled study conducted in Cambridge, UK that involved 162 patients treated with antibiotics found that supplementation with a combination of two strains of L. acidophilus and two strains of Bifidobacterium during and after antibiotic therapy alleviated the antibiotic-induced disruption of the intestinal microbiota [15]. Supplementation with probiotics was also found to counteract the increase in the incidence of antibiotic resistance of enterococci after antibiotic therapy [15], although the probiotic strains used were antibiotic-sensitive. A possible effect of probiotics on H. pylori eradication by antibiotics was not assessed in this study.

 

One of the largest studies on the effect of probiotics in patients with H. pylori infection, conducted in South Korea, involved 347 H. pylori-infected patients undergoing triple therapy (proton pump inhibitor, clarithromycin, and amoxicillin) reported that taking a yogurt containing L. acidophilus, L. casei, B. longum, and S. thermophilus (all 4 species are MegaEl-Dena components) was associated with an increase in the H. pylori eradication rate; this effect reached statistical significance in one of the two types of data analysis used [16].

 

A recent meta-analysis of ten clinical trials of supplementation with Lactobacillus and Bifidobacterium species in subjects infected with H. pylori (1,469 participants in total) concluded that intake of probiotics has beneficial effects on the eradication rate and is associated with a significant decrease in the incidence of side effects of antibiotic therapy [17]. Similarly, a meta-analysis of 34 randomized double-blinded placebo-controlled trials (4,138 patients in total) found that the pooled relative risk of antibiotic-associated diarrhea caused by H. pylori infection treatment was reduced on average by almost 2/3 by probiotic supplementation [18].

 

Overall, most studies have reported that supplementation with probiotic bacteria that are included in MegaEl-Dena (L. acidophilus, L. casei, B. lactis, and possibly also B. longum and S. thermophilus) have beneficial effects in patients undergoing H. pylori eradication therapy in terms of reducing the H. pylori bacterial load and/or alleviating the side effects of antibiotic therapy, although the optimal combinations of particular probiotics and antibiotics remain to be determined.

 

Crohn's disease

A distinct, non-infectious type of inflammation of the gastrointestinal tract is found in patients with Crohn's disease, which is primarily an autoimmune disorder characterized by patchy transmural inflammation that may involve any part of the gastrointestinal tract [19] and may be triggered by an imbalance between beneficial and harmful bacteria [20]. Several studies attempted using Lactobacillus species in patients with Crohn's disease but most of them found no effect on the maintenance of remission (reviewed by Isaacs and Herfarth [21] and Haller and colleagues [22]). It has been suggested that deficiencies in particular species of Firmicutes (such as Faecalibacterium prausnitzii) rather than Bifidobacterium or Lactobacillus could play a role in Crohn’s disease [23]. This might explain the lack of the effect of Lactobacillus-based probiotics and indicate that development of different probiotic formulations may be needed for patients with Crohn’s disease.

 

References

  1. Tancrede, C. Role of human microflora in health and disease. Eur J Clin Microbiol Infect Dis 11, 1012-1015 (1992).
  2. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  3. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  4. Blaser, M.J. Who are we? Indigenous microbes and the ecology of human diseases. EMBO Rep 7, 956-960 (2006).
  5. Kusters, J.G., van Vliet, A.H. & Kuipers, E.J. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 19, 449-490 (2006).
  6. Weyermann, M., Rothenbacher, D. & Brenner, H. Acquisition of Helicobacter pylori infection in early childhood: independent contributions of infected mothers, fathers, and siblings. Am J Gastroenterol 104, 182-189 (2009).
  7. Pounder, R.E. & Ng, D. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol Ther 9 Suppl 2, 33-39 (1995).
  8. Dethlefsen, L., Huse, S., Sogin, M.L. & Relman, D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6, e280 (2008).
  9. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  10. Wang, K.Y. et al. Effects of ingesting Lactobacillus- and Bifidobacterium-containing yogurt in subjects with colonized Helicobacter pylori. Am J Clin Nutr 80, 737-741 (2004).
  11. Yang, Y.J. & Sheu, B.S. Probiotics-containing yogurts suppress Helicobacter pylori load and modify immune response and intestinal microbiota in the Helicobacter pylori-infected children. Helicobacter 17, 297-304 (2012).
  12. Szajewska, H., Albrecht, P. & Topczewska-Cabanek, A. Randomized, double-blind, placebo-controlled trial: effect of lactobacillus GG supplementation on Helicobacter pylori eradication rates and side effects during treatment in children. J Pediatr Gastroenterol Nutr 48, 431-436 (2009).
  13. Dang, Y., Reinhardt, J.D., Zhou, X. & Zhang, G. The effect of probiotics supplementation on Helicobacter pylori eradication rates and side effects during eradication therapy: a meta-analysis. PLoS One 9, e111030 (2014).
  14. Navarro-Rodriguez, T. et al. Association of a probiotic to a Helicobacter pylori eradication regimen does not increase efficacy or decreases the adverse effects of the treatment: a prospective, randomized, double-blind, placebo-controlled study. BMC Gastroenterol 13, 56 (2013).
  15. Plummer, S.F. et al. Effects of probiotics on the composition of the intestinal microbiota following antibiotic therapy. Int J Antimicrob Agents 26, 69-74 (2005).
  16. Kim, M.N. et al. The effects of probiotics on PPI-triple therapy for Helicobacter pylori eradication. Helicobacter 13, 261-268 (2008).
  17. Wang, Z.H., Gao, Q.Y. & Fang, J.Y. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol 47, 25-32 (2013).
  18. Videlock, E.J. & Cremonini, F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther 35, 1355-1369 (2012).
  19. Mulder, D.J., Noble, A.J., Justinich, C.J. & Duffin, J.M. A tale of two diseases: the history of inflammatory bowel disease. J Crohns Colitis 8, 341-348 (2014).
  20. Marteau, P. Bacterial flora in inflammatory bowel disease. Dig Dis 27 Suppl 1, 99-103 (2009).
  21. Isaacs, K. & Herfarth, H. Role of probiotic therapy in IBD. Inflamm Bowel Dis 14, 1597-1605 (2008).
  22. Haller, D. et al. Guidance for substantiating the evidence for beneficial effects of probiotics: probiotics in chronic inflammatory bowel disease and the functional disorder irritable bowel syndrome. J Nutr 140, 690S-697S (2010).
  23. Swidsinski, A., Loening-Baucke, V., Vaneechoutte, M. & Doerffel, Y. Active Crohn's disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis 14, 147-161 (2008).

[endmore]

[more]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH ATOPIC ALLERGY

Many of the microorganisms that inhabit the gastrointestinal tract (commensal microbiota, or commensal microflora) can be considered as our symbionts; their important function is to protect our bodies from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [1, 2]. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract [3].

[endshort]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH ATOPIC ALLERGY

Many of the microorganisms that inhabit the gastrointestinal tract (commensal microbiota, or commensal microflora) can be considered as our symbionts; their important function is to protect our bodies from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [1, 2]. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract [3].

 

Soon after birth, the sterile gastrointestinal tract of a newborn baby is colonized by various microorganisms; colonization is complete after approximately one week, but the numbers and species of intestinal bacteria change considerably in the first several months [4]. Antimicrobial medication, sterile food, and exposure of newborns to “incorrect” sets of microorganisms in hospitals lead to an imbalance between beneficial and harmful bacteria (dysbiosis, or dysbacteriosis) [2, 5, 6]. Dysbiosis is associated with several immunological disorders, including atopic allergy, which is manifested as allergic rhinitis (or rhinoconjunctivitis), atopic dermatitis (atopic eczema), and asthma; the gut microbiota differs in healthy and allergic babies [6].

 

There are multiple regulatory mechanisms that mediate the communication between the commensal microbiota and host. The ability of the microbiota to regulate human immunity is illustrated by a study that involved healthy volunteers, which found that supplementation with L. acidophilus, L. casei, and L. rhamnosus for 7 weeks resulted in changes in the expression of genes involved in regulatory networks that control immunity and mucosal homeostasis [7]. Bacteria may directly interact with intestinal epithelial or immune cells through specific receptors and can also produce bioactive compounds that act as immune modulators [1, 2, 8]. In particular, the microbiota composition may affect the balance between Th1 and Th2 T helper cells; Th2 cells play a central role in the development of atopic allergy [9]. In 80% of atopic allergy patients, the IgE antibodies are also involved [9].

 

One way to help correct disturbances in the intestinal microbiota and their consequences is to use supplements containing probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [10]. MegaEl-Dena contains 8 species of viable beneficial bacteria: 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus.

There have been multiple clinical studies of the efficiency of probiotics in prevention and management of atopic allergies (reviewed by Kalliomäki and colleagues [6] and Cabana [11]). Some examples of such studies are discussed below.

 

Atopic dermatitis (eczema)

Most available data on the benefits of probiotics in patients with atopic allergy concern atopic dermatitis. Among probiotics, L. rhamnosus (one of the species included in MegaEl-Dena) has been most extensively used.

 

A study conducted in Finland found that pre- (one month) and postnatal (six months of age) administration of L. rhamnosus was associated with a significant reduction in the incidence of atopic dermatitis during the first seven years of life [12, 13]. Likewise, a more recent study conducted in New Zealand compared supplementation with another strain of L. rhamnosus and supplementation with B. lactis. Supplementation was performed either in mothers (from 35 weeks of gestation until six months after birth) or in infants (from birth until two years of age) [14]. The authors reported that both types of supplementation with L. rhamnosus were associated with a reduced prevalence of eczema (by ~50%) at the age of two and four years; significant reduction (by 31–44% depending on the parameter used) persisted at least until the age of six years [14]. In contrast, supplementation with B. lactis had no effect [14].

