Probiotics for gastrointestinal diseases

INTRODUCTION — The intestinal tract is host to a vast ecology of microbes that are necessary for health, but also have the potential to contribute to the development of diseases in susceptible individuals by a variety of mechanisms. Genetic or environmentally triggered perturbations in intestinal epithelial barrier function or innate immune bacterial killing, for example, can lead to an inflammatory response caused by increased uptake of bacterial and food antigens that stimulate the mucosal immune system [1-4]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)

Interactions between intestinal microbes and the host are the subject of intensive ongoing research since they may influence a variety of diseases. Part of this research involves the deliberate manipulation of the intestinal microbiota with a therapeutic intention. The greatest experience has been in the inflammatory bowel diseases, ulcerative colitis, Crohn disease, pouchitis, and irritable bowel syndrome, although clinical trials are emerging in several other conditions.

There are four general methods by which the intestinal microbiota can be altered: administration of antibiotics, therapeutic diets and prebiotics (ie, dietary components that promote the growth and metabolic activity of beneficial bacteria), probiotics (ie, beneficial bacteria), or fecal microbial transplant (FMT). Combination of these methods is also possible (synbiotics). Interest in these approaches has extended well beyond the clinical sciences since a role for intestinal microbes in health and disease has been recognized in alternative and complementary forms of medicine for many years [5]. In a case control study, 51 percent of ulcerative colitis patients and 43 percent of patients with Crohn disease used probiotics compared with 21 percent of healthy controls [6]. In comparison, systematic evaluation of the efficacy of probiotics is relatively recent. This topic review focuses on clinical trials of probiotics in gastrointestinal diseases.

DEFINITION — Probiotics are microorganisms that have beneficial properties for the host. Most commercial products have been derived from food sources, especially cultured milk products. The list of such microorganisms continues to grow and includes many strains of lactic acid bacilli (eg, Lactobacillus and Bifidobacterium), a nonpathogenic strain of Escherichia coli (eg, E. coli Nissle 1917), Clostridium butyricum, Streptococcus salivarius, and Saccharomyces boulardii (a nonpathogenic strain of yeast). Also under development are strains of bacteria that have been genetically engineered to secrete immunomodulators (such as interleukin-10, trefoil factors, or defensins, or express altered surface proteins such as lipoteichoic acid), which have the potential to favorably influence the immune system [7-9]. More recently, the concept of restoring levels of protective commensal bacterial species that are diminished in certain disorders, such as Crohn disease, has been advanced [4,10-14].

Studies of selected probiotic species (given alone or in combination) have suggested potential efficacy in several gastrointestinal illnesses, the best studied of which are the inflammatory bowel diseases (particularly pouchitis) [4,15-22]. Therapeutic benefit has also been suggested in several other disorders, including antibiotic-related diarrhea, Clostridioides difficile toxin-induced colitis, infectious diarrhea, hepatic encephalopathy, irritable bowel syndrome, and allergy [23-27].

Some of the more commonly available probiotics include:

●VSL#3 (Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. bulgaricus, Streptococcus thermophilus) [Note: Studies before 2015 were all performed with the original Italian (DeSimone) preparation]). The United States VSL#3 formulation is somewhat different and has different functional properties [28].

●Align (B. infantis)

●Culturelle (L. rhamnosus GG)

●DanActive (L. casei)

●Mutaflor (E. coli Nissle 1917)

●Florastor (S. boulardii)

MECHANISMS OF BENEFIT — Mechanisms for the benefits of probiotics are incompletely understood. However, four general benefits have been described [4,29-31]:

●Suppression of growth or epithelial binding/invasion by pathogenic bacteria [32].

●Improvement of intestinal barrier function [33-35].

●Modulation of the immune system. Several probiotic species or their products induce protective cytokines, including IL-10 and TGF-beta, and suppress proinflammatory cytokines, such as TNF, in the mucosa of patients with pouchitis, ulcerative colitis, and Crohn disease, in murine experimental colitis, and in isolated splenocytes [10,11,30,32,34,36-41]. S. boulardii limited the migration of T-helper 1 cells in inflamed colon tissue in a mouse colitis model and Lactobacillus casei protects from experimental colitis by inducing TLR-2-mediated regulatory T cells [42,43].

●Modulation of pain perception. Some Lactobacillus strains appear to induce expression of micro-opioid and cannabinoid receptors in intestinal epithelial cells and mediate analgesic functions in the gut in a manner similar to the effects of morphine [44].

