2Centre for Gastroenterology, Royal Free Hospital, London, NW3 2QG, UK
Keywords: Diarrhea; Probiotics; Dysbiosis; Inflammatory Bowel Diseases; Bifidobacterium; Lactobacillus
One way of boosting the natural beneficial bacteria in the gastrointestinal tract is by increasing the level of prebiotics in the diet. Prebiotics are forms of carbohydrate that only the gut bacteria can feed upon. Good sources of prebiotics in the diet include bananas, onions, garlic, asparagus, artichoke and chicory. These foods can cause unwanted side effects however e.g. bloating and increased bowel frequency, so some prefer to consume healthy bacteria instead and thus take a probiotic product. Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host . Probiotics may elicit immunomodulatory effects through direct interactions with the intestinal epithelium, especially in the small intestine, which is less densely populated by the commensal microbiota . By contrast, probiotic immunomodulatory effects in the colon, where microbiota are densely populated, are more likely to occur via modulation of the endogenous microbiota .
There are a few possible mechanisms by which modulation of the gut microbiota specifically improves gastrointestinal disorders, although none of this is fully understood yet.
In Irritable Bowel Syndrome (IBS), probiotics and synbiotics (probiotic and prebiotic) can correct bacterial imbalances (dysbiosis) when increased intestinal permeability and barrier dysfunction exist . A decrease in microbial biodiversity and increase in fungi has been found in mucosa and faeces of IBD patients; pre- and probiotics can modulate gut microbiota . The leading hypothesis for IBD and pouchitis is that dysbiosis plays an active role in inducing and maintaining persistent inflammation. The dysbiosis in pouchitis patients is characterised by reduced diversity of the microbiota, which may lead to abnormal mucosal immune regulation triggering the inflammatory processes in genetically predisposed patients . Thus treating the dysbiosis is considered a treatment. In cancer, dysbiosis in the human gut microbiota after chemotherapy may favour colonisation with C. difficile and Enterococcus faecium, thus introducing competitive probiotic bacteria back into the gut may offer protection . Unlike chemotherapy, it is not known which specific bacteria are involved in causing diarrhoea during pelvic radiotherapy, but there is evidence that dysbiosis occurs as a result of this treatment . C. difficile is a bacterial infection in itself, resulting from gut microbiota dysbiosis. High numbers of protective bacteria, have been shown to reduce incidence of C. difficile infection as it is thought that some bacteria are better at competing than C. difficile . Preventing dysbiosis is the key here, as modulating gut bacteria after infection proves difficult. In travellers’ diarrhoea, the potential mechanisms by which balanced gut microbiota fights infectious diarrhoea include exclusion of pathogens by means of competition for binding sites and available substrates, lowering of luminal pH and production of bacteriocins, and promotion of the production of mucus . Quite differently, in lactose intolerance, when some probiotics are introduced into the gut, they produce beta- galactosidase or lactase intracellularly that may assist in the digestion of lactose. These enzymes may alleviate clinical symptoms brought about by undigested lactose for other reasons (influence of colonic flora, the colonic pH), and hydrogen production .
There are many controversies regarding probiotics. Some of these are around which type of patients can benefit from their use, or even be put at risk from their use. For example, during immunosuppression and critical illness, fungemia is theoretically possible from yeast probiotics such as S. boulardii. Other controversy includes the difficulty in drawing conclusions from heterogeneity of probiotic studies (Table 1). Due to such uncertainty and limited evidence, the use of probiotics is confusing for both doctor and patient.
There are many different types of probiotics which are available, some in liquid form such as fermented milk drinks and yoghurts, as well as in supplements in the form of tablets, capsules or sachets. The most commonly used probiotics for diarrhoea disorders include: , Lactobacillus acidophilus (L. acidophilus), Lactobacillus brevis (L. brevis), Lactobacillus casei (L. casei), Lactobacillus rhamnosus strains (L. rhamnosus/ L. rhamnosus GG), Bifidobacterium brevis (B. brevis), Bifidobacterium lactis (B. lactis), Bifidobacterium longum (B. longum) and Streptococcus thermophilus (S. thermophilus). These probiotic bacteria have been used in relation to travellers’ diarrhoea, IBS, cancer, IBD, pouchitis, Clostridium difficile (C.difficile) and lactose intolerance. Undoubtedly, the combination of bacterial species and dose is important, however defining the most appropriate probiotic has been largely been based more on marketing, rather than the best evidence.