 

A specific difference between the effects of different bacterial species has also been reported by another Finnish study [15]. This study enrolled infants with atopic dermatitis associated with suspected cow's milk allergy; the patients received either L. rhamnosus, a mixture of four probiotic bacteria, three of which are components of MegaEl-Dena (B. breve and two strains of L. rhamnosus), or placebo for four weeks. In both groups that received probiotics, the severity of dermatitis was reduced similarly by 65%, four weeks after supplementation. However, when IgE-sensitized infants were analyzed separately, the authors found that beneficial effects of L. rhamnosus were more pronounced than those of the probiotic mixture [15].

 

The source of sensitization may also affect the beneficial effects of probiotics in patients with atopic dermatitis, as suggested by a study by Sistek and colleagues [16] which found that supplementation with a combination of L. rhamnosus and B. lactis was associated with reduced severity of dermatitis only in food-sensitized children.

 

Allergic rhinitis

Most studies on the effects of probiotics in patients with allergic rhinitis have been conducted in adults. In contrast to its beneficial effects in patients with atopic dermatitis, L. rhamnosus has been reported to have no effect in patients with allergic rhinitis [17]. However, several other probiotic species have been reported to reduce nasal symptoms and/or to improve the overall quality of life. These include two species that are components of MegaEl-Dena, L. acidophilus [18] and B. longum [19]. Another MegaEl-Dena constituent, L. casei, has been reported to have beneficial effects in pre-school children [20] but not in adults [21] (however, different L. casei strains were used in the two studies).

 

A notable case is the successful use of heat-killed Lactobacillus paracasei in adults with allergic rhinitis induced by house dust mites [22] (L. paracasei is closely related the MegaEl-Dena component L. casei and is considered by some authors as a subspecies of L. casei [23]). The authors reported that the beneficial effects of heat-killed bacteria were indistinguishable from those of live bacteria of the same species. These data imply that at least in this case the underlying mechanism did not rely on correction of dysbiosis but on direct regulation of the immune response by a bacterial antigen.

 

Asthma

The data on the effects of probiotics in patients with asthma are scarce and most studies have not found any significant effects [6, 24]. However, a recent study found positive effects of probiotics in children suffering from concomitant asthma and allergic rhinitis [25], indicating that the field needs further exploration.

 

Thus, the available data suggest that several components of MegaEl-Dena have beneficial effects for patients with atopic dermatitis (L. rhamnosus and possibly B. lactis) and allergic rhinitis (L. acidophilus and B. longum, and possibly L. casei), but probably not for patients with asthma. In most cases of the use of probiotics in patients with atopic allergy, no notable adverse effects have been reported, however on rare occasions probiotics have been reported to increase the risk of wheezing bronchitis or atopic sensitization in high-risk children [6].

References

  1. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  2. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  3. Bengmark, S. Gut microbial ecology in critical illness: is there a role for prebiotics, probiotics, and synbiotics? Curr Opin Crit Care 8, 145-151 (2002).
  4. Fanaro, S., Chierici, R., Guerrini, P. & Vigi, V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 91, 48-55 (2003).
  5. Hawrelak, J.A. & Myers, S.P. The causes of intestinal dysbiosis: a review. Altern Med Rev 9, 180-197 (2004).
  6. Kalliomäki, M. et al. Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of allergic diseases by probiotics. J Nutr 140, 713S-721S (2010).
  7. van Baarlen, P. et al. Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci U S A 108 Suppl 1, 4562-4569 (2011).
  8. Hemarajata, P. & Versalovic, J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 6, 39-51 (2013).
  9. Biedermann, T. & Rocken, M. Th1/Th2 balance in atopy. Springer Semin Immunopathol 21, 295-316 (1999).
  10. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  11. Cabana, M.D. Early probiotic supplementation for the prevention of atopic disease in newborns-probiotics and the hygiene hypothesis. Biosci Microflora 30, 129-133 (2011).
  12. Kalliomäki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076-1079 (2001).
  13. Kalliomäki, M., Salminen, S., Poussa, T. & Isolauri, E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol 119, 1019-1021 (2007).
  14. Wickens, K. et al. Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Clin Exp Allergy 43, 1048-1057 (2013).
  15. Viljanen, M. et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy 60, 494-500 (2005).
  16. Sistek, D. et al. Is the effect of probiotics on atopic dermatitis confined to food sensitized children? Clin Exp Allergy 36, 629-633 (2006).
  17. Helin, T., Haahtela, S. & Haahtela, T. No effect of oral treatment with an intestinal bacterial strain, Lactobacillus rhamnosus (ATCC 53103), on birch-pollen allergy: a placebo-controlled double-blind study. Allergy 57, 243-246 (2002).
  18. Ishida, Y. et al. Clinical effects of Lactobacillus acidophilus strain L-92 on perennial allergic rhinitis: a double-blind, placebo-controlled study. J Dairy Sci 88, 527-533 (2005).
  19. Xiao, J.Z. et al. Probiotics in the treatment of Japanese cedar pollinosis: a double-blind placebo-controlled trial. Clin Exp Allergy 36, 1425-1435 (2006).
  20. Giovannini, M. et al. A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus casei in pre-school children with allergic asthma and/or rhinitis. Pediatr Res 62, 215-220 (2007).
  21. Tamura, M. et al. Effects of probiotics on allergic rhinitis induced by Japanese cedar pollen: randomized double-blind, placebo-controlled clinical trial. Int Arch Allergy Immunol 143, 75-82 (2007).
  22. Peng, G.C. & Hsu, C.H. The efficacy and safety of heat-killed Lactobacillus paracasei for treatment of perennial allergic rhinitis induced by house-dust mite. Pediatr Allergy Immunol 16, 433-438 (2005).
  23. Smokvina, T. et al. Lactobacillus paracasei comparative genomics: towards species pan-genome definition and exploitation of diversity. PLoS One 8, e68731 (2013).
  24. Vliagoftis, H., Kouranos, V.D., Betsi, G.I. & Falagas, M.E. Probiotics for the treatment of allergic rhinitis and asthma: systematic review of randomized controlled trials. Ann Allergy Asthma Immunol 101, 570-579 (2008).
  25. Chen, Y.S., Jan, R.L., Lin, Y.L., Chen, H.H. & Wang, J.Y. Randomized placebo-controlled trial of lactobacillus on asthmatic children with allergic rhinitis. Pediatr Pulmonol 45, 1111-1120 (2010).

[endmore]

[more]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH DIARRHEA

Diarrhea may be caused by a variety of factors; two major groups of conditions accompanied by diarrhea are due to various infections of the gastrointestinal tract and disturbances of the intestinal microbiota as a result of antibiotic therapy. Regardless of the exact cause of diarrhea, supplementation with probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [1], may have beneficial effects in prevention or reducing the severity of diarrhea. In some cases, beneficial effects of prebiotics (food ingredients that are non-digestible for humans but stimulate the growth of beneficial bacteria (2)) have also been described. Fructooligosaccharides (FOS) are the most widely known prebiotics [2]. MegaEl-Dena contains both prebiotics (FOS) and probiotics, i.e. 8 species of viable beneficial bacteria, including 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus. Below we consider in more detail, examples of studies that have documented the benefits of probiotics and prebiotics in patients with diarrhea.

[endshort]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH DIARRHEA

Diarrhea may be caused by a variety of factors; two major groups of conditions accompanied by diarrhea are due to various infections of the gastrointestinal tract and disturbances of the intestinal microbiota as a result of antibiotic therapy. Regardless of the exact cause of diarrhea, supplementation with probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [1], may have beneficial effects in prevention or reducing the severity of diarrhea. In some cases, beneficial effects of prebiotics (food ingredients that are non-digestible for humans but stimulate the growth of beneficial bacteria (2)) have also been described. Fructooligosaccharides (FOS) are the most widely known prebiotics [2]. MegaEl-Dena contains both prebiotics (FOS) and probiotics, i.e. 8 species of viable beneficial bacteria, including 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus. Below we consider in more detail, examples of studies that have documented the benefits of probiotics and prebiotics in patients with diarrhea.

 

Acute infectious diarrhea (acute gastroenteritis) is a collective name for various infections, which are mainly caused by viruses (particularly noroviruses) but also by bacterial pathogens such as salmonella or Clostridium difficile, and are accompanied by vomiting and abdominal pain. The incidence of acute infectious diarrhea has been estimated as 0.6 episodes per adult person per year in the USA and Germany and may be fatal, particularly in the elderly [3]. Acute infectious diarrhea is treated with oral rehydration solutions (since diarrhea may lead to dehydration), antibiotics (which however may exacerbate diarrhea; see the next section), and gut motility-suppressing agents [4]. A number of studies have addressed whether probiotics may be helpful for patients with acute diarrhea.

 

Two pioneering studies, one conducted in Finland [5] and one in the USA [6], found that intake of Lactobacillus rhamnosus (a MegaEl-Dena component) was associated with a reduced incidence of traveler’s diarrhea. Curiously, the Finnish study, which involved 756 subjects who traveled to two different destinations in Turkey, found that the effect was much more pronounced in one destination than in the other [5]; this might indicate that the extent of the beneficial effect of probiotics depends on the pathogen that causes diarrhea.