Probiotics differ in their ability to resist gastric acid and bile acids, colonize the intestinal tract, and influence cytokines secreted by intestinal epithelial cells [34,36,41,45-50]. Thus, not all probiotics are alike; as a result, benefits observed clinically with one species or with a combination of species are not necessarily generalizable to another [51].

Although yogurt is commonly recommended as a source of probiotics, not all of the live cultures contained in yogurt survive well in an acidic environment nor do they colonize the microbiota efficiently [52,53]. Furthermore, the residual lactose contained in yogurt can increase symptoms in patients with lactose intolerance, including those who develop secondary lactose intolerance due to an antecedent gastroenteritis (a setting in which probiotics have been recommended). Fermented dairy beverages, such as kefir, that contain much higher concentrations of live cultures than yogurt or cultures that are relatively resistant to gastric acid are also available [54]. Of interest, a fermented food diet increased diet microbiota diversity and decreased inflammatory markers to a greater extent than did dietary fiber [55].

Interesting observations indicate that it may not be necessary to administer living organisms to achieve a benefit. Secreted proteins and DNA of one probiotic preparation (VSL#3, Nature's Pharmaceuticals, Inc.) blocked cytokine activation and prevented apoptosis of epithelial cells [56,57]. The effects depended upon the specific DNA from the different bacterial species that were components of the preparation [56]. Non-methylated DNA from VSL#3, as well as other randomly selected E. coli strains, suppressed experimental colitis in several animal models [58]. These therapeutic effects are mediated through toll-like receptor 9 and with induction of type 1 interferons alpha/beta [59]. Defined molecular weight proteins from other probiotic species, including Lactobacillus GG, can also inhibit proinflammatory signaling and inflammatory cytokine-induced apoptosis in colonic epithelial cells through an epidermal growth factor receptor (EGFR)-dependent mechanism [34,35], while secreted products from a variety of species can inhibit cytokine production [10]. Similarly, heat-killed Lactobacillus casei Lbs2 induces regulatory T cell via TLR2 signaling [43], while native microbial products, such as flagellin from Roseburia intestinalis, can target the NLRP3 inflammasome and pyroptosis [60].

Some studies demonstrate that products of endogenous resident microbiota can have beneficial effects, creating opportunities for therapeutic manipulation beyond the traditional Lactobacillus and Bifidobacterium species. For example, Faecalibacterium prausnitzii, which is decreased in Crohn disease, secretes yet to be defined products that suppress experimental colitis and proinflammatory cytokines [10], and polysaccharide A of Bacteroides fragilis stimulates regulatory T cells in a TLR2, IL-10-dependent fashion [61]. Likewise, outer membrane vesicles from E. coli Nissle attenuated experimental colitis [62]. Clostridium species comprising Groups IV and XIVA, which are selectively decreased in active IBD patients, can induce IL-10 producing regulatory T cells [11,63]. This approach will likely be available for therapeutic use in the near future [13,14].

The use of probiotics to manage gastrointestinal disorders has received intense interest for the past several decades, but documentation of their efficacy and safety has suffered from the lack of large rigorous trials. This, in part, is because probiotics are classified as food additives and, therefore, are not required to undergo US Food and Drug Administration approval for use. Efficacy of existing data is summarized by two rigorously structured technical reviews by the American Gastroenterological Association (AGA) and the Cochrane Collaboration [25,51].

GASTROINTESTINAL INFLAMMATION

Pouchitis — For the surgical treatment of ulcerative colitis and familial adenomatous polyposis, proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the favored alternative to proctocolectomy with permanent ileostomy since it preserves intestinal continuity and sphincter function and removes almost all of the colorectal mucosa. This procedure consists of total abdominal colectomy and the construction of a J or S-shaped ileal pouch that is anastomosed to the anus.

The most frequently observed long-term complication of IPAA is acute and/or chronic inflammation of the ileal reservoir, called pouchitis. Symptoms of pouchitis include increased stool frequency, urgency, hematochezia, abdominal pain, fever, and extraintestinal manifestations of inflammatory bowel diseases (see "Pouchitis: Epidemiology, pathogenesis, clinical features, and diagnosis"). Pouchitis affects approximately 20 percent of ulcerative colitis patients in the first year after creation of the IPAA and 50 percent of patients after five years, but less than 1 percent of patients with colectomies to treat familial polyposis.