Number of colony forming units used/alive in dose
Form of product: powder/capsule/dairy drink or yoghurt
Single strain vs. multi strain doses
Inclusion of prebiotics in the dose or diet
Type of patient population
Number of patients treated
Randomisation, controls and blinding of clinical trials
Studies have demonstrated mixed results when administering probiotics to travellers. For example in a RCT study of travellers to Egypt, a mixture of L. acidophilus, B. bifidum, L. bulgaricus, and S. thermophilus or placebo, reduced the frequency of diarrhoea (43% versus 71% in the placebo) . Oksanen et al.  compared L. rhamnosus GG with placebo in travellers’ to Turkey, and found a reduction in diarrhoea (23.9% versus 39.5% in the placebo group). A double blinded placebo-controlled trial of L. rhamnosus GG in United States travellers’ also showed a significant effect, with diarrhoea developing in 3.9% per day at risk compared with 7.4% in the placebo group .
However, other studies have failed to show a beneficial effect. In 50 travellers’ to Mexico, prophylactic ingestion of a mixture of L. acidophilus and L. bulgaricus was not effective in reducing the frequency or duration of new-onset diarrhoea . In a study of British soldiers who were deployed to Belize, there was no significant difference in the prevalence of diarrhoea between groups that received administered Lactobacillus. fermentum strain KLD, L. acidophilus or placebo. There were no significant differences in the incidence of diarrhoea between any groups after 3 weeks (23.8%, 25.7% and 23.8% respectively) .
A meta-analysis of 12 published RCT’s which met inclusion and exclusion criteria and found that S. boulardii and a mixture of L. acidophilus and B. bifidum probiotics appear the best at preventing travellers’ diarrhea .
A prospective study of 96 individuals returning from abroad with at least 11 days of travellers’ diarrhoea already, were given 150-450mg S. boulardii which on average halted diarrhoea within 5 days. 67% of these patients had previously tried anti-diarrhoeal agents or antibiotics, however only S. boulardii worked .
The problem with all the studies is knowing what should be the correct combination of bacterial species within a probiotic therapy and in what dose to prescribe them. Additionally, different types of travellers’ diarrhoea from different countries may require different probiotic species.
It is however important to note that effects are strain specific for each IBS symptom and one strain does not fit all . Four review articles of probiotics in IBS [27-30] were subject to a meta-analysis which concluded that probiotics could improve the global IBS symptom score and reduce abdominal pain, but may not significantly affect specific IBS symptoms of diarrhoea, constipation, and/or bloating .
A Canadian systematic review of 19 RCT’s and concluded probiotics appear to be efficacious in IBS, but the magnitude of benefit and the most effective species and strain are uncertain . Three studies of three probiotics evaluated diarrhoea as a secondary end point. Two studies reported no difference between specific probiotic treatments and placebo [33,34] and one study reported a significant increase of diarrhoea with the probiotic compared with placebo . A review of 42 RCT’s looked at the effect of lactic acid bacteria on IBS symptoms . Thirty-four of these trials reported benefit in at least one of the end points studied, but only the VSL#3 mixture (L. acidophilus, L. bulgaricus, L. casei, L. plantarum, S. thermophilus, B. breve, B. infantis, B. longum) was found to reduce diarrhoea . Another review of 16 RCT’s found that 11 trials were not blinded well enough, were too short/small, and/or lacked intention to treat analysis , but they concluded that only Bifidobacterium infantis [39,40] showed significant improvements in bowel movements compared with placebo.
Most recently, a European Consensus Committee following systematic review of the literature and a Delphi process of consensus concluded specific probiotics help reduce overall symptoms burden and abdominal pain in some IBS patients. Symptom improvement includes reduced bloating, distension and improvement in bowel frequency and some probiotics improved quality of life .