 

A later study, which involved 240 children with acute diarrhea caused by rotavirus and other pathogens and used Lactobacillus paracasei (this species is closely related the MegaEl-Dena component L. casei and is considered by some authors as a subspecies of L. casei [7]), found that the probiotic was ineffective against severe diarrhea caused by rotavirus but was beneficial for patients with less severe diarrhea caused by other pathogens [8]. Recent studies found that administration of a mixture containing L. acidophilus, L. rhamnosus, B. longum, and a yeast species had differential effects on different aspects of the disease such as duration of diarrhea, fever, vomiting, and hospitalization [9, 10]. These somewhat contrasting results may indicate that particular probiotic species may be beneficial for patients with diarrhea caused by particular pathogens. If so, taking probiotics that contain a mixture of several bacterial species (such as MegaEl-Dena) might increase the chance of a positive effect. These considerations may be particularly applicable in cases where the exact pathogen remains unknown. In line with this suggestion, administration of L. rhamnosus alone was found to be associated with a smaller reduction in the duration of diarrhea than administration of a mixture of B. bifidum, L. delbrueckii var bulgaricus, L. acidophilus, and S. thermophilus, whereas two other probiotics each containing only one species had no effect [11].

 

A review of clinical studies and meta-analyses of the studies that used probiotics in patients with acute infectious diarrhea (63 studies in total that involved 8,014 participants, mainly infants and children) concluded that most studies reported a reduced duration of diarrhea and stool frequency in patients who received probiotics, although the extent of the differences with the control varied [4]. No adverse events were attributed to the use of probiotics.

 

Antibiotic-associated diarrhea

Although antibiotics are intended to kill pathogenic bacteria, they reduce the total number of bacteria and cause changes in microbiota composition (dysbiosis), which are transient in most cases but may occasionally last for several months [12]. These disturbances may lead to antibiotic-associated diarrhea (AAD) and sometimes this leads to the prevalence of harmful bacteria, such as Clostridium difficile (which may cause C. difficile infections, also called C. difficile colitis), which are also accompanied by diarrhea. Antibiotic therapy is one of the three major risk factors for C. difficile infections (the other two being immunosuppression and old age) [13]; therefore, C. difficile infections are often considered together with AAD. Additional risk factors for AAD and associated infections are serious illnesses, old age, immunosuppression, the length of the hospital stay, and exposure to harmful microorganisms in the hospital [14].

 

An analysis of 16 studies (3,432 participants) concluded that, of several probiotic species tested, administration of L. rhamnosus (a component of MegaEl-Dena) in parallel with antibiotics reduced the risk of AAD onset (15); however, other combinations such as B. lactis and and S. thermophilus (both are components of MegaEl-Dena) may be also beneficial [16]. A randomized double blind placebo-controlled trial that involved elderly hospital patients taking antibiotics found that consumption of a drink containing S. thermophilus, L. casei, and other Lactobacillus species during and after antibiotic therapy was associated with a reduced incidence of AAD/C. difficile-associated diarrhea [17]. As in the case of the use of probiotics in patients with acute infectious diarrhea, no serious adverse effects of probiotics have been reported in AAD patients.

 

There is also some evidence for beneficial effects of prebiotics and synbiotics in patients with AAD/C. difficile-induced diarrhea. A randomized clinical trial of treatment of C. difficile infection with specific antibiotics conducted in the UK found that taking FOS was associated with increased counts of bifidobacteria and significantly fewer relapses [18]. A placebo-controlled study conducted in Sweden compared the effects of probiotics (L. acidophilus and B. longum) and a corresponding synbiotic (the same bacterial species supplemented with FOS) on healthy volunteers subjected to antibiotic treatment [19]. The authors found that C. difficile could be isolated after antibiotic treatment at a similar rate from the stool of patients who received placebo and probiotics, but at a much lower rate from that of patients who received the synbiotic. The authors also found that L. acidophilus (but not B. longum) efficiently colonized the intestines [19].

 

A recent meta-analysis of 82 clinical trials that included 11,811 participants concluded that there is a statistically significant association between the intake of probiotics and reduction in AAD, although it is not yet clear which probiotics are associated with the greatest efficacy and what are the best probiotic/antibiotic combinations [20]. An independent meta-analysis of 34 randomized double-blinded placebo-controlled trials (4,138 patients in total) found that the pooled relative risk of AAD was reduced by ~50% by probiotic supplementation [21].

 

Thus, the available evidence suggests that several components of MegaEl-Dena (both probiotics and prebiotics) have beneficial effects for patients with or at risk of acute diarrhea caused by infections (L. rhamnosus and likely also other components such as L. acidophilus, B. longum, B. bifidum, and/or S. thermophilus) and antibiotic therapy (L. rhamnosus, B. lactis, and S. thermophilus, as well as FOS), whereas no adverse effects of probiotics have been observed.

 

References

  1. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  2. Gibson, G.R. & Roberfroid, M.B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125, 1401-1412 (1995).
  3. DuPont, H.L. Acute infectious diarrhea in immunocompetent adults. N Engl J Med 370, 1532-1540 (2014).
  4. Allen, S.J., Martinez, E.G., Gregorio, G.V. & Dans, L.F. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev, CD003048 (2010).
  5. Oksanen, P.J. et al. Prevention of travellers' diarrhoea by Lactobacillus GG. Ann Med 22, 53-56 (1990).
  6. Hilton, E., Kolakowski, P., Singer, C. & Smith, M. Efficacy of Lactobacillus GG as a Diarrheal Preventive in Travelers. J Travel Med 4, 41-43 (1997).
  7. Smokvina, T. et al. Lactobacillus paracasei comparative genomics: towards species pan-genome definition and exploitation of diversity. PLoS One 8, e68731 (2013).
  8. Sarker, S.A. et al. Lactobacillus paracasei strain ST11 has no effect on rotavirus but ameliorates the outcome of non rotavirus diarrhea in children from Bangladesh. Pediatrics 116, e221-228 (2005).
  9. Feizizadeh, S., Salehi-Abargouei, A. & Akbari, V. Efficacy and safety of Saccharomyces boulardii for acute diarrhea. Pediatrics 134, e176-191 (2014).
  10. Grandy, G., Medina, M., Soria, R., Teran, C.G. & Araya, M. Probiotics in the treatment of acute rotavirus diarrhoea. A randomized, double-blind, controlled trial using two different probiotic preparations in Bolivian children. BMC Infect Dis 10, 253 (2010).
  11. Canani, R.B. et al. Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations. BMJ 335, 340 (2007).
  12. Dethlefsen, L., Huse, S., Sogin, M.L. & Relman, D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 6, e280 (2008).
  13. Friedman, G. The role of probiotics in the prevention and treatment of antibiotic-associated diarrhea and Clostridium difficile colitis. Gastroenterol Clin North Am 41, 763-779 (2012).
  14. Rohde, C.L., Bartolini, V. & Jones, N. The use of probiotics in the prevention and treatment of antibiotic-associated diarrhea with special interest in Clostridium difficile-associated diarrhea. Nutr Clin Pract 24, 33-40 (2009).
  15. Johnston, B.C., Goldenberg, J.Z., Vandvik, P.O., Sun, X. & Guyatt, G.H. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, CD004827 (2011).
  16. Correa, N.B., Peret Filho, L.A., Penna, F.J., Lima, F.M. & Nicoli, J.R. A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for prevention of antibiotic-associated diarrhea in infants. J Clin Gastroenterol 39, 385-389 (2005).
  17. Hickson, M. et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 335, 80 (2007).
  18. Lewis, S., Burmeister, S. & Brazier, J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol 3, 442-448 (2005).
  19. Orrhage, K., Sjostedt, S. & Nord, C.E. Effect of supplements with lactic acid bacteria and oligofructose on the intestinal microflora during administration of cefpodoxime proxetil. J Antimicrob Chemother 46, 603-612 (2000).
  20. Hempel, S. et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 307, 1959-1969 (2012).
  21. Videlock, E.J. & Cremonini, F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther 35, 1355-1369 (2012).

[endmore]

[more]

 

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH DYSBIOSIS

The human body is inhabited by a variety of microorganisms, mainly bacteria, most of which reside in the gastrointestinal tract; these microorganisms are referred to as the commensal microbiota (or commensal microflora). It has been estimated that the number of bacterial cells in the human body exceeds the number of our own cells by one order of magnitude [1]. Because of the complex interactions among different bacterial species and between the host and the intestinal microbiota, our digestive tract can be considered as an ecosystem [2]. Many of these microorganisms can be considered as our symbionts; their important function is to protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [3, 4].

 [endshort]

BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS WITH DYSBIOSIS

The human body is inhabited by a variety of microorganisms, mainly bacteria, most of which reside in the gastrointestinal tract; these microorganisms are referred to as the commensal microbiota (or commensal microflora). It has been estimated that the number of bacterial cells in the human body exceeds the number of our own cells by one order of magnitude [1]. Because of the complex interactions among different bacterial species and between the host and the intestinal microbiota, our digestive tract can be considered as an ecosystem [2]. Many of these microorganisms can be considered as our symbionts; their important function is to protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation [3, 4].

 

Dysbiosis (dysbacteriosis) is a collective name for disturbances in the composition of the intestinal microbiota that lead to an imbalance between beneficial and harmful bacteria [5]. Potential causes of dysbiosis include the use of antibiotics, vaccinations, general antimicrobial strategies, exposure of newborns to “incorrect” sets of microorganisms in hospitals, psychological stress, and diet components; in particular, the microbiota composition is affected by the content of sulfates, sugars, proteins, and the ratio between dietary intake of proteins and fibers/indigestible starch [4, 6]. Smoking has been recently shown to be also associated with dysbiosis [7].

