Probiotics: A Review for Clinical Use.
Interest in modifying the gut flora by consuming foods or microbes that may improve overall health dates back to the early 1900s, when it was theorized that certain milks and yogurts may provide a health benefit to the populations consuming them.
The mechanisms of action of probiotics in various diseases are not completely understood, but several hypotheses have been proposed. One theory is that the gut microbiome influences visceral hypersensitivity and pain and that Lactobacillus-induced expression of mu-opioid and cannabinoid receptors in the intestinal epithelium may be able to mediate pain in a manner similar to that of opioids. Another proposed mechanism is modulation of the immune system, and several studies have found that probiotics or their products suppress inflammatory cytokines and stimulate protective cytokines, mostly in models of inflammatory bowel disease (IBD). Finally, probiotics may promote integrity of the intestinal epithelium, protecting intestinal epithelial tight junctions and barrier function, and may create biofilms that secrete factors that can inhibit pathogen invasion.
As understanding of the gut microbiota and the complex interactions involved in inflammation, gut permeability, and dysbiosis advances, the use of probiotics is appealing to clinicians and patients alike. However, while enthusiasm has skyrocketed—particularly in the world of nutritional supplements—scant data support the use of probiotics; the gastrointestinal diseases for which they have benefits and the species that confer these benefits remain unclear, resulting in confusion among both clinicians and consumers. This article provides recommendations for the selection of a probiotic regimen where evidence appears strong and discussion of certain areas where more research is needed before more conclusive recommendations can be made.
The methods used for finding the recommendations involved searching via PubMed, OVID, and the Cochrane Review Library for the terms “probiotics,” “indications,” “dosing,” “pouchitis,” “infectious diarrhea,” “antibiotic-associated diarrhea,” “constipation,” “irritable bowel syndrome,” “hepatic encephalopathy,” “ulcerative colitis,” “Crohn’s disease,” and “Clostridium.” Results were further narrowed into randomized controlled trials, meta-analyses, and review articles in which information about specific strains and dosing could be found. Recommendations were selected based on the relative robustness of the relevant data.
The diagnostic indication in which the data are the strongest is pouchitis. In severe ulcerative colitis (UC) and familial adenomatous polyposis for which a total colectomy is required, the appropriate procedure is a proctocolectomy with ileal pouch–anal anastomosis. The most frequent long-term complication of this surgical correction is acute or chronic inflammation of the S- or J-shaped ileal pouch. Symptoms of pouchitis include abdominal pain, fever, hematochezia, urgency, and increased stool frequency. Pouchitis patients have distinct microbial patterns likely due to fecal stasis and colonic metaplasia from the original ileal mucosa, creating an inflammatory milieu associated with bacterial species such as Bacteriodaceae and Clostridiaceae species. Enterococcaceae may have a role in maintaining immunologic homeostasis in the mucosa. The use of probiotics has been found to be most effective in randomized, placebo-controlled trials in both primary and secondary prophylaxis, particularly with the use of VSL#3 (Alfasigma)—a probiotic containing Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. bulgaricus, and Streptococcus thermophiles.
Primary prophylaxis has been studied at a dose of 3 g per day for 12 months. Secondary prophylaxis of relapsing pouchitis has been studied at a dose of 6 g per day from 9 months to 1 year. Although antibiotics remain the drug of choice for periods of inflammation, high-dose VSL#3 at a dose of 2 sachets twice daily (3,600 billion bacteria per day) for 4 weeks has been found to be effective for the treatment of mild pouchitis (between 7 and 12 on the Pouchitis Disease Activity Index).
Infectious diarrhea is another well-studied indication warranting the use of probiotics, but most data are in the pediatric population. A Cochrane Review found that all included studies reported a reduced stool frequency by day 2 and shortened duration of diarrhea by around 25 hours in patients who received probiotics. Probiotics were not associated with any adverse effects (AEs). The most common organism evaluated is the L. casei strain GG, which has been used in 13 studies at a dose of 6×10 colony forming units (CFU) twice a day for 5 days.
The use of probiotics also has been studied for prevention of traveler’s diarrhea. Specifically, Lactobacillus GG has been shown to be effective because it is acid and bile resistant, adheres to ileal cells, and produces an antimicrobial substance. In a double-blind, placebo-controlled study from Finland, Lactobacillus GG was used to prevent traveler’s diarrhea, with protection rates of 1.8% to 39.5%. Another study found that taking Lactobacillus GG powder in capsules at a dose of 2×10 bacteria starting 2 days before departure and continuing throughout the trip reduced the risk for diarrhea from 7.4% per day to 3.9% per day.
