A Gastroenterologist's Guide to Probiotics

Matthew a. Ciorba, MD

Disclosures

Clin Gastroenterol Hepatol. 2012;10(9):960-968. 

In This Article

Probiotic Therapy for Gastrointestinal Conditions

Acute Onset Infectious Diarrhea

Several RCTs have evaluated the use of probiotics in acute infectious diarrhea. The data are largely from pediatric studies where both prevention and treatment were examined. Trials were conducted across the world with durations of up to 1 year. In the pediatric population, rotavirus has been the most common cause of infectious diarrhea. Data suggest that the benefit of probiotics in preventing acute infectious diarrhea is modest.[15,16]Lactobacillus rhamnosus GG (LGG), Lactobacillus reuteri and Lactobacillus casei all have shown benefit, with an approximate number needed-to-treat (NNT) of 7 children to prevent 1 case of rotavirus in the child care center setting.[17,18,19] With the currently available rotavirus vaccine in consideration, the American Academy of Pediatrics states that probiotics for preventing acute infectious diarrhea are not universally endorsed, but acknowledges that they may have a role in special circumstances.[15] According to the US Center for Disease Control, data are not sufficient to support the use of probiotics such as LGG to prevent traveler's diarrhea of bacterial origin.

The data supporting treatment of acute infectious diarrhea with probiotics are stronger. LGG is the most effective probiotic reported to date, reducing both severity and duration of diarrhea by approximately 1 day.[20,21] The American Academy of Pediatrics supports the recommendation of LGG early in the course of acute infectious diarrhea to reduce symptom duration.[15]

Antibiotic Associated Diarrhea

Antibiotic use is common in children, and diarrhea develops in approximately 20% of those taking antibiotics. Prevention of non–C difficile-related antibiotic-associated diarrhea (AAD) with probiotics has been assessed in RCTs. A 2011 Cochrane Review evaluating more than 3400 patients from 16 studies concluded that the overall evidence suggests a protective effect of probiotics in preventing AAD.[22] Studies using LGG and S boulardii produced the most convincing results.[23] The NNT to prevent 1 case of AAD was approximately 7 in the Cochrane Review. The American Academy of Pediatrics supports the recommendation of probiotics for prevention of, but not treatment of, AAD.[15]

In the adult population probiotics also appear effective in limiting AAD. A meta-analysis evaluating studies on various probiotics and antibiotic regimens published between 1977 and 2005 found that both LGG and S boulardii offered a reduction in risk of AAD development (combined RR 0.31 and 0.37, respectively).[24] Two recent placebo-controlled RCTs evaluated combination probiotic products for the prevention of AAD as their primary end point. Hickson et al used the probiotic mixture currently marketed as DanActive (Dannon) in the United States and found that it significantly reduced AAD (12% vs 34%) in an older cohort of hospitalized patients.[25] A second study evaluated a combination probiotic containing both L casei and Lactobacillus acidophilus (Bio-K+; Bio-K Plus International, Laval, Quebec, Canada) in 255 patients. Patients given the higher dose of probiotic concurrent with antibiotics (and for 5 days afterward) had fewer occurrences of AAD (15.5% vs 44.1%).[26] As a secondary end point, both of these studies also showed a reduction in development of CDAD (discussed below).

C Difficile-associated Diarrhea

C difficile–associated diarrhea is a common nosocomial and community-based medical condition. Typically linked to antibiotic-induced disturbance of the intestinal microbiota, CDAD is now increasingly identified in patients without recent antibiotic exposure.[27] Antibiotic therapy with metronidazole, oral vancomycin, and now fidaxomicin make up the current treatment paradigm.[28] Recurrence of CDAD remains a clinical problem. In 1994, a trial reported that S boulardii (500 mg twice a day) offered for 4 weeks after antibiotic therapy reduced overall CDAD recurrence rates.[29] However, the finding was only significant for those with a history of recurrent CDAD. A follow-up study, designed to be confirmatory, did not find S boulardii to significantly reduce CDAD recurrence after standard therapy.[30] Though a favorable trend was found in patients treated with high-dose vancomycin (2 g/d) in the latter study, the clinical significance of this is less clear. Lactobacillus probiotics have been tested as single species and as combination probiotic products for preventing CDAD recurrence. While some results have been promising, most studies are underpowered, have methodological flaws, or have not been reproduced.[31]