Detailed studies of the microbiota in patients with pouchitis have demonstrated unique patterns, including the persistence of Fusobacteria and enteric species, increased Clostridium perfringens, and the absence of Streptococcus and Faecalibacterium species in the inflamed pouch [64-67]. These observations and a high rate of response to various antibiotics support an important role for bacteria in the pathogenesis of pouchitis and provide a rationale for clinical trials aimed at altering the microbiota with probiotics.

Small controlled trials have suggested that at least one probiotic preparation (VSL#3; original Italian formulation) containing 5 X 10(11) per gram of four Lactobacillus species, three Bifidobacterium species, and one strain of Streptococcus salivarius subspecies thermophilus may be effective in prevention of recurrent pouchitis after antibiotic induction of remission.

●A randomized, placebo-controlled trial included 40 patients with a history of chronic, relapsing pouchitis who were placed into clinical and endoscopic remission with broad-spectrum antibiotics [68]. Patients were randomly assigned to VSL#3 6 g/day or placebo. After nine months of daily treatment, significantly fewer patients in the probiotic group had experienced a relapse (15 versus 100 percent). Within three months of stopping treatment, all patients in the VSL#3 group had relapsed. Likewise, fecal Lactobacillus and bifidobacteria concentrations returned to pretreatment levels within one month after therapy was discontinued, indicating that permanent colonization with the probiotic species did not occur.

●A second study from the same group and investigators in London included 36 patients with recurrent or refractory pouchitis who had required antibiotics at least twice in the previous year [69]. After achieving remission with antibiotics, patients were randomly assigned to VSL#3 or placebo once daily for one year. Significantly more patients in the probiotic group remained in remission (85 versus 6 percent). Patients randomized to VSL#3 also had significantly better quality of life.

●A third study from the Gionchetti group included 40 consecutive patients who underwent IPAA for ulcerative colitis [70]. Patients were randomly assigned to receive VSL#3 3 g/day or placebo immediately after ileostomy closure for one year. Patients receiving the probiotic had significantly fewer episodes of pouchitis (10 versus 40 percent). Probiotic treatment was also associated with significant improvement in quality of life compared with placebo.

●Different conclusions were reached in an observational study in the United States that involved 31 patients with antibiotic-dependent pouchitis who were treated with VSL#3 after achieving remission with ciprofloxacin [71]. After eight months, only a minority of patients remained on probiotic therapy and in symptomatic remission (most having stopped it due to recurrence of symptoms or adverse effects).

Other studies have demonstrated a benefit from other probiotics including Lactobacillus rhamnosus GG, Lactobacillus plantarum 299, and B. infantis [44,72,73]. Several systematic reviews have suggested that VSL#3 may be more effective than placebo for preventing relapse of chronic pouchitis and preventing onset of pouchitis [21,74]. However, both the AGA Systematic Review and two Cochrane database systematic reviews judged that the quality of the supporting evidence was very low [21,51,75].

Ulcerative colitis — Convincing data to support the use of probiotic preparations in ulcerative colitis are lacking [51,76-79]. Although various probiotic species have shown promise in the treatment of ulcerative colitis, because of the small number of patients in these studies and the risks associated with probiotics, systematic reviews have reached variable conclusions regarding the use of probiotics for the induction and maintenance of remission of ulcerative colitis [22,25,80,81], but publication bias may influence results.

The following observations were made in randomized trials:

●E. coli 1917 Nissle was as effective as low dose 5-ASA in preventing relapse of ulcerative colitis in adults [82,83] and in an open label trial in children [84]. Rectal administration of E. coli 1917 Nissle enemas had equivocal results [85].

●Lactobacillus GG appeared to be more effective than standard treatment involving mesalazine in prolonging relapse-free time, but did not influence relapse rates in patients with quiescent ulcerative colitis [86].

●The combination of a prebiotic and a probiotic (B. longum) was associated with improvement in histologic scores and measures of immune activation in a one-month randomized controlled trial [87].

●The combination of the original VSL#3 preparation plus balsalazide was slightly more effective than balsalazide or mesalazine alone in a randomized trial of patients with acute mild-to-moderate ulcerative colitis [88]. A randomized trial involving 29 children with ulcerative colitis found that VSL#3 was more effective than placebo in maintaining remission (73 versus 21 percent at one year) when given in conjunction with steroid induction and mesalamine maintenance treatment [89].