 

Chronic dysbiosis is associated with a number of pathological conditions, such as gastrointestinal disturbances [8], Helicobacter pylori infection [9], inflammatory bowel disease [5, 10, 11], ankylosing spondylitis [12], colorectal cancer [13, 14, 15], chronic fatigue syndrome [16], non-alcoholic fatty liver disease [17, 18], and obesity [17]. Chronic dysbiosis caused by diseases can be exacerbated by external factors. For example, smoking both causes dysbiosis in healthy subjects and exacerbates it in patients with Crohn's disease (a form of inflammatory bowel disease) [7]. Finally, genetic predisposition may also play a role in the development of dysbiosis. For example, variations in the genes related to immunity and inflammation (NOD2, IRGM, and IL23R) and autophagy (ATG16L) have been found to influence the microbiota composition [4], and gastrointestinal dysfunction in patients with cystic fibrosis (which is a genetic disease) has been found to be associated with excessive growth of Escherichia coli [19].

 

In many cases, dysbiosis is asymptomatic, or its consequences may be difficult to detect without dedicated studies. For example, a retrospective study conducted in the Netherlands examined a hypothesis about a link between dysbiosis and cervical cancer [20]. This study involved 100,605 women, including 1,439 with a fungus Candida vaginalis and 5,302 with dysbacteriosis (the rest had normal cervical smears). The authors found that dysbacteriosis but not the presence of C. vaginalis was significantly increased the risk of developing (pre)neoplastic changes.

 

One way to help correct dysbiosis is to use supplements containing probiotics, defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [21]. The beneficial effects of Bifidobacterium (from the phylum Actinobacteria) and Lactobacillus (from the phylum Firmicutes) are best documented and species from these two genera are most often used in probiotic formulations [22]. However, the improvement of gut microbiota by taking probiotics may be transient. Another way to modulate the intestinal microbiota is supplementation with so-called prebiotics, i.e. food ingredients that are non-digestible for humans but stimulate the growth of beneficial bacteria [23]. Since these bacteria are already present in the intestines (even if their numbers may be reduced in the case of dysbiosis), the concept of prebiotics postulates that taking these compounds would stimulate the growth of these bacteria and help normalize the microbiota. The most widely known prebiotics are non-digestible oligosaccharides, in particular fructooligosaccharides (FOS) [23].

 

The two approaches are not mutually exclusive; moreover, they can be used as complementary, leading to the concept of synbiotics, i.e. supplements containing both probiotics and prebiotics that synergistically stimulate the growth of beneficial bacteria, both endogenous and those introduced with the supplement [23, 24]. MegaEl-Dena is a synbiotic containing FOS and as many as 8 species of viable beneficial bacteria: 4 species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus.

 

Dysbiosis may also lead to serious, clinically obvious consequences. One example is neonatal necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants. NEC is an inflammatory condition characterized by necrosis of bowel tissues and is a major cause of morbidity and mortality in premature infants [25]. Although the exact causes of NEC are still a matter of debate, dysbiosis is thought to play a role. In particular, recent evidence indicates that prediagnosis fecal samples from NEC infants contain abundant Clostridium perfringens or Klebsiella sp. [26]. A recent meta-analysis of 24 studies showed that in most studies supplementation with probiotics significantly reduced the incidence of severe NEC (this effect was observed in 20 studies) and mortality (17 studies) [27]. Formulations containing either Lactobacillus species only or Lactobacillus in combination with Bifidobacterium (i.e. similar to MegaEl-Dena) were found to be most effective. No systemic infections with the probiotic species were noted in any of the analyzed studies.

 

Another pathological condition encountered in preterm newborns is systemic fungal infections, including those with Candida species (candidemia, or invasive candidiasis), the incidence of which is increased because of Candida overgrowth owing to the deficiency in the intestinal bacterial microbiota. A study conducted in Italy found that supplementation with two Lactobacillus species (used separately) significantly reduced the presence of Candida sp. in the stool as well as the incidence of late-onset sepsis and abnormal neurological outcomes [28]. Likewise, a randomized, double-blind, placebo-controlled study conducted in Finland found that consuming cheese containing probiotic bacteria suppressed oral Candida overgrowth in the elderly [29], and Lactobacillus supplementation has long been known to suppress Candida overgrowth in the vagina [30].

 

Irritable bowel syndrome and chronic idiopathic constipation have no firmly established causes (as the name of the latter condition indicates), but dysbiosis may be involved at least in some cases [31, 32, 33]. Therefore, a number of studies have attempted to use probiotics, prebiotics or synbiotics in patients with these conditions. A recent meta-analysis of 43 such randomized controlled trials found that probiotics have beneficial effects in patients with irritable bowel syndrome, including such symptoms as abdominal pain, bloating, and flatulence scores [34]. Whether prebiotics are effective alone or in combination with probiotics could not be unequivocally established because of scarcity of the data. Both probiotics and synbiotics appeared to have beneficial effects in patients with chronic idiopathic constipation, however this conclusion needs further confirmation because of a limited number of such studies [34].

 

According to the analysis by McFarland [22], probiotics are generally more efficient in patients who initially have normal intestinal microbiota but had to be subjected to a microbiota-disrupting treatment (such as antibiotic therapy) that results in dysbiosis than in patients with pre-existing chronic dysbiosis. Clinical efficacy of probiotics is associated with strains capable of correcting dysbiosis, i.e. restoring the normal microbiota [22], which confirms that beneficial effects of such supplements on the microbiota are linked to its normalization.

 

The current challenge is that in many cases the best combinations of probiotics and prebiotics for patients with particular kinds of dysbiosis are not yet defined; moreover, only a limited proportion of intestinal microorganisms can be identified by traditional culturing. In this respect, the introduction of next-generation sequencing and metagenomics [35] can be expected to yield a much more complete picture of the effects of probiotics and prebiotics on the commensal microbiota in the near future. Since precise information about the deficiencies in particular bacterial species remains unavailable in many cases of dysbiosis, the most promising option for dysbiosis correction in such cases may be using synbiotics, such as MegaEl-Dena, that contain several bacterial species.

 

References

  1. Tancrede, C. Role of human microflora in health and disease. Eur J Clin Microbiol Infect Dis 11, 1012-1015 (1992).
  2. Dubos, R. & Schaedle, R.W. The digestive tract as an ecosystem. Am J Med Sci 248, 267-272 (1964).
  3. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  4. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  5. Tamboli, C.P., Neut, C., Desreumaux, P. & Colombel, J.F. Dysbiosis in inflammatory bowel disease. Gut 53, 1-4 (2004).
  6. Hawrelak, J.A. & Myers, S.P. The causes of intestinal dysbiosis: a review. Altern Med Rev 9, 180-197 (2004).
  7. Benjamin, J.L. et al. Smokers with active Crohn's disease have a clinically relevant dysbiosis of the gastrointestinal microbiota. Inflamm Bowel Dis 18, 1092-1100 (2012).
  8. Williams, B.L. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS One 6, e24585 (2011).
  9. Yang, Y.J. & Sheu, B.S. Probiotics-containing yogurts suppress Helicobacter pylori load and modify immune response and intestinal microbiota in the Helicobacter pylori-infected children. Helicobacter 17, 297-304 (2012).
  10. Marteau, P. Bacterial flora in inflammatory bowel disease. Dig Dis 27 Suppl 1, 99-103 (2009).
  11. Seksik, P. [Gut microbiota and IBD]. Gastroenterol Clin Biol 34 Suppl 1, S44-51 (2010).
  12. Costello, M.E., Elewaut, D., Kenna, T.J. & Brown, M.A. Microbes, the gut and ankylosing spondylitis. Arthritis Res Ther 15, 214 (2013).
  13. Kostic, A.D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22, 292-298 (2012).
  14. Jobin, C. [Microbial dysbiosis, a new risk factor in colorectal cancer?]. Med Sci (Paris) 29, 582-585 (2013).
  15. Sobhani, I. et al. Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One 6, e16393 (2011).
  16. Lakhan, S.E. & Kirchgessner, A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond) 7, 79 (2010).
  17. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179-185 (2012).
  18. Turnbaugh, P.J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480-484 (2009).
  19. Hoffman, L.R. et al. Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis. Clin Infect Dis 58, 396-399 (2014).
  20. Engberts, M.K., Verbruggen, B.S., Boon, M.E., van Haaften, M. & Heintz, A.P. Candida and dysbacteriosis: a cytologic, population-based study of 100,605 asymptomatic women concerning cervical carcinogenesis. Cancer 111, 269-274 (2007).
  21. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  22. McFarland, L.V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open 4, e005047 (2014).
  23. Gibson, G.R. & Roberfroid, M.B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr125, 1401-1412 (1995).
  24. Roberfroid, M.B. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr 80, S197-202 (1998).
  25. Panigrahi, P. Necrotizing enterocolitis: a practical guide to its prevention and management. Paediatr Drugs 8, 151-165 (2006).
  26. Sim, K. et al. Dysbiosis anticipating necrotizing enterocolitis in very premature infants. Clin Infect Dis 60, 389-397 (2015).
  27. AlFaleh, K. & Anabrees, J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 4, CD005496 (2014).
  28. Romeo, M.G. et al. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. J Perinatol 31, 63-69 (2011).
  29. Hatakka, K. et al. Probiotics reduce the prevalence of oral candida in the elderly--a randomized controlled trial. J Dent Res 86, 125-130 (2007).
  30. Hilton, E., Isenberg, H.D., Alperstein, P., France, K. & Borenstein, M.T. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 116, 353-357 (1992).
  31. Attaluri, A., Jackson, M., Valestin, J. & Rao, S.S. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS. Am J Gastroenterol 105, 1407-1411 (2010).
  32. Quigley, E.M. The enteric microbiota in the pathogenesis and management of constipation. Best Pract Res Clin Gastroenterol 25, 119-126 (2011).
  33. Simren, M. IBS with intestinal microbial dysbiosis: a new and clinically relevant subgroup? Gut 63, 1685-1686 (2014).
  34. Ford, A.C. et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol 109, 1547-1561; quiz 1546, 1562 (2014).
  35. Preidis, G.A. & Versalovic, J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 136, 2015-2031 (2009).