Probiotic-based primary prevention still may be an approach to the current scourge of C difficile. The 2 recent probiotic trials discussed previously in the AAD section suggest that this may be feasible. The Hickson study reported that DanActive (Dannon) supplementation in older hospitalized adults reduced AAD, but also CDAD (0% vs 17% placebo).[25] The study evaluating the combination probiotic Bio-K+ (Bio-K Plus International) also showed a reduction in CDAD in the treated cohort (1.2% vs 23.8% placebo).[26] The high incidence rate of C difficile positivity in the placebo groups (17% and 23.8%) is a criticism for both of these studies. Nonetheless, if confirmatory studies show similar results, these intriguing findings may lead to a paradigm shift in managing older adults requiring antibiotic therapy.

While controversy exists, current society guidelines and expert opinion panels state that existing data are not sufficient to justify recommending available probiotics for preventing primary or recurrent CDAD.[31,32,33]

Irritable Bowel Syndrome

Irritable bowel syndrome is characterized by symptoms of abdominal pain and altered bowel habits which occur over at least 3 months. This common disorder is managed with varying clinical styles as no dominant therapeutic strategy has emerged.[34] The pathophysiology of IBS remains unknown, but several lines of evidence link symptomatic expression of this disorder with the intestinal microbiota. IBS patients may have subtle differences in their luminal and mucosal-associated intestinal microbiota compared with controls.[35,36] New-onset IBS symptoms can develop in up to a third of individuals after recovery from a self-limited episode of infectious gastroenteritis.[37,38] Small-bowel bacterial overgrowth has been reported in a proportion of IBS patients, and antibiotics offer relief of IBS symptoms in some individuals.[39,40] Although controversy exists, bacteria likely contribute to at least some symptoms of IBS.[41]

Several clinical trials have investigated the potential for probiotics as therapy in IBS. These trials are the subject of several single-topic reviews.[42–44] Systematic summarization of these results is complicated by the inclusion of several probiotic strains/species, single or combination preparations, dosing regimens, and unique study designs. Several studies included end points which were not clinically applicable, or demonstrated improvement over baseline, but not compared with placebo.[42] Most studies were short-term only; data on long-term efficacy are still lacking.

A meta-analysis of 3 RCTs suggests that LGG moderately improves pain symptoms in children with IBS (NNT = 4).[45] Traditional IBS treatment end points have not been adequately met in studies of other single strain lactobacillus species in adults.[42] A Bifidobacterium infantis strain (B infantis;[35624] Align, Proctor and Gamble, Cincinnati, Ohio) was evaluated in 2 clinical trials. One study found significant reductions in pain, bloating, bowel movement difficulty, and composite symptom score vs placebo and a lactobacillus species.[46] In a larger follow-up study, reduction in pain and global relief of IBS symptoms were significantly greater in the B infantis–treated group compared with placebo.[47]

General recommendations from the American College of Gastroenterology as well as expert consensus panels from both the United States and in Europe are similar.[32,34,48] There is reasonable rationale for why probiotics may work as treatment for IBS. There are at least some positive controlled studies showing that probiotic supplementation reduces IBS symptoms in some patients. The evidence of benefit is not sufficiently strong to support the general recommendation of probiotics for IBS; however, the benefit appears greatest for bifidobacteria species and certain combinations of probiotics which include bifidobacteria species rather than single species lactobacillus probiotics.

With probiotics, patients might experience a global improvement in symptomatology rather than specific improvement in bowel function. Because treatment options for IBS remain limited in both number and efficacy, a therapeutic trial of probiotics is reasonable for patients interested in this approach.

Inflammatory Bowel Diseases

Evidence points to the intestinal microbiome being a key player in the development and perpetuation of the inflammatory bowel diseases.[49] Defects in the innate immune response to commensal intestinal bacteria resulting in an exaggerated adaptive immune response to these organisms are implicated in the pathogenesis of CD.[50] Several key CD risk genes have functions related to bacterial killing, and antibiotics have therapeutic efficacy in CD and pouchitis.[51,52] Compared with CD, a central role for gut bacteria is less strongly implicated in the pathogenesis of UC.[53] However, the evidence supporting probiotics in patient management is better for UC and pouchitis than for CD.

Several limitations exist with trials which have evaluated probiotic therapy in the inflammatory bowel diseases. These include small cohort sizes, use of different probiotic doses and strains, varied treatment durations, and differences in concurrent conventional treatments. Regardless, patients with inflammatory bowel disease often take or consider taking probiotics and appreciate their clinician having knowledge of the topic.