●Emerging evidence suggests that VSL#3 can induce remission and reduce disease activity in patients with mild/moderate active ulcerative colitis [90-93]. A randomized trial of 77 patients found that VSL#3 was more effective than placebo in improving the ulcerative colitis disease activity index (UCDAI) by 50 percent at six weeks (33 versus 10 percent) and inducing remission at 12 weeks (43 versus 16 percent) [90]. A second randomized trial examined 144 patients who were receiving a 5-ASA, azathioprine, and/or methotrexate [93]. The trial similarly found that patients who received VSL#3 were more likely to have at least a 50 percent decrease in the UCDAI after eight weeks compared with patients who received placebo (63 versus 41 percent). Remission rates were also higher in the VSL#3 group (48 versus 32 percent). However, histologic scores were not significantly improved with VSL#3 therapy.

●A small, double-blind, placebo-controlled trial showed no significant difference in the rates of maintenance of remission in patients with left-sided ulcerative colitis randomized to 52 weeks of L. acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12 or placebo (relapse rate 75 versus 92 percent) [94].

●Another small, double-blind, placebo-controlled study reported significantly lower clinical and endoscopic disease activity in pediatric patients with ulcerative colitis treated with Lactobacillus reuteri ATCC 55730 [95].

●A two-year comparison of low-dose mesalamine alone versus mesalamine plus L. salivarius, L. acidophilus, and B. bifidus BGN4 showed improved outcomes with adjunctive probiotics [96].

Crohn disease — Clinical trials of probiotics in Crohn disease have shown mixed results. The reasons for the heterogeneity are unclear, but could be due to several factors such as the specific probiotics (and doses) used, differences in study duration, characteristics of the included patients (eg, location of disease), and endpoints that were measured. Likewise, use of probiotics in prevention of postoperative recurrence of Crohn disease has been unsuccessful [97].

In the aggregate, the available data do not support clinical effectiveness of probiotic therapy for either induction or maintenance of remission in patients with Crohn disease [25,26,51,78,80,98-100]. Whether certain patient subgroups might benefit remains to be determined. A report of clinical improvement with combination of a probiotic, B. longum, and a prebiotic [101] suggested the possibility of using a synbiotic approach to treating Crohn disease, although previous reports with other agents were less positive. While probiotics administration is generally regarded as safe, toxicity can occur in the setting of immunosuppression and enhanced mucosal permeability, as evidenced by Lactobacillus-induced sepsis in a Crohn disease and HIV-infected patient taking a self-made yogurt [102].

Diverticular colitis — Infrequently, patients with diverticular disease develop a segmental colitis, most commonly in the sigmoid colon, which can occasionally be symptomatic. Combination therapy with VSL#3 and oral beclomethasone dipropionate (a locally acting corticosteroid not available in the United States) was beneficial in a case series. (See "Segmental colitis associated with diverticulosis".)

Radiation enteritis — A meta-analysis of six randomized controlled trials of probiotics in radiation-induced diarrhea detected slight overall benefit in diarrhea, but no difference in Bristol Stool Scales or antidiarrheal mediation use [103]. Results of individual studies were variable. Basic research indicates that intestinal bacteria contribute to radiation-induced injury and repair, so this therapeutic application is open to investigation [104]. Lachnospiraceae and their short-chain fatty acids and tryptophan metabolites were associated with survival to total body irradiation in a mouse model [105].

DIARRHEAL ILLNESSES

C. difficile infection — Issues related to probiotics and C. difficile infection are discussed separately. (See "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Alternative therapies'.)

Infectious diarrhea — The use of probiotics in children with presumed acute infectious diarrheal illness has no benefit. Probiotic use in adults with acute infectious gastroenteritis is unproven. Older systematic reviews have demonstrated a modest reduction in the duration of infectious diarrhea with the use of probiotics, although there was heterogeneity among studies [25,106-111]. However, two large prospective, randomized multicenter trials demonstrated no benefit of various commonly used probiotic strains on clinical progression or duration of symptoms in infants and young children seen in emergency rooms for early acute gastroenteritis [112-114]. These studies led a European Society for Pediatric Gastroenterology, Hepatology, and Nutrition working group to conclude that evidence supporting benefits of various probiotics in managing acute gastroenteritis in children was weak, low to very low certainty, while evidence of the lack of benefit for combinations of Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0052 was strong [115]. Likewise, the AGA Technical Review on probiotics in gastrointestinal diseases concluded that probiotics were not beneficial for treating children with acute gastroenteritis (moderate evidence) [51].

Data to support the specific type, dose, or duration of probiotic and the mechanism of protection from specific etiologic agents are limited. It is also unclear whether probiotics reduce important complications of diarrheal illness such as dehydration and malnutrition.

