The Gut Microbiota
The human intestinal tract is home to approximately 100 trillion microorganisms.1 With 100 billion to 1 trillion microorganisms per gram, the human colon is the most densely populated and complex microecosystem known. This enormous biomass has been thought to harbor 500 to 1000 known diverse bacterial species, but recent work using molecular phylogenetic sequencing of genes for 16S ribosomal RNA reveals staggering diversity. The human gut appears to host more than 1800 genera and between 16,000 and 36,000 bacterial species about most of which we know next to nothing.2 In addition to promoting normal gastrointestinal functions and providing protection from infection, a normal intestinal microbiota exerts important beneficial effects on systemic metabolism, immune function, and even brain maturation.3,4 Conversely, a dysbiotic microbiota is associated with a myriad of autoimmune, atopic, and metabolic diseases.3,5 It is becoming increasingly clear that restoration of a healthy, balanced intestinal microbiota using probiotics and prebiotics safely and effectively prevents and treats an array of gastrointestinal and systemic disorders.
Probiotics are viable microorganisms that exert health benefits upon ingestion. Two genera of lactic–acid producing bacteria have been the primary focus of research for their health benefits: Lactobacillus and Bifidobacterium. Lactobacilli are gram-positive, rod-shaped, facultative anaerobes found throughout the gastrointestinal tract, especially in the distal ileum. Bifidobacteria are gram-positive, microaerophilic, or obligate anaerobes that are highly prevalent in the colon. Lactobacilli and bifidobacteria are early colonizers of an infant's intestinal tract and normally persist in the gut throughout life.6 Other lactic–acid producing probiotic organisms include the yogurt starter Streptococcus thermophilus; Enterococcus faecium; and certain Lactococcus, Leuconostoc,and Pediococcus species. Non-lactic-acid producing probiotics include a specific healthful strain of Escherichia coli called Nissle 1917, Bacillus and Propionibacterium species, and the nonpathogenic yeast Saccharomyces boulardii.
Prebiotics are substances, usually polysaccharides, that when ingested change the composition and/or activity of the gastrointestinal microflora that confer health benefits.7 Prebiotics are selectively fermented by probiotic microbes such as Bifidobacterium and Lactobacillus and have the additional benefit of increasing the numbers and activity of healthful intestinal bacteria such as the short-chain fatty acid (SCFA)-producing Eubacterium and Roseburia.8 Prebiotic effects are best documented for digestion-resistant oligosaccharides such as inulin and galactooligosaccharides (GOS).9
Evidence for the Use of Probiotics and Prebiotics
Probiotics and prebiotics have been best studied for various gastrointestinal and atopic disorders.10,11 It is difficult to compare studies because patient populations have been very heterogeneous, probiotic and prebiotic formulas and dosing highly variable, and endpoints inconsistently defined.12 Clinicians must also be aware in interpreting study results that probiotic clinical research is usually driven by profit motive to demonstrate the efficacy of patented strains or formulations. Although the methodology has its limitations, in the area of probiotics and prebiotics, meta-analyses conducted by independent investigators offer the most useful assessment of their role in treating gastrointestinal and atopic diseases. Probiotics and prebiotics are not panaceas, but they are very useful modalities in many clinical settings. We offer our approach to using probiotics and prebiotics to treat the following disorders based on our review of the literature, our experience, and the reports we hear almost daily from patients, families, and practitioners.