[endmore]

[more]

 

BENEFITS OF MEGAEL-DENA FOR PATIENTS WITH BACTERIAL VAGINOSIS AND DURING PREGNANCY AND BREASTFEEDING

The human body is inhabited by at least 10,000 species of microorganisms (commensal microbiota, or microflora), many of which still remain to be identified [1]. They protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation, and disturbances in the composition of the commensal microbiota (dysbiosis, or dysbacteriosis) are associated with a number of pathological conditions [2, 3]. Although most commensal microorganisms inhabit the gastrointestinal tract, some live in or on other parts of the body, such as the skin, buccal cavity, respiratory tract, and vagina, where they also benefit human health [4].

[endshort]

BENEFITS OF MEGAEL-DENA FOR PATIENTS WITH BACTERIAL VAGINOSIS AND DURING PREGNANCY AND BREASTFEEDING

The human body is inhabited by at least 10,000 species of microorganisms (commensal microbiota, or microflora), many of which still remain to be identified [1]. They protect the host from invasion by pathogenic microorganisms, either by direct competition or via immunomodulation, and disturbances in the composition of the commensal microbiota (dysbiosis, or dysbacteriosis) are associated with a number of pathological conditions [2, 3]. Although most commensal microorganisms inhabit the gastrointestinal tract, some live in or on other parts of the body, such as the skin, buccal cavity, respiratory tract, and vagina, where they also benefit human health [4].

 

Various microorgamisms colonize the initially sterile gastrointestinal tract of a newborn baby. This colonization is largely complete in ~1 week [5]; the first exposure to commensal microorganisms occurs during the infant's passage through the birth canal [6] and continues as the baby is breastfed, because breast milk also contains commensal microorganisms, which presumably translocate there from the mother’s gastrointestinal tract via mesenteric lymph nodes [7]. Colonization by “incorrect” sets of microorganisms (which may be due to such factors as antimicrobial medication or sterile food) results in dysbiosis [3, 8, 9]. Dysbiosis is associated with several immunological disorders, including atopic allergy; the gut microbiota differs in healthy and allergic babies [9]. There is increasing evidence that dysbiosis not only in infants but also in expectant mothers is a risk factor for development of atopic allergies, likely because the composition of the vaginal microflora and that of breast milk affects the composition of the infant’s microflora [10]. The importance of the vaginal microflora for establishing the correct microflora in an infant is suggested by a study which found that the incidence of IgE-associated allergic disease was elevated in cesarean-delivered children and could be reduced to a level similar to that in children delivered naturally by administration of probiotics [11].

 

The correct composition of the vaginal microflora is also important for women’s health regardless of pregnancy. Bacterial vaginosis is a form of dysbiosis characterized by a loss of the normal vaginal microbiota, which is dominated by Lactobacillus species, and their replacement by other bacteria, mainly anaerobes [12]. Lactobacilli are thought to suppress the growth of other bacteria by producing H2O2 and bacteriocins and by lowering the pH [13]. In many cases, bacterial vaginosis is asymptomatic, but it may also cause vaginitis (inflammation of the vagina) and is reportedly associated with an increased risk of Neisseria gonorrhoeae and Chlamydia trachomatis infections [14] and several viral infections, including HIV [15]; it may be both a cause and a consequence of vaginal infections [16]. Bacterial vaginosis may also make it more difficult for women to become pregnant and is associated with an increased risk of miscarriage or preterm delivery [16, 17, 18, 19]. Some examples of studies of the effectiveness of probiotics in patients with bacterial vaginosis and in expectant mothers for prevention of atopic allergies in infants are considered below.

 

Bacterial vaginosis is treated with antibacterial agents or probiotics (Lactobacillus species), or a combination of both. A collaborative Canadian–Nigerian study conducted in Nigeria compared the effectiveness of bacterial vaginosis treatment with an antibacterial agent (metronidazole) and a probiotic that included two Lactobacillus species, L. rhamnosus (one of the components of MegaEl-Dena) and L. reuteri [20]. This study found that bacterial vaginosis was cured in significantly fewer patients who received metronidazole in comparison with patients who received the probiotic [20]. In a parallel study, the same team compared the effects of combinations of metronidazole with the above probiotic or placebo and found that, among 106 subjects, 88% were cured at the 30-day follow-up in the metronidazole/probiotic group but only 40% were cured in the metronidazole/placebo group [21]. Thus, these studies suggested that bacterial vaginosis can be treated using probiotics alone or as part of combination therapy.

 

In a study of 18–40-year-old non-pregnant women with no urogenital infections conducted in Italy, Marcone and colleagues [22] found that administration of oral metronidazole followed by vaginal application of L. rhamnosus was more efficient in preventing bacterial vaginosis recurrence than metronidazole alone. However, a double-blind placebo-controlled randomized study conducted in Australia concluded that another Lactobacillus species, L. acidophilus, did not reduce the recurrence when used together with antibacterial therapy [23]. These contrasting results may underscore the importance of the choice of probiotic bacterial species. In fact, not only different species and but even different strains of the same Lactobacillus species colonize the vagina with different efficiency [24]; further research is needed to optimize probiotic formulations used for this purpose. In the absence of detailed information in this respect, the use of formulations that contain several Lactobacillus species, such as MegaEl-Dena (which contains three species of this genus), may be more promising than the use of single-species formulations.

 

A recent meta-analysis of 12 trials (1,304 patients in total) has confirmed the overall beneficial effect of probiotics for patients with bacterial vaginosis (especially for European populations and in shorter follow-up periods), but concluded that analysis is somewhat hampered by the heterogeneity of study design and that large-scale studies are needed to further ascertain the effectiveness of probiotics for bacterial vaginosis treatment [25].

 

Atopic dermatitis

There have been multiple clinical studies on the efficiency of probiotics in the prevention and management of atopic allergies, including in expecting mothers (reviewed by Kalliomäki and colleagues [9] and Cabana [26]). A study conducted in Finland found that pre- (one month) and postnatal (six months of age) administration of L. rhamnosus was associated with a significant reduction in the incidence of atopic dermatitis during the first seven years of life [27, 28]. Another study by the same team specifically examined the effect of probiotics on allergic sensitization in children born from allergic mothers and thus presumably genetically predisposed to atopic allergies [29]. The authors found that the risk of sensitization was increased by breastfeeding and that probiotic supplementation during pregnancy and lactation had a protective effect. Although the validity of their conclusion about the effect of breastfeeding on sensitization has been considered controversial by an independent team, the main conclusion, that probiotic supplementation reduces the risk of sensitization, has not been questioned [30].

 

A more recent study conducted in New Zealand compared supplementation with another strain of L. rhamnosus and supplementation with B. lactis. Supplementation was performed either in mothers (from 35 weeks of gestation until six months after birth) or in infants (from birth until two years of age) [31]. The authors reported that both types of supplementation with L. rhamnosus were associated with a reduced prevalence of eczema, another form of atopic allergy (by ~50%) at the age of two and four years; a significant reduction (by 31–44% depending on the parameter used) persisted at least until the age of six years [31]. In contrast, supplementation with B. lactis had no effect [31].

 

Overall, since MegaEl-Dena contains 3 species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), supplementation with this formulation may be useful for patients with bacterial vaginosis and expecting mothers, especially those considered at risk of atopic allergies.

 

References

  1. Ehrlich, E. The Human Microbiome Project. TuftScope 13, 20-22 (2013).
  2. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  3. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  4. McFarland, L.V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open 4, e005047 (2014).
  5. Fanaro, S., Chierici, R., Guerrini, P. & Vigi, V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 91, 48-55 (2003).
  6. Preidis, G.A. & Versalovic, J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 136, 2015-2031 (2009).
  7. Perez, P.F. et al. Bacterial imprinting of the neonatal immune system: lessons from maternal cells? Pediatrics 119, e724-732 (2007).
  8. Hawrelak, J.A. & Myers, S.P. The causes of intestinal dysbiosis: a review. Altern Med Rev 9, 180-197 (2004).
  9. Kalliomäki, M. et al. Guidance for substantiating the evidence for beneficial effects of probiotics: prevention and management of allergic diseases by probiotics. J Nutr 140, 713S-721S (2010).
  10. Benn, C.S. et al. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol 110, 72-77 (2002).
  11. Kuitunen, M. et al. Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort. J Allergy Clin Immunol 123, 335-341 (2009).
  12. Livengood, C.H. Bacterial vaginosis: an overview for 2009. Rev Obstet Gynecol 2, 28-37 (2009).
  13. Reid, G. & Burton, J. Use of Lactobacillus to prevent infection by pathogenic bacteria. Microbes Infect 4, 319-324 (2002).
  14. Wiesenfeld, H.C., Hillier, S.L., Krohn, M.A., Landers, D.V. & Sweet, R.L. Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia trachomatis infection. Clin Infect Dis 36, 663-668 (2003).
  15. Gillet, E. et al. Bacterial vaginosis is associated with uterine cervical human papillomavirus infection: a meta-analysis. BMC Infect Dis11, 10 (2011).
  16. Kovachev, S.M. Obstetric and gynecological diseases and complications resulting from vaginal dysbacteriosis. Microb Ecol 68, 173-184 (2014).
  17. Hillier, S.L. et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N Engl J Med 333, 1737-1742 (1995).
  18. Larsson, P.G. et al. Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma. APMIS 113, 233-245 (2005).
  19. Donati, L. et al. Vaginal microbial flora and outcome of pregnancy. Arch Gynecol Obstet 281, 589-600 (2010).
  20. Anukam, K.C. et al. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes Infect 8, 2772-2776 (2006).
  21. Anukam, K. et al. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Microbes Infect 8, 1450-1454 (2006).
  22. Marcone, V., Calzolari, E. & Bertini, M. Effectiveness of vaginal administration of Lactobacillus rhamnosus following conventional metronidazole therapy: how to lower the rate of bacterial vaginosis recurrences. New Microbiol 31, 429-433 (2008).
  23. Bradshaw, C.S. et al. Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial. PLoS One 7, e34540 (2012).
  24. Cadieux, P. et al. Lactobacillus strains and vaginal ecology. JAMA 287, 1940-1941 (2002).
  25. Huang, H., Song, L. & Zhao, W. Effects of probiotics for the treatment of bacterial vaginosis in adult women: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet 289, 1225-1234 (2014).
  26. Cabana, M.D. Early probiotic supplementation for the prevention of atopic disease in newborns-probiotics and the hygiene hypothesis. Biosci Microflora 30, 129-133 (2011).
  27. Kalliomäki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076-1079 (2001).
  28. Kalliomäki, M., Salminen, S., Poussa, T. & Isolauri, E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol 119, 1019-1021 (2007).
  29. Huurre, A., Laitinen, K., Rautava, S., Korkeamaki, M. & Isolauri, E. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization: a double-blind placebo-controlled study. Clin Exp Allergy 38, 1342-1348 (2008).
  30. van der Aa, L.B., Sprikkelman, A.B. & van Aalderen, W.M. Impact of maternal atopy and probiotic supplementation during pregnancy on infant sensitization. Clin Exp Allergy 38, 1698; author reply 1698-1699 (2008).
  31. Wickens, K. et al. Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Clin Exp Allergy 43, 1048-1057 (2013).