●A 2010 meta-analysis that included 63 randomized controlled trials (using several different probiotic preparations) in adults and children found that probiotics reduced the overall risk of diarrhea lasting four or more days by 59 percent (relative risk 0.41, 95% CI 0.32-0.53) and the mean duration of diarrhea by 25 hours (95% CI 16-34 hours) [110]. The two most commonly studied probiotics were Lactobacillus GG and S. boulardii.

●In a randomized double-blinded trial of 971 children three months to four years of age presenting to an emergency room with acute gastroenteritis symptoms, a five-day course of L. rhamnosus GG did not significantly alter symptom severity or duration relative to placebo [112]. In a similarly designed study of 886 children ages 3 to 48 months, L. rhamnosus R0011 and L. helveticus R0052 given for five days did not alter gastroenteritis clinical progression, duration of symptoms, or health care utilization compared with placebo [113]. An analysis of fecal specimens from the L. rhamnosus R0011 and L. helveticus R0052 study showed no viral-specific benefits or accelerated viral clearance by the probiotics [114].

The role of probiotics in the prevention of traveler's diarrhea is discussed in detail separately [116]. (See "Travelers' diarrhea: Treatment and prevention".)

Collagenous colitis — Collagenous colitis, a subtype of microscopic colitis, is a diarrheal illness characterized by the presence of a thickened subepithelial collagenous plate and lymphocytic infiltrate in the colonic mucosa. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management".)

A possible benefit of E. coli strain Nissle 1917 was suggested in an open-label study of 14 patients [117]. The authors hypothesized that the benefit may have been due to an antagonistic effect of the probiotic against strains of Yersinia species. In a second placebo-controlled trial, a combination of L. acidophilus and B. animalis strains had no significant effect on primary endpoints but were associated with some improvement in symptoms [118].

Celiac disease — Probiotics can degrade or alter gluten and gliadin [119-123], and Lactobacillus and Bifidobacterium concentrations are decreased in patients with celiac disease [124]. However, there is no evidence to support the use of probiotics in patients with celiac disease [125]. In a randomized controlled trial, 22 adults with celiac disease on a gluten-containing diet were randomized to treatment with B. infantis NLS super strain or placebo [126]. Although patients treated with B. infantis reported a significant improvement in constipation, indigestion, and gastroesophageal reflux as compared with placebo, there was no significant difference in diarrhea, abdominal pain, or celiac serologies. In contrast, in a randomized trial in which 33 children were assigned to treatment with B. longum CECT7347 or placebo added to a gluten-free diet, treatment with B. longum CECT7347 resulted in a reduction of fecal secretory IgA [127]. Suggestions that probiotics might be clinically effective are provided by a lack of activation of mucosal cytokine responses following consumption of bread degraded ex vivo by 10 probiotic Lactobacillus strains [122] and probiotic-digested gliadin-improved function of cultured epithelial cell lines [123]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Clinical manifestations'.)

CONSTIPATION — Evidence to support the use of single or combination probiotics in children or adults with functional constipation are lacking [128,129]. Multiple small, randomized, placebo-controlled trials of probiotics in patients with chronic constipation without irritable bowel syndrome, and in normal subjects with a tendency toward infrequent stools, suggest improvement in defecation frequency, stool consistency, and intestinal transit time with Bifidobacterium lactis DN-173 010, B. lactis BB12, Lactobacillus casei Shirota, L. reuteri DSM 19738 and E. coli Nissle 1917 [130-135]. However, these results using probiotics in the management of severe constipation should be interpreted with caution due to marked heterogeneity in study design and results, as well as publication bias [136,137]. Limited heterogeneous studies do not support use of probiotics in children with functional constipation [138,139].

IRRITABLE BOWEL SYNDROME — Evidence remains unconvincing for benefits of probiotics for treating irritable bowel syndrome (IBS), probably due to marked heterogeneity in this disorder and variability between the agents studied [51]. A number of controlled trials of probiotics in IBS have been published, many of which can be criticized for methodologic limitations [51,140-154]. All were short-term studies and none has provided clear evidence as to the potential role of probiotic treatment. Furthermore, the magnitude of benefit in studies with positive results was modest, suggesting that the probiotics under consideration are unproven, but may have the potential to impact the management of IBS [25,99,143,155-158]. It is possible that a clinically important benefit might be achieved in certain subgroups of patients, particularly those with diarrhea-predominant symptoms in light of data of alterations in the composition of resident enteric bacterial species in this subset of IBS [159] and its response to Rifaximin [158]. As in inflammatory bowel disease, a preferred approach may be to correct the altered microbiome in an individual based on observed compositional changes, rather than use a generic exogenous probiotic preparation for all patients.