A form of infectious diarrhea related to the use of antibiotics is caused by Clostridium difficile and is referred to as Clostridium difficile–associated diarrhea (CDAD). It is a commonly encountered infection that probiotics have been proven to prevent. The mechanism of action includes alteration of intestinal flora, antimicrobial activity, intestinal barrier protection, and immunomodulation. A systematic review of probiotic use to prevent C. difficile infection in hospitalized patients found that probiotics reduced the risk for CDAD by more than 50% when they were taken within 2 days of the first antibiotic dose, with no evident increase in AEs.
There are 2 recommended probiotic regimens. The first is L. acidophilus at a dose of 25×10 CFU per day for 2 days, followed by 50×10 CFU per day for the duration of the antibiotic course. Alternatively, L. casei can be used at a dose of 19×10 CFU per day with L. bulgaris 1.9×10 CFU per day and S. thermophiles19×10 CFU per day, started within 48 hours of initiating antibiotic therapy and continuing until 7 days after cessation of antibiotic therapy. There is insufficient evidence to recommend probiotics alone as treatment for active CDAD, but they may be used as adjunctive therapy to antibiotics in non-severe recurrent disease if no significant comorbidities are present (refer to the previously described regimens).
Helicobacter pylori Infection
Another antibiotic-associated indication for probiotics is in patients undergoing therapy to eradicate Helicobacter pylori. In an updated, evidence-based international consensus, experts concluded that probiotics are helpful as adjuvant therapy to prevent or reduce the duration or intensity of associated diarrhea in patients receiving H. pylori treatment. In a randomized, placebo-controlled study, patients taking a standard H. pylori regimen supplemented with probiotics reported a lower incidence of AEs, including diarrhea, and overall treatment tolerability was improved. The probiotic was given during and for 7 days after H. pylori therapy; patients received one of several effective regimens, including Lactobacillus GG (Giflorex, Errekappa Euroterapici) administered twice daily, Saccharomyces boulardii (Codex, SmithKline Beecham) given twice daily, and a combination of Lactobacillus and Biphidobacteria administered twice daily.
Using probiotics in patients who have non-severe chronic constipation and do not have irritable bowel syndrome (IBS) also has been studied. A randomized, double-blind, placebo-controlled study showed that a probiotic beverage containing L. casei Shirota at a dose of 6.5×10 CFU or 65 mL per day for 4 weeks resulted in a significant improvement in both stool frequency and consistency starting in the second week of intervention.23 Another randomized controlled trial found that E. coli Nissle 1917 at a dose of 25×10 CFU for 8 weeks increased stool frequency.
Irritable Bowel Syndrome
In IBS, the data are limited largely by methodological shortcomings, but they are more promising for the diarrhea variant (IBS-D). Controlled trials have shown that B. infantis 35624 at a dose of 1×10 CFU per day for 4 weeks can improve abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining, and the passage of gas. One capsule of B. bifidum MIMBb75 dosed at 1×10 CFU over 4 weeks effectively alleviates global IBS and improves IBS symptoms simultaneously with a subjectively reported improvement in quality of life. Studies examining a number of Lactobacillus species, including L. salivarius UCC4331, L. plantarum DSM9843, L. plantarum LPO1, and L. plantarum 299V, as well as B. bifidum MIMBb75, B. breve BR, and VSL#3, also have shown an improvement in patient-reported symptoms, including flatulence and bloating, but have shown no overall effect on stool quality or frequency.
In various forms of chronic liver disease, the liver—secondary to damage and diverted blood flow—loses the ability to clear ammonia from the body. The increasing levels of ammonia lead to a reversible encephalopathy known as hepatic encephalopathy. Treatment is aimed at either increasing the excretion of or decreasing the production of ammonia. Lactulose, a prebiotic, works via ion trapping coupled with a potent laxative effect. Rifaximin (Xifaxan, Salix) works by decreasing the population of urease-producing bacteria. Probiotics are theorized to work by making the gut environment more favorable for non–urease-producing bacterial species or modifying the pH of the gut lumen, thereby decreasing the production of ammonia and preventing or reversing hepatic encephalopathy.