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BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS UNDERGOING ANTIBIOTIC THERAPY, CHEMOTHERAPY, AND RADIOTHERAPY

Some types of therapy, especially antibiotic therapy as well as chemotherapy and radiotherapy in cancer patients, can directly or indirectly damage the intestinal microbiota. Although antibiotics are intended to kill pathogenic bacteria, they reduce the total number of bacteria and cause changes in microbiota composition (dysbiosis); these changes are transient in most cases but may occasionally last for several months [1]. In particular, in babies and infants, antibiotic therapy has been reported to cause dramatic shifts in both the total numbers and composition of intestinal microbiota [2]. Antibiotic treatment can reduce bacterial abundance in babies’ feces (used as a proxy for the abundance of intestinal microbiota) by as much as six orders of magnitude, but the dynamics of the microbial species composition differs in different babies [2].

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BENEFITS OF TAKING MEGAEL-DENA FOR PATIENTS UNDERGOING ANTIBIOTIC THERAPY, CHEMOTHERAPY, AND RADIOTHERAPY

Some types of therapy, especially antibiotic therapy as well as chemotherapy and radiotherapy in cancer patients, can directly or indirectly damage the intestinal microbiota. Although antibiotics are intended to kill pathogenic bacteria, they reduce the total number of bacteria and cause changes in microbiota composition (dysbiosis); these changes are transient in most cases but may occasionally last for several months [1]. In particular, in babies and infants, antibiotic therapy has been reported to cause dramatic shifts in both the total numbers and composition of intestinal microbiota [2]. Antibiotic treatment can reduce bacterial abundance in babies’ feces (used as a proxy for the abundance of intestinal microbiota) by as much as six orders of magnitude, but the dynamics of the microbial species composition differs in different babies [2].

 

The intestinal microbiota protects the human body from pathogenic microorganisms by direct competition with them and by immunomodulation [3, 4]. The latter mechanism may be particularly important because approximately 70% of immune system cells are located in the gastrointestinal tract [5]. Beneficial bacteria may directly interact with intestinal epithelial or immune cells of the host through specific receptors and produce bioactive compounds that act as immune modulators [3, 4, 6]. Disruption of the normal intestinal microbiota may allow propagation of harmful microorganisms such as pathogenic bacteria (like Clostridium difficile) or fungi (Candida species); these complications are considered in detail below.

 

One way to help correct disturbances in the intestinal microbiota is to take probiotics and/or prebiotics. Probiotics are defined as “microorganisms that have a favorable influence on the host by improving the indigenous microflora” [7], whereas prebiotics are substances that are non-digestible for humans but stimulate the growth of beneficial bacteria [8]. MegaEl-Dena contains both prebiotics (fructooligosaccharides FOS) and probiotics and therefore is called a synbiotic. MegaEl-Dena contains 8 species of viable beneficial bacteria, including four species of Bifidobacterium (B. bifidum, B. breve, B. lactis, and B. longum), three species of Lactobacillus (L. acidophilus, L. casei, and L. rhamnosus), and Streptococcus thermophilus.

 

In particular, the ability of probiotics to regulate human immunity is illustrated by a study that involved healthy volunteers, which found that supplementation with lactic bacteria (L. acidophilus, L. casei, and L. rhamnosus) for seven weeks resulted in changes in the expression of genes involved in regulatory networks that control immunity and mucosal homeostasis [9]. Multiple clinical studies have documented the beneficial effects of probiotics and/or prebiotics for patients undergoing antibiotic therapy, chemotherapy, or radiotherapy.

 

Fungal infections

Disruption in the intestinal microflora caused by the use of broad-spectrum antibiotics may promote, by an as yet poorly understood mechanism, excessive colonization of intestinal mucosa by fungi, in particular Candida species [10]. This colonization is a risk factor for invasive candidiasis, a systemic life-threatening infection, which is most frequent in immunocompromised, severely ill, and pediatric patients [10, 11,12]. Since probiotics help to restore endogenous microflora, they can be expected to be beneficial for the prevention of Candida infections. Indeed, supplementation with Lactobacillus, in particular L. acidophilus (one of the components of MegaEl-Dena), has long been known to prevent and suppress Candida overgrowth in the vagina [13, 14].

 

More recently, Kumar and colleagues [15] investigated the effect of a synbiotic similar in composition to MegaEl-Dena (but also containing yeast) in children treated with broad-spectrum antibiotics. The authors found that the prevalence of Candida colonization was reduced by 34–37% in the group that received the synbiotic in comparison with the placebo group, and concluded that probiotics could be useful to reduce gastrointestinal Candida colonization [15].

 

Antibiotic-associated diarrhea

Diarrhea is a serious symptom of microbiota damage, as it may lead to dehydration and malnutrition, and in severe cases to cardiovascular compromise and death [6]. Sometimes the use of antibiotics leads to the prevalence of the harmful bacterium C. difficile, which may cause antibiotic-induced diarrhea (AAD). Antibiotic therapy is one of the three major risk factors for C. difficile infections (the other two being immunosuppression and old age) [17], which are often considered together with AAD.

 

An analysis of 16 studies (3,432 participants in total) concluded that, of several probiotic species tested, administration of L. rhamnosus (a component of MegaEl-Dena) or Saccharomyces Boulardii, simultaneously with antibiotics, was associated with a reduced risk of AAD onset [18]; other combinations, such as B. lactis and S. thermophilus (both are components of MegaEl-Dena), may be also beneficial [19]. A randomized double-blind placebo-controlled trial that involved elderly hospital patients taking antibiotics found that consumption of a drink containing S. thermophilus, L. casei, and another lactobacterium during and after antibiotic therapy was associated with a reduced incidence of AAD and C. difficile-associated diarrhea [20]. No serious adverse effects of probiotics have been reported in AAD patients.

 

There is also some evidence for beneficial effects of prebiotics and synbiotics in patients with AAD/C. difficile-induced diarrhea. A randomized clinical trial of treatment of C. difficile infection with specific antibiotics conducted in the UK found that taking FOS was associated with increased counts of bifidobacteria and significantly fewer relapses [21]. A placebo-controlled study conducted in Sweden compared the effects of probiotics (L. acidophilus and B. longum) and a corresponding synbiotic (the above bacterial species supplemented with FOS) on healthy volunteers subjected to antibiotic treatment. The authors found that C. difficile could be isolated after antibiotic treatment at a similar rate from the stool of patients who received placebo and probiotics, but at a much lower rate from that of patients who received the synbiotic [22]. The authors also found that L. acidophilus (but not B. longum) efficiently colonized the intestines.

 

A recent meta-analysis of 82 clinical trials, which included 11,811 participants, concluded that there is a statistically significant association between the intake of probiotics and reduction in AAD, although the effects of combinations of particular probiotics and antibiotics need further investigation [23]. An independent meta-analysis of 34 randomized double-blinded placebo-controlled trials (4,138 patients in total) found that the pooled relative risk of AAD was reduced by ~50% by probiotic supplementation [24]. These studies also did not report any adverse effects of probiotics.

 

Diarrhea induced by chemotherapy and radiotherapy

According to the Physician Data Query database of the NIH National Cancer Institute [25], on average 14% of cancer patients undergoing chemotherapy experience moderate-to-severe diarrhea. According to other estimates, the overall incidence of chemotherapy-induced diarrhea (CID) in cancer patients is 20%–40% [26]. The incidence of diarrhea can be as high as 50%–80% with some chemotherapeutic regimens, in particular those containing fluoropyrimidines or irinotecan [25, 26]. Diarrhea occurs in 60% of patients (with 10% having severe diarrhea) undergoing chemotherapy with tyrosine kinase inhibitors and antibodies and may interfere with the efficiency of chemotherapy [16]. Pathophysiology of CID is far from clear but is thought to involve the loss of intestinal epithelium, impaired water absorption in the colon and changes to the intestinal microbiota [26].