The efficacy of probiotics has been best demonstrated for diarrheal diseases ranging from rotavirus to traveler's diarrhea.10 A large number of clinical trials show that probiotics can reduce the risk of antibiotic-associated diarrhea (AAD) and may be useful in the prevention and treatment of Clostridium difficile-associated diarrhea (CDAD).13,14 AAD occurs in 5% to 39% of adults and 11% to 50% of children depending on the series and definition of diarrhea. It may occur up to two months following a course of antibiotics. It is caused by antibiotic disruption of the gut microbiota and is associated with a drop in colonic SCFA concentrations. Up to 50% of cases are caused by C. difficile, which has a high relapse rate. A meta-analysis of 25 randomized, controlled trials involving 2810 patients concluded that probiotics significantly reduced the relative risk of antibiotic-associated diarrhea by 57%.13 Three types of probiotics were found to be most beneficial: S. boulardii, L. rhamnosus GG, and multispecies probiotic combinations. A meta-analysis of 23 randomized, controlled trials conducted by the UK West Midlands Health Technology Assessment Group found that probiotics significantly reduced the relative risk of CDAD by 46%.15 S. boulardii has been consistently found to reduce the risk of new and recurrent cases of CDAD.16
Recommendations for Prevention of AAD
The key probiotic for preventing AAD is Saccharomyces boulardii used in therapeutic doses. S. boulardii will be more effective when combined with a formulation containing Lactobacillus rhamnosus and Bifidobacterium species. Consider the use of inulin-based probiotics to support SCFA-producing species. Probiotics should be started at the time antibiotics are prescribed and continued for a total duration of 30 days.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) refers to two chronic, relapsing or remitting diseases: ulcerative colitis (UC) and Crohn's disease (CD).17 In IBD, higher numbers of Bacteroides, Enterobacteriaceae, and Peptostreptococcus and lower numbers of Bifidobacterium are found in inflamed mucosa than are encountered in healthy controls.18,19 Although people with IBD clearly seem to be mounting an inappropriate immune response to a dysbiotic gut microbiota, the evidence for a benefit for probiotics in IBD is strongly conflicted, with most studies showing no benefit.17A notable exception is the use of probiotics for pouchitis. Pouchitis is inflammation of an ileal pouch connected to the anus after colectomy for ulcerative colitis. Three studies have found that a proprietary combination of L. casei, L. plantarum, L. acidophilus, L. bulgaricus, B. longum, B. breve, B. infantis, and S. thermophilus (VSL#3) can maintain remission in antibiotic-dependent pouchitis. Two studies of Lactobacillus rhamnosus GG have yielded conflicting results in pouchitis. In UC, three studies have found that E. coli Nissle 1917 is as effective as mesalamine at maintaining remission. One study has found that S. boulardii plus mesalamine reduced relapses in patients with CD to 6.3% over a six-month period compared with 37.5% for mesalamine alone. In UC, one study found no benefit for the addition of S. boulardii to mesalamine, while another uncontrolled pilot study found that 17 of 25 patients completing the study attained remission using S. boulardii alone.20 Inulin and fructooligosaccharides alone and with B. longum have been found to have benefit in IBD.21-23 All of the above studies except for those involving E. coli Nissle 1917 have been very small. Standard therapy of IBD is clearly unsatisfactory and patients have little to lose with a trial of probiotics to maintain remission. We base our recommendations in part on the evidence that multispecies probiotic formulations are generally more effective than single strains.12
Recommendations for IBD
For pouchitis, a high-dose, multispecies probiotic containing Lactobacillus and Bifidobacterium species as well as S. thermophilus should be used. Bifidogenic doses of an inulin prebiotic should be considered. For UC, very high doses of a multispecies probiotic containing Lactobacillus and Bifidobacterium species as well as S. thermophilus should be used. Bifidogenic doses of an inulin prebiotic should be considered. One may also consider E. coli Nissle 1917, although it is expensive and has a short shelf life. S. boulardii may also be added to a regimen. For CD, the most effective probiotic is S. boulardii. Bifidogenic doses of an inulin prebiotic may be considered as well as high doses of a multispecies probiotic formulation.
Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is a multifactorial disorder characterized by flatulence, diarrhea, constipation, and abdominal discomfort and pain. It affects 10% to 20% of adults and is characterized by heightened visceral sensitivity and gut dysbiosis. Although challenging to study because of the heterogeneous patient populations, clinical trials found that the individual strains B. infantis and L. plantarum effectively reduced the spectrum of IBS symptoms.24,25 In a small pilot study of patients with IBS, a food elimination diet followed by treatment with a probiotic preparation (Vital-10 powder) containing multiple species including B. bifidum, B. infantis, L. acidophilus, L. rhamnosus, L. plantarum, L. salvarius, L. bulgaricus, L. casei, L. brevis,and S. thermophilus improved pain, stool frequency, and quality of life scores.26 A recent meta-analysis of 19 randomized clinical trials involving 1650 patients found that probiotics were significantly better than placebo in relieving IBS symptoms.27 B. infantis, L. plantarum, and multispecies formulations were effective and the number needed to treat was quite low at four.