A randomized controlled trial has shown that a dose of 3 capsules per day containing 112.5 billion viable lyophilized bacteria per capsule, each containing 4 strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus, and L. delbrueckiisubspp bulgaricus), 3 strains of Bifidobacterium (B. longum, B. breve, and B. infantis), and 1 strain of Streptococcus salivarius (subspp thermophilus) was more effective than no treatment for secondary prophylaxis of clinical hepatic encephalopathy, and was as effective as standard lactulose therapy. Overall, however, no mortality benefit has been identified to support the use of probiotics alone in the treatment of hepatic encephalopathy.
Alterations in gut microbiota have been shown to play a role in the pathogenesis of Crohn’s disease (CD) and UC. As with many of the other indications discussed, strong evidence is lacking in IBD because of small sample sizes, variations in probiotic regimens, or variations in dosing. However, in 2 randomized controlled trials, E. coli Nissle 1917 given at a dose of 200 mg per day (2.5-25×10 viable bacteria per capsule) for 12 months was found to be at least as effective as mesalamine in the prevention of relapse of UC during symptom-free periods in patients followed over 1 year. Furthermore, there were no significant differences between mesalamine and E. coli Nissle 1917 in safety and tolerability measures in UC patients.
In CD, the data, again, are minimal and overall show either no significant difference between any studied probiotic strain alone and placebo or, less optimistically, show worse outcomes compared with standard medical therapies. A small randomized controlled trial has shown that a dose of 2×10 CFU of freeze-dried viable B. longum in a gelatin capsule, and a sachet containing 6 g of Synergy I (Orafti, Tienen) given twice daily for 6 months, resulted in an improvement in both endoscopic and histologic scoring of CD compared with placebo alone. This intervention, however, did not lead to improvement in patient-reported symptoms. At the time of this writing, there were no data recommending the use of probiotics alone in the maintenance or induction of remission in CD.
Cautions and Considerations
It is imperative that clinicians consider and discuss contraindications and risks when recommending and prescribing probiotics for patients. Hypothetically, probiotics may translocate out of the gut, causing bacteremia or fungemia, as well as contamination of the product, and, therefore, caution is advised when they are used in immunocompromised, hospitalized, or postoperative patients. In addition, commercially available probiotics may be contaminated with allergens, such as cow’s milk protein, and, therefore, should be avoided in patients with severe allergies.37 An abstract from the Celiac Disease Center presented at the 2018 Digestive Disease Week found that there is significant contamination of probiotics with gluten, and, thus, celiac patients should be cautious when using these products. In addition, there are not enough safety data on the use of probiotics during pregnancy, although published studies thus far have not found any AEs.39 Pregnant women also should avoid any unpasteurized products.
Another important aspect of counseling patients when recommending probiotics is to discuss the utility of eating yogurt as a source of probiotics. Some yogurts made in the United States are pasteurized, a process that kills live bacterial cultures. In addition, studies have shown that live cultures in yogurt may not survive in the low pH of the product; they may not persist during prolonged shelf time or transit through the acidic stomach; and they may not resist degradation in the small intestine by hydrolytic enzymes and bile salts.40 Therefore, it is not known how much of the live cultures reach the distal gut and colonize the microbiota after the above processes, leading to questions about the clinical utility of ingesting yogurt for the probiotic content. Other foods to consider that contain live cultures include kimchi (a Korean fermented cabbage dish), sauerkraut (fermented cabbage), miso (a fermented soybean-based paste), pickles, kombucha (a fermented tea), and apple cider vinegar (made from fermented apple sugars).
The data remain strongest for the use of probiotics in pouchitis at a dose of 3 g per day of VSL#3 for primary prophylaxis, and 6 g per day for secondary prophylaxis. Symptomatic relief of infectious diarrhea also may be achieved with a dose of 6×109 CFU of L. casei strain GG twice a day for 5 days. There is not enough evidence to use probiotics alone to treat C. difficile infection, but there are probiotic regimens that are effective as a preventive measure in people at high risk for infection while they are receiving antibiotic therapy. The evidence for probiotics in IBS and hepatic encephalopathy is promising. With regard to IBD, currently there are not enough supporting data to use probiotics.
When discussing probiotic use with patients, ensure you’ve discussed the risks, benefits, and contraindications of their use. Consider concentrated, rigorously tested probiotic strains, in addition to foods that are able to deliver live bacterial cultures past the initial stages of digestion. Make sure patients are taking the correct regimen for the appropriate indication, and caution them that the data for other diseases are preliminary and likely will advance in the coming years. As such, the recommendations on probiotic strains and dosing may change as research continues in this field.