Crohn's Disease

Probiotic use in the management of CD is not supported by currently available RCT data. Trials have found LGG and other lactobacilli not superior to placebo as an additive to standard care for inducing or maintaining remission in CD or for preventing postoperative relapse.[54–56] There are also no solid data to support the use of ECN or S boulardii in CD.[57]

Ulcerative Colitis

Several published RCTs have shown benefit of probiotics in the management of UC. These studies have examined induction of remission and maintenance of remission typically by comparing the probiotic with oral mesalamine or adding the probiotic to standard therapy. ECN at 200 mg/d was similar in efficacy to 1500 mg of mesalamine for maintaining UC in remission.[58]

High dose VSL#3 (3.6 trillion colony-forming units per day; Sigma-Tau Pharmaceuticals, Inc, Towson, MA) has shown therapeutic efficacy in 2 RCTs evaluating patients with mild-to-moderately active UC. When offered to UC patients having a flare while taking mesalamine or an immunomodulator, the probiotic cohort demonstrated improved symptom-based disease activity indexes and rectal bleeding, but not endoscopic scores, compared with the placebo group.[59] A study conducted in India included 144 adults with relapsing UC and showed the VSL#3 group to have significantly higher remission rates (42.9% vs 15.9%) and endoscopic healing (32% vs 14.7%).[60] Most patients in both groups remained taking a stable dose of mesalamine therapy. A high dropout rate in both groups (29% VSL#3, 59% placebo) was a limitation of the latter study. VSL#3 was also shown to improve rates of induction and maintenance of remission in children with UC (n = 29 total).[61] Recent Cochrane reviews conclude that there are insufficient data to demonstrate that probiotics have efficacy in maintaining remission in UC; however, they have not recently addressed induction of remission in UC.[62] Single strain Lactobacillus and Bifidobacterium (infantis,35624 Align, Proctor and Gamble) probiotics did not show efficacy for maintaining UC remission in clinical trials.[63,64]

In summary, the overall evidence suggests that ECN and VSL#3 have modest efficacy, similar to and perhaps complementary to mesalamine, in inducing and maintaining remission for mild-to-moderately active UC.

Pouchitis

Chronic or recurrent pouchitis is an important complication occurring in approximately 10% to 20% of UC patients after ileal anal pouch formation surgery. VSL#3 (Sigma-Tau Pharmaceuticals, Inc) was shown beneficial in prophylaxis against pouchitis onset after surgical take-down[65] and in maintaining clinical remission after antibiotic induction.[66,67] These trials were conducted in Europe and included approximately 20 patients per group. A practice-based report from the Cleveland Clinic found only 19% of patients (6 of 31) who started taking VSL#3 after treatment with antibiotics to still be taking the probiotic at 8 months.[68] A single study from the Netherlands found that compared with a historical cohort, patients taking LGG had a delayed onset of pouchitis at 3 years (7% vs 29%).[69]

Clinical expert-generated guidelines concur that probiotics (VSL#3) can be effective for preventing recurrence of pouchitis.[32,70,71]

Complications of Chronic Liver Disease/Hepatic Encephalopathy

Luminal microbiota play an important role in the pathogenesis of both spontaneous bacterial peritonitis and hepatic encephalopathy. Ammonia produced by gut bacteria is believed to play a key role in hepatic encephalopathy. Antibiotics are employed in clinical practice to reduce severity or frequency of both these chronic liver disease complications. Lactulose, a mainstay of therapy, is a prebiotic for lactobacilli which can limit bacterial ureases.

The role for probiotics in these disorders is an area of ongoing investigation.[72] Treatment of hepatic encephalopathy with L acidophilus was studied as early as 1965.[73] More recently, Liu and colleagues offered a probiotic and prebiotic mixture to 97 patients with minimal hepatic encephalopathy and observed a reduction in ammonia levels and improvement in encephalopathy.[74] Another group found that a yogurt-based probiotic supplement significantly improved quantitative measurements of minimal hepatic encephalopathy in patients with nonalcoholic cirrhosis.[75] The latter group is now completing a more comprehensive trial using the probiotic LGG in a similar patient cohort.[76]

Society guidelines and expert consensus panels do not currently support a recommendation of probiotic use for any chronic liver disease–associated condition.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....