 

Taking probiotics is recommended as one of several measures to help prevent CID [16], although the evidence for their efficiency is mainly preclinical with so far only one randomized clinical study conducted in Finland, which involved 150 colorectal cancer patients who received two different regimens of 5-fluorouracil (fluoropyrimidine-based chemotherapy) following surgery; some patients received L. rhamnosus supplementation and fiber during chemotherapy [27]. The study found that L. rhamnosus supplementation did not affect the overall toxicity of chemotherapy but was associated with a reduced frequency of grade 3 or 4 diarrhea and less abdominal discomfort. No toxicity associated with the supplement was noted. Limitations of this study were that it was neither placebo-controlled nor blinded. The same authors are now conducting a prospective, multicenter, randomized, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT00197873), the results of which should be available soon.

 

Radiotherapy-induced diarrhea occurs in 50% of cancer patients undergoing pelvic or abdominal radiotherapy [28]. An early small-scale study (24 patients) conducted in Finland found that L. acidophilus supplementation in patients with gynecological malignancies undergoing pelvic or abdominal radiotherapy was associated with a significant reduction in radiotherapy-associated diarrhea [29]. These early findings have been more recently supported by other studies; in particular, the beneficial effect of probiotics may be more pronounced when they are administered simultaneously with radiotherapy as opposed to administration after radiotherapy [25, 30].

 

Thus, several components of MegaEl-Dena are expected to have beneficial effects for patients undergoing antibiotic therapy - L. rhamnosus, B. lactis, and S. thermophilus, as well as FOS, chemotherapy - L. rhamnosus, and radiotherapy - L. acidophilus.

 

References

  1. Dethlefsen, L., Huse, S., Sogin, M.L. & Relman, D.A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol6, e280 (2008).
  2. Palmer, C., Bik, E.M., DiGiulio, D.B., Relman, D.A. & Brown, P.O. Development of the human infant intestinal microbiota. PLoS Biol5, e177 (2007).
  3. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  4. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  5. Bengmark, S. Gut microbial ecology in critical illness: is there a role for prebiotics, probiotics, and synbiotics? Curr Opin Crit Care 8, 145-151 (2002).
  6. Hemarajata, P. & Versalovic, J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 6, 39-51 (2013).
  7. Erickson, K.L. & Hubbard, N.E. Probiotic immunomodulation in health and disease. J Nutr 130, 403S-409S (2000).
  8. Gibson, G.R. & Roberfroid, M.B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 125, 1401-1412 (1995).
  9. van Baarlen, P. et al. Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci U S A 108 Suppl 1, 4562-4569 (2011).
  10. Charles, P.E. & Bruyere, R. Preventing invasive candidiasis in high-risk critically ill patients: avoid antibiotics or give probiotics? Crit Care Med 41, 689-690 (2013).
  11. Tagliaferri, E. & Menichetti, F. Treatment of invasive candidiasis: between guidelines and daily clinical practice. Expert Rev Anti Infect Ther, 1-5 (2015).
  12. Tragiannidis, A., Tsoulas, C. & Groll, A.H. Invasive candidiasis and candidemia in neonates and children: update on current guidelines. Mycoses 58, 10-21 (2015).
  13. Elmer, G.W., Surawicz, C.M. & McFarland, L.V. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 275, 870-876 (1996).
  14. Hilton, E., Isenberg, H.D., Alperstein, P., France, K. & Borenstein, M.T. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 116, 353-357 (1992).
  15. Kumar, S., Bansal, A., Chakrabarti, A. & Singhi, S. Evaluation of efficacy of probiotics in prevention of candida colonization in a PICU-a randomized controlled trial. Crit Care Med 41, 565-572 (2013).
  16. Stein, A., Voigt, W. & Jordan, K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2, 51-63 (2010).
  17. Friedman, G. The role of probiotics in the prevention and treatment of antibiotic-associated diarrhea and Clostridium difficile colitis. Gastroenterol Clin North Am 41, 763-779 (2012).
  18. Johnston, B.C., Goldenberg, J.Z., Vandvik, P.O., Sun, X. & Guyatt, G.H. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, CD004827 (2011).
  19. Corrêa, N.B., Péret Filho, L.A., Penna, F.J., Lima, F.M. & Nicoli, J.R. A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for prevention of antibiotic-associated diarrhea in infants. J Clin Gastroenterol 39, 385-389 (2005).
  20. Hickson, M. et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ 335, 80 (2007).
  21. Lewis, S., Burmeister, S. & Brazier, J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study. Clin Gastroenterol Hepatol3, 442-448 (2005).
  22. Orrhage, K., Sjostedt, S. & Nord, C.E. Effect of supplements with lactic acid bacteria and oligofructose on the intestinal microflora during administration of cefpodoxime proxetil. J Antimicrob Chemother 46, 603-612 (2000).
  23. Hempel, S. et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 307, 1959-1969 (2012).
  24. Videlock, E.J. & Cremonini, F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther 35, 1355-1369 (2012).
  25. National Cancer Institute, N.I.H. PDQ (Physician Data Query). J Natl Cancer Inst106 (2014).
  26. Gibson, R.J. & Keefe, D.M. Cancer chemotherapy-induced diarrhoea and constipation: mechanisms of damage and prevention strategies. Support Care Cancer 14, 890-900 (2006).
  27. Osterlund, P. et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br J Cancer 97, 1028-1034 (2007).
  28. Benson, A.B., 3rd et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22, 2918-2926 (2004).
  29. Salminen, E., Elomaa, I., Minkkinen, J., Vapaatalo, H. & Salminen, S. Preservation of intestinal integrity during radiotherapy using live Lactobacillus acidophilus cultures. Clin Radiol 39, 435-437 (1988).
  30. Muehlbauer, P.M. et al. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy- and radiotherapy-induced diarrhea. Clin J Oncol Nurs 13, 336-341 (2009).

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REVIEW OF CLINICAL GUIDELINES FOR MEGAEL-DENA COMPONENTS

The volume of research on probiotics has steadily increased over the first 15 years of this century and probiotics are increasingly available to consumers, mostly as food supplements.

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REVIEW OF CLINICAL GUIDELINES FOR MEGAEL-DENA COMPONENTS

The volume of research on probiotics has steadily increased over the first 15 years of this century and probiotics are increasingly available to consumers, mostly as food supplements. 

The graph demonstrates the number of publications with Google Scholar search containing the word “probiotics” and the general term “intestine” in their titles over the last 25 years. While the number of publications using the general term "intestine" has remained steady, a robust increase in the number of publications on probiotics is observed in the 21st century.

 

Although the beneficial effects of probiotics and prebiotics in patients with various conditions are supported by a number of clinical studies (recently reviewed by McFarland [1]), regulation of the use of probiotics and prebiotics is complicated by several factors.

 

First, the complexity of the indigenous microflora (also called commensal microbiota) is not yet fully characterized, in part because only a limited proportion of intestinal microorganisms can be identified by traditional culturing [2].


Second, the best species/strains or combinations of probiotics for particular conditions are not yet defined, although in some cases circumstantial evidence suggests that particular species are more efficient than others (for example, one of the components of
Megael-Dena, Lactobacillus rhamnosus, appears to be more efficient than other probiotic species in patients with atopic dermatitis [3, 4]).

 

Third, although several mechanisms of action of probiotics have been suggested, such as direct competition with pathogenic microorganisms or modulation of immune responses [5, 6], the actual mechanisms in particular cases of successful use of probiotics remain mostly hypothetical.

 

In 2001−2002, a working group of experts from 11 countries (Argentina, Canada, Chile, Finland, France, Ireland, Italy, New Zealand, Sweden, Switzerland, and the USA) developed guidelines on “properties, functionality, benefits, safety, and nutritional features of probiotic foods” (primarily those containing lactic bacteria, which are mostly used as probiotics) on behalf of the Food and Agriculture Organization (FAO) of the United Nations and the World Health Organization (WHO) to assist governments in developing their own regulations on health claims regarding probiotics. The latest edition of these guidelines (2006) [7] is also used for training purposes by the United Nations Educational, Scientific and Cultural Organization (UNESCO) [8]. The guidelines adopted a definition of probiotics as “live microorganisms which when administered in adequate amounts, confer a health benefit on the host,” (although currently there is no universally accepted definition of probiotics and a number of slightly different definitions are in use [9]) and recommended that the guidelines be promoted at an international level and followed for any bacterial strain called “probiotic”. They also recommended development of the regulations “to allow specific health claims on probiotic food labels in cases where scientific evidence exists,” and applying good manufacturing practices (GMP) to the manufacture of probiotic foods. Some studies on which these guidelines were based were pilot studies conducted on a small number of patients. For example, the working group cited a study by Biller et al. [10] conducted in the USA. The authors used supplementation with Lactobacillus rhamnosus (one of the components of Megael-Dena) in four children (aged between five months and five and a half years) who had undergone antibacterial therapy for Clostridium difficile infection but still had several relapses of the infection. The study found that all patients became asymptomatic two weeks after starting the probiotic and two of them had no further relapses; two other patients had relapses and were given the same probiotic again, after which they remained asymptomatic [10]. Some publications referred to by the FAO/WHO working group were larger scale placebo-controlled studies, such as the one by Kalliomäki et al., conducted in Finland [11]. This was a double-blind, randomized placebo-controlled trial of L. rhamnosus, which involved 132 expectant mothers whose children were considered at risk of atopic allergy, as well as their children born in the course of the study. Mothers were given the probiotic pre- and postnatally (for six months). The authors found that the incidence of atopic eczema was halved in the probiotic group in comparison with the placebo group [1].