Conclusion: A mixture of bacterial strains including lactobacillus and bifidobacteria may be the most effective in IBS collective symptoms with a good safety record and are thus appropriate for therapeutic trial in holistic IBS therapy.
Three studies using L. rhamnosus GG concluded no effects in Crohn’s disease [43-45]. In addition, a meta-analysis on eight clinical trials looking at different probiotic strains confirmed this lack of benefit . There is limited evidence that S. boulardii probiotic given in conjunction with mesalazine can increase remission time , The British Dietetic Association 2013 guidelines concludes that there does not appear to be a benefit for probiotic use in Crohn’s disease patients .
Using probiotics in Ulcerative Colitis (UC) can induce remission . Studies using preparations containing mainly bifidobacteria and commercial mixtures, including VSL#3 [50– 56] revealed efficacy in the maintenance therapy of UC patients. In a meta-analysis of 23 RCT’s only VSL#3 significantly increased the remission rates compared with controls in patients with active UC  and the most recent meta-analysis states that the same formulation is also safe and more effective than conventional therapy alone in achieving higher response and remission rates in mild to moderately active ulcerative colitis  .
Up to 60% of patients following proctocolectomy and ilealanal pouch formation develop an inflammatory condition often associated with bowel urgency and frequency, termed pouchitis. There appears to be a derangement in the pouch microbiome hence benefit has been shown for both antibiotics and probiotics.
Studies have tended to be small and of variable length. One study used the probiotic L. rhamnosus GG ; the other studies used combination of probiotics [60–64], including VSL#3. The comparison was made to placebo-treated control groups receiving maize starch or microcrystalline cellulose. The clinical efficacy of the probiotic intervention was evaluated based on clinical, histological, endoscopic and microbiological criteria, including the pouchitis disease activity index. The five studies using high dose probiotic mixture demonstrated clinical efficacy in pouchitis [60-64]. The study using L. rhamnosus GG alone observed alterations in intestinal microbiota but no other effects on clinical parameters . In the most recent meta-analysis of 23 RCT’s, only VSL#3 significantly reduced the clinical relapse rates for maintaining remission in patients with pouchitis . Primary prevention of pouchitis and reducing the likelihood of relapse after successful antibiotic treatment has led to the highest possible rating, an ‘A’ recommendation .
Conclusion: Probiotics, especially those containing multiple strains can maintain remission in ulcerative colitis and also demonstrate efficacy in pouchitis. There is currently no evidence for probiotics in Crohn’s disease.
In a study of hospitalized patients, L. acidophilus alone or in combination with L. casei appears to prevent C. difficile infection [71-74]. A dairy drink including Lactobacillus casei, Lactobacillus delbrueckii subsp. bulgaricus and S. thermophilus also reduces rates of C. difficile infection . A meta-analysis of 6 trials found the relative risk of getting antibiotic associated diarrhoea is significantly reduced while taking L. rhamnosus GG .. Despite the evidence, probiotics were considered insufficient to classify as the high grade ‘A’ recommendation in C. difficile associated diarrhoea .
In 2013, a more recent review and meta-analysis of 23 RCT’s, including 4213 patients, suggests moderate quality evidence that probiotics are both safe and effective for preventing C. difficileassociated diarrhoea . A further systematic review and meta-analysis of 16 studies found that probiotics were safe and effective for use in preventing antibiotic associated diarrhoea and C. difficile in inpatients requiring antibiotics . They also conclude that Lactobacillus based products are slightly better than the others to prevent this type of diarrhoea and infection .
Conclusion: Lactobacillus species appear to be the most effective in preventing C. difficile infections, but more randomised trials need to be undertaken to identify whether a single strain or a mixture of probiotics work best.
Conclusion: There is a benefit from taking probiotics in lactose intolerance. There is most evidence for L. rhamnosus and bifidobacterium, often in combination.