Recommendations for IBS
It is important to assess each person for food allergies and intolerance as well as gluten sensitivity. Most people with IBS will benefit from high doses of a multispecies formulation with a high Lactobacillus and Bifidobacterium content. Consider digestive enzymes with meals. If a person improves, probiotic intake generally needs to continue indefinitely.
Allergic diseases constitute a pandemic affecting more than 20% of the world's population.28 Given that 70% to 80% of the body's immune system resides in the gastrointestinal tract, it is of no surprise that the development of atopic disorders is linked to aberrations in the intestinal microbiota characterized by reduced levels of Bifidobacteria and increased numbers of pathogens such as Staphylococci and clostridia.29 Probiotics have been conclusively shown to modulate the Th2 immune responses associated with allergies.30 A meta-analysis of 10 randomized clinical trials found that probiotics effectively treat atopic dermatitis in children.31 Children with moderately severe disease were most responsive. L. rhamnosus and B. lactis strains were the most commonly used probiotics and were efficacious alone or in combination with other species. Probiotics administered to pregnant women, nursing mothers, and infants have been shown to provide long-term protection against eczema.32 A multispecies formulation of L. bulgaricus, L. paracasei,and Streptococcus thermophilus has been shown to significantly reduce symptoms and improve quality of life in young adults with perennial allergic rhinitis.33 GOS and inulin prebiotics have been found to reduce the incidence of atopic dermatitis and allergic urticaria in infants.34 Beta-1,3-glucan has been found to be effective for seasonal allergies in adults.35 Probiotics have not been shown to be of benefit in asthma, although there is currently a multicenter study under way to assess this application.
Recommendations for Prevention of Atopic Diseases
Prebiotics and probiotics should be considered for pregnant women at risk of having an infant who will develop atopic disease. In infants at risk for atopy or who have developed atopic disease, a low D(-)-lactate Lactobacillus and Bifidobacterium probiotic may provide benefit. Administration of probiotics to nursing mothers provides the same benefit to infants as does giving the infant probiotics directly. Consider GOS/beta-glucan for bottle-fed infants until weaned. In children and adults with atopy, a multispecies probiotic with L. rhamnosus along with a GOS/beta-1,3-glucan prebiotic may be beneficial.
Genitourinary Disorders in Women
As in the intestinal tract, the normal vulvovaginal microbiota can be disrupted and undesirable microorganisms can proliferate, especially during and following courses of antibiotics. Historically, preparations of probiotic lactic acid bacteria, introduced either as yogurt soaked tampons or douches or encapsulated probiotic suppositories, have been used to check the growth of Candida andotherpathogens with favorable clinical results. Unfortunately, studies on the efficacy of probiotics for vaginal infections often have mixed results, probably due to differences in study design, selection of proper probiotic strains, probiotic viability, and other factors. Direct vaginal application of probiotics is not necessary, as studies show that orally administered probiotics can reduce the incidence of recurrent yeast vaginitis, bacterial vaginosis, and urinary tract infections.36
Most of the clinical research on probiotics and nonsexually transmitted genitourinary tract infections in women has involved L. acidophilus and a patented proprietary product containing L. rhamnosus GR-1 and L. fermentum RC-14(renamed L. reuteri RC-14).37-39 L. rhamnosus GR-1 and L. fermentum RC-14given orally in a dose exceeding 1 billion CFUs daily results in vaginal Lactobacillus predominance, a 50% cure rate in bacterial vaginosis, and higher cure rates in women with vulvovaginal candidiasis when combined with fluconazole than does fluconazole. L. acidophilus has been found to be as effective as trimethoprim/sulfamethoxazole in decreasing the incidence of urinary tract infections in young girls' reflux of urine from the bladder into the ureters. Orally administered B. longum, which produces both lactic acid and hydrogen peroxide, reduces Candida urinary tract infections by 70% in immunocompromised women. Probiotic species that produce high amounts of lactic acid and hydrogen peroxide appear to offer the most benefit to prevent recurrent genitourinary tract infections in women.