 

Because of a high variability in the design of such studies, which hampered cross-study analysis, the FAO/WHO working group recommended following the standard methods for clinical evaluations, i.e. Phase 1 trials to assess safety, Phase 2 (randomized, double-blind, placebo-controlled studies to assess the efficacy and measure adverse effects), Phase 3 (effectiveness), and finally Phase 4 (surveillance). Clinical studies should use sample sizes calculated for specific endpoints and perform appropriate statistical tests to establish statistically significant differences.

 

Most probiotics are sold as foods or food supplements and thus only general health claims are allowed. The FAO/WHO working group recommended allowing more specific health claims when they are supported by sufficient scientific evidence, with product manufacturers’ claims being verified by independent experts. In this respect, current guidelines differ in different countries. In the USA, probiotics are available as dietary supplements; only “structure/function” health claims are allowed by the United States Food and Drug Administration (FDA), i.e. claims that the supplement affects “the structure or function in humans” or the claims of the documented mechanism of such action [12]. Such claims can be, but do not necessarily need to be, approved by the FDA [9]. In the USA, probiotics cannot be formally considered to cure or treat any diseases [1], even if this is supported by clinical trials (however, particular health organizations may issue their own guidelines, see below). Studies that intend to demonstrate such effects of probiotics are subject to restrictive regulations (normally applied to new drug trials) by the FDA Center for Biologics Evaluation and Research; this has reportedly hampered such studies in the US [9].

 

Specific claims regarding the use of probiotics to prevent or cure diseases are formally allowed in European countries and have to be substantiated by properly conducted human trials in the targeted population or in healthy volunteers [1]. However, most of such applications have been rejected by the European Food Safety Authority (EFSA) [1, 9, 13], in part because it judged the scientific evidence to support specific health claims insufficient or based on indirect effects [14]. In 2011, the EFSA issued detailed requirements for health claims related to gut and immune function, including claims related to the gastrointestinal microbiota [15]. In the document, the EFSA concluded that it was not satisfied by the existing evidence that “increasing the number of any groups of microorganisms, including lactobacilli and/or bifidobacteria” has beneficial physiological effects. The same year, in order to facilitate the approval by the EFSA of claims related to the use of probiotics for specific diseases and pathological conditions, an international panel of experts from nine European Union countries published suggested guidelines on the design of probiotic studies intended to substantiate such specific health claims [13]. The ruling by the EFSA has been considered by some authors as controversial but will likely result in a more rigorous approach to the design of clinical studies on the effects of probiotics and prebiotics [16, 17].

 

Finally, it should be noted that some health organizations have issued their own evidence-based guidelines on the use of probiotics. For example, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the European Society for Paediatric Infectious Diseases (ESPID) published guidelines for the management of acute gastroenteritis in children [18]. The authors of these guidelines note that out of many available probiotic microorganisms only two species have been proven to be efficient for acute gastroenteritis patients (in combination with rehydration therapy). One of these probiotics is the Megael-Dena component L. rhamnosus [18]. These conclusions were based on a review of several published meta-analyses of clinical trials. Similarly, the Cincinnati Children's Hospital guidelines recommend using L. rhamnosus in children with acute gastroenteritis [19] and outline the optimal conditions (treatment should be started as soon as possible at a dose of at least 1010 colony-forming units per day, and continued for 5–7 days). These recommendations are mainly based on two reviews of clinical studies [20, 21] and the above ESPGHAN/ ESPID guidelines.

 

The University of Texas at Austin considers that “there is high certainty that the benefits [of probiotics and prebiotics] are substantial” in patients undergoing antibiotic therapy to eradicate Helicobacter pylori [22]. The recommendation of this university to use probiotics in such patients is based on a published meta-analysis of 34 randomized double-blind, placebo-controlled trials (4,138 patients in total), which found that the pooled relative risk of antibiotic-associated diarrhea was reduced by ~50% by probiotic supplementation [23], and a review by Boyanova and Mitov who note that several species of Lactobacillus and Bifidobacterium (seven out of eight bacterial species included in Megael-Dena belong to these genera) are beneficial for patients undergoing antibiotic therapy [24].

 

The American Academy of Pediatrics has published guidelines on the efficiency and safety of probiotic and prebiotic products in pediatric patients, which are based on an extensive review of published clinical studies [25]. The guidelines point out that probiotics are effective for treatment of acute viral gastroenteritis and prevention of antibiotic-associated diarrhea and possibly a number of other conditions in healthy children, but should be used with caution in immunocompromised or chronically debilitated children because of possible complications. The guidelines of the British Society of Gastroenterology point out that there is evidence of benefit of probiotics in maintenance and treatment of ulcerative colitis but not Crohn’s disease [26].

 

The World Gastroenterology Organisation (WGO) has issued detailed guidelines on the use of probiotics and prebiotics [27] as part of its “Global Guidelines.” In particular, the WGO guidelines recognize the effectiveness of such Megael-Dena components as Lactobacillus casei and L. rhamnosus in treatment of acute infectious diarrhea, Bifidobacterium lactis, L. rhamnosus, and Streptococcus thermophilus in prevention of antibiotic-associated and nosocomial diarrhea, B. lactis and L. casei in prevention of common community-acquired gastrointestinal infections, L. casei as adjuvant therapy during H. pylori eradication therapy, and L. acidophilus, L. casei, B. bifidum, and oligofructose (fructooligosaccharides) in prevention of Clostridium difficile–associated diarrhea [27]. In the USA, the WGO guidelines have been endorsed in a review commissioned by the American College of Gastroenterology [28].

 

References

  1. McFarland, L.V. Use of probiotics to correct dysbiosis of normal microbiota following disease or disruptive events: a systematic review. BMJ Open 4, e005047 (2014).
  2. Preidis, G.A. & Versalovic, J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 136, 2015-2031 (2009).
  3. Viljanen, M. et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy 60, 494-500 (2005).
  4. Wickens, K. et al. Early supplementation with Lactobacillus rhamnosus HN001 reduces eczema prevalence to 6 years: does it also reduce atopic sensitization? Clin Exp Allergy 43, 1048-1057 (2013).
  5. Kelly, D., Conway, S. & Aminov, R. Commensal gut bacteria: mechanisms of immune modulation. Trends Immunol 26, 326-333 (2005).
  6. Round, J.L. & Mazmanian, S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9, 313-323 (2009).
  7. World Health Organization, Food and Agriculture Organization of the United Nations. Probiotics in Food: Health and Nutritional Properties and guidelines for evaluation.  FAO Food and Nutrition Paper 85. ftp://ftp.fao.org/docrep/fao/009/a0512e/a0512e00.pdf
  8. United Nations Education, Science and Cultural Organization (UNESCO). Probiotics in Food - Health and Nutritional Properties and Guidelines for Evaluation. http://otp.unesco-ci.org/training-resource/nutrition/probiotics-food-health-and-nutritional-properties-and-guidelines-evaluat.
  9. Donovan, S.M., Schneeman, B., Gibson, G.R. & Sanders, M.E. Establishing and evaluating health claims for probiotics. Adv Nutr 3, 723-725 (2012).
  10. Biller, J.A., Katz, A.J., Flores, A.F., Buie, T.M. & Gorbach, S.L. Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr 21, 224-226 (1995).
  11. Kalliomäki, M. et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 357, 1076-1079 (2001).
  12. U.S. Food and Drug Administration. Guidance for Industry: A Food Labeling Guide (8. Claims) http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/LabelingNutrition/ucm064908.htm#structfunct.
  13. Gibson, G.R. et al. The design of probiotic studies to substantiate health claims. Gut Microbes 2, 299-305 (2011)
  14. Binnendijk, K.H. & Rijkers, G.T. What is a health benefit? An evaluation of EFSA opinions on health benefits with reference to probiotics. Benef Microbes 4, 223-230 (2013).
  15. (EFSA), E.F.S.A. Guidance on the scientific requirements for health claims related to gut and immune function. EFSA J 9, 1984 (2011).
  16. Clemente, A. Probiotics and prebiotics: An update from the World Gastrointestinal Organization (WGO). Eur J Food Res Rev 2, 24-28 (2012).
  17. Katan, M.B. Why the European Food Safety Authority was right to reject health claims for probiotics. Benef Microbes 3, 85-89 (2012).
  18. Guarino, A. et al. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe. J Pediatr Gastroenterol Nutr 46 Suppl 2, S81-122 (2008).
  19. Anderson, James M. Evidence-Based Decision Making. Center for Health System Excellence. http://www.cincinnatichildrens.org/service/j/anderson-center/evidence-based-care/default.
  20. Guandalini, S. Probiotics for children with diarrhea: an update. J Clin Gastroenterol 42 Suppl 2, S53-57 (2008).
  21. Szajewska, H. & Mrukowicz, J.Z. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr 33 Suppl 2, S17-25 (2001).
  22. Agency for Healthcare Research and Quality. National Guideline Clearinghouse. http://www.guideline.gov/content.aspx?f=rss&id=46427&osrc=12.
  23. Videlock, E.J. & Cremonini, F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther 35, 1355-1369 (2012).
  24. Boyanova, L. & Mitov, I. Coadministration of probiotics with antibiotics: why, when and for how long? Expert Rev Anti Infect Ther 10, 407-409 (2012).
  25. Thomas, D.W. & Greer, F.R. Probiotics and prebiotics in pediatrics. Pediatrics 126, 1217-1231 (2010).
  26. Mowat, C. et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 60, 571-607 (2011).
  27. Guarner, F. et al. World Gastroenterology Organisation Global Guidelines: probiotics and prebiotics October 2011. J Clin Gastroenterol 46, 468-481 (2012).
  28. Ringel, Y., Quigley, E.M.M. & Lin, H.C. Prebiotics and probiotics: their role in the management of gastrointestinal disorders in adults. Am J Gastroenterol Suppl 1, 34-40 (2012).

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