Components in our diet may affect the gut microbiota and influence colorectal oncogenesis. Excess fat in the diet means that more bile will be produced and more bile acids will escape the enterohepatic circulation. In the colon, these can be metabolised to mutagenic components . Probiotics such as Lactobacilli metabolise heterocyclic amines and are not fermented . Meat cooked at high temperatures contains high levels of heterocyclic amines which have been found to be fermented by gut microbiota and the byproducts of this process can damage DNA and increase the risk of colorectal cancer . There is a completed Phase 2 trial assessing the role of probiotics on gut microbiota and colorectal cancer but the results have not been published yet . The role of the VSL#3 probiotic combinations in rectal cancer is being investigated in a phase 3 clinical trial and results are also due .
Some cancer therapies can be associated with gastrointestinal disturbance often including diarrhoea. The role of probiotics has been assessed in these patients. There is more information for patients with colorectal cancer , than other cancers at present. The theoretical risk of giving probiotics to potentially immunocompromised patients appears not to be substantiated in published studies although S. boulardii has been associated with fungemia [90-92]. In one randomised study of 150 patients diagnosed with colorectal cancer, half were given L. rhamnosus GG supplementation during 5-FU-based chemotherapy. L. rhamnosus GG was well tolerated and reduced the frequency of of grade 3 or 4 diarrhoea (22% v's 37%) and abdominal discomfort related to 5-FUbased chemotherapy . In another study, 398 men and women who were free from tumour but who had at least two colorectal tumours removed were given wheat bran and/or L. casei. It was found that L. casei prevented atypia of colorectal tumours . A study of 31 subjects undergoing elective colorectal resection for cancer ware given a mixture of B. longum and L. johnsonii. It was found that only L. johnsonii adhered to the colonic mucosa and affects intestinal microbiota by reducing the concentration of pathogens and modulates local immunity . In a study of 37 high grade dysplastic, cancer and 43 polypectomized patients were given a synbiotic preparation of oligofructose- enriched inulin, L. rhamnosus GG and B. lactis. The number of stool Bifidobacterium and Lactobacillus increased, stool Clostridium perfringens decreased, and there was a reduction of colorectal proliferation . Additionally in another study, 50 patients with colorectal carcinoma scheduled for radical colorectomy were given probiotics containing Lactobacillus plantarum, L. acidophilus and B. longum, for 16 days (six days preoperatively and ten days postoperatively). The treatment decreased the rate of postsurgical infection .
Patients undergoing radiotherapy may also benefit from probiotic use. Radiotherapy to the pelvic area often results in radiation–induced diarrhoea. In one study, B. bifidum and L. acidophilus significantly reduced both diarrhoea and use of antidiarrhoeal agents in 32 women undergoing chemo (cisplatin) -radiation therapy for cervical cancer . In a larger study of 251
A selective benefit of S. boulardii and a mixture of L. acidophilus, B. bifidum, L. bulgaricus and S. thermophilus probiotics as prophylaxis of travellers’ diarrhoea. S. boulardii may be useful in treating travellers’ diarrhoea where other medical treatments have failed.
Irritable Bowel Syndrome
A mixture of bacterial strains including lactobacillus and bifidobacteria may be the most effective in IBS collective symptoms with a good safety record and are thus appropriate for therapeutic trial in holistic IBS therapy.
Inflammatory Bowel Syndrome
Probiotics, especially those containing multiple strains can maintain remission in ulcerative colitis and also demonstrate efficacy in pouchitis. There is currently no evidence for probiotics in Crohn’s disease.
C. difficile and antibiotic associated diarrhoea
Lactobacillus species appear to be the most effective in preventing C.difficile infections.
There is benefit from taking probiotics in lactose intolerance. There is most evidence for L. rhamnosus and bifidobacterium, often in combination.
Probiotics, mainly lactobacillus and bifidobacteria, have a beneficial role in the care of patients with diarrhoea associated with chemotherapy and radiotherapy.
Conclusion: Probiotics, mainly lactobacillus and bifidobacteria, have a beneficial role in the care of patients with diarrhoea associated with chemotherapy and radiotherapy.
Defining the optimal dose and combination of probiotic species is a difficult task, especially when diet will also play an important factor. There is however good evidence for the role of probiotics in diarrhoeal disorders and the development of well structured, RCT’s are required.
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