Prevention of Recurrent GU Infections in Women
Consider the use of L. rhamnosus GR-1/L. reuteri RC-14. Alternatively, a multispecies probiotic formulation containing large numbers of high lactate and peroxide producing microorganisms may be used. Long-term probiotic usage is generally necessary.
Probiotic Selection and Dosing
Practitioners and the public should use care in selecting probiotic formulations. Industry and consumer studies have found that 30% to 50% of probiotic products contain significantly fewer viable microorganisms than claimed on their labels. Probiotics marketed as dairy free are often not free of milk allergens. Companies claiming a dairy-free status should be able to provide proof of independent allergen testing. Probiotics should be sourced from companies that are independently certified as complying with FDA-mandated good manufacturing practices. Selection of probiotics that give an expiration date is strongly suggested because it means that the company has stability and shelf life data for the product. Multispecies probiotic formulations are preferable, as they consistently provide greater benefit than single-strain products for a broader spectrum of conditions. As a general rule, probiotics are best consumed with food. Gastric pH is significantly lower when fasting than it is after food consumption.40 Low fasting pH will significantly degrade probiotics. Survival is much higher when probiotics are consumed with food. Bacterial probiotics shoud be taken one hour before or two hours after antibiotics. S. boulardii is not susceptible to antibiotics, but is sensitive to standard antifungals and should be taken away from them. When high-dose probiotics are used, it is best to begin with daily doses in the range of 10 to 25 billion CFUs and titrate up over a period of several weeks. This approach will minimize the incidence of gas and bloating that can occur when large doses are consumed for the first time.
Theoretical safety concerns for probiotics involve risk of infection, adverse metabolic effects, immune reactions, and gene transfers. Worldwide use of probiotics is extensive. Many of the Bifidobacterium, Lactobacillus, and Streptococcus probiotics have been used for millenia. Probiotics are very safe.41 There are no documented cases of translocation of probiotics from the gut even when intestinal mucosal ulcerations are present. No case of Bifidobacterium bacteremia has ever been documented except in cases of pelvic infections or bowel perforations. There are very rare reports of Lactobacillus bacteremias, usually in people not consuming probiotics. There is one report of probiotic L. rhamnosus endocarditis in a patient who chewed probiotics after dental extraction. There are sporadic reports of S. boulardii fungemia in debilitated patients or in hospitalized patients with an indwelling central venous catheter. Bifidobacterium, Lactobacillus, and Streptococcus probiotics have been used safely in pregnant women and nursing mothers. Infants have been given probiotics in doses up to 110 CFUs per kilogram of body weight. Probiotics are widely used in very-low-birth-weight and premature infants to prevent necrotizing enterocolitis. No probiotic safety issues in infants and children have ever arisen. Probiotics are safe in immunosuppressed patients and patients undergoing chemotherapy or radiation in whom they can prevent and treat diarrhea.
For more than a century, people have knowingly consumed probiotics for health benefits. They are an effective approach to correcting intestinal dysbiosis and treating gastrointestinal and systemic diseases. Consumption of probiotics is safe in a variety of patient populations and clinical scenarios. Care should be taken to select documented, tested probiotics from reputable manufacturers. As we learn more about how gastrointestinal dysbiosis is related to disorders throughout the body, the spectrum of diseases amenable to probiotic intervention will continue to expand.
Stephen Olmstead, MD, is chief science officer at ProThera Inc., where he directs clinical trials of ProThera and Klaire Labs nutraceutical products. His current research focus is the use of enzymes and chelating agents to disrupt pathogenic GI biofilm. Dr. Olmstead graduated from the University of New Mexico with distinction in biology and chemistry. He attended the University of New Mexico School of Medicine, and trained at Harvard Medical School, Massachusetts General Hospital. He is board certified in both internal medicine and cardiovascular diseases.
Dennis E. Meiss, PhD, is a founder of ProThera Inc. and acts as president and CEO. He is the primary formulator of ProThera and Klaire Labs products and directs the company's management team. Dr. Meiss received his PhD in neurobiology from the University of Connecticut.
Janet Ralston, BS, is a founder of ProThera Inc. She serves as vice president of the company, where she directs marketing efforts and client service programs. She is a graduate of the University of California, Davis, Nutrition and Dietetics program.
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