Meta-analyses of randomized controlled trials found important methodologic limitations of most of the studies [143,158]. There was some evidence of efficacy for B. infantis 35624 in two appropriately designed studies. The following illustrate the range of findings in some of the largest controlled trials:

●The probiotic B. infantis was significantly more effective than placebo at four weeks in a controlled trial of 362 patients with IBS [142]. However, the benefit was confined to only one of three doses tested, and there was no clear dose-response relationship.

●In one trial, 77 patients with IBS were randomly assigned to a malted milk drink containing Lactobacillus salivarius UCC4331 or B. infantis 35624 or to a malted milk drink alone [144]. Symptoms were significantly improved at most time points in the group receiving B. infantis. There was a corresponding normalization in the ratio of serum IL-10/IL-12 suggesting that the probiotic may help reduce a proinflammatory state associated with IBS.

●Improvement in abdominal pain and a trend towards normalization of stool frequency in constipated patients was found in the probiotic-treated group in a placebo-controlled trial of 40 patients randomly assigned to L. plantarum 299V or placebo [160]. By contrast, no benefit was observed in a second placebo-controlled trial [161]. No overall improvement was observed in a randomized, placebo-controlled trial involving 100 patients with IBS treated with a combination of four probiotic species [162].

●In a trial with 122 patients with IBS, Bifidobacterium bifidum MIMBb75 was compared with placebo. Patients who received B. bifidum MIMBb75 had a 52 percent overall response rate compared with 21 percent for patients who received placebo [163].

●A placebo-controlled blinded trial of a low fermentable oligo- di- and monosaccharides and polyols (FODMAP) diet with or without multi-strain probiotics in 104 IBS patients showed reduced symptom scores with the low FODMAP diet, but no added benefit of the probiotics [150].

●A multicenter controlled trial of B. infantis 35624 in 302 non-patients with abdominal discomfort and bloating showed no benefit in symptoms beyond a significant placebo effect [151].

●A multicenter German controlled trial reported that nonviable Bifidobacterium bifidum HI-MIMBb75 daily for eight weeks in 443 IBS patients led to at least 30 percent improvement in abdominal pain and decreased activity of other IBS symptoms in at least four of the eight weeks of treatment in 34 percent of subjects, compared with improvement in 19 percent of placebo-treated subjects (risk ratio 1.7, 95% CI 1.3-2.4) [164].

LACTOSE INTOLERANCE — Ingestion of lactase-containing probiotics has the potential to aid lactose digestion in patients with lactose intolerance. Several studies have evaluated the benefit of various probiotics in patients with lactose intolerance [145,165]. A systematic review of 15 controlled trials found inconsistent results among strains, but a positive effect of probiotics and suggested further studies on specific strains in which a benefit was suggested [165]. A study of a lactose-fermenting Lactobacillus acidophilus strain showed reduced symptoms after an in vivo lactose challenge, laying the foundation for further long-term trials [166].

HEPATIC ENCEPHALOPATHY — The role of probiotics in the treatment of hepatic encephalopathy is discussed separately. (See "Hepatic encephalopathy in adults: Treatment", section on 'Modification of colonic flora (prebiotics and probiotics)'.)

PANCREATITIS — A multicenter, double-blind, placebo-controlled randomized trial of multispecies probiotic preparation and placebo demonstrated that probiotics did not reduce the risk of infectious complications and actually increased mortality from mesenteric ischemia in patients with pancreatitis [167,168]. As a result, probiotics are not recommended in severe acute pancreatitis.

SMALL BOWEL BACTERIAL OVERGROWTH — The role of probiotics in small bowel bacterial overgrowth is unproven. (See "Small intestinal bacterial overgrowth: Management".)

ALLERGY — Probiotics have the potential to reduce intestinal permeability and the generation of proinflammatory cytokines that are elevated in patients with a variety of allergic disorders. The role of probiotics in the treatment of allergic disease is discussed separately. (See "Prebiotics and probiotics for prevention of allergic disease".)

H. PYLORI — The role of probiotics in treatment of H. pylori infection is discussed separately. (See "Treatment regimens for Helicobacter pylori in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Probiotics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Probiotics (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Several probiotic preparations have promise in preventing or treating various conditions. However, most studies have been small and use highly variable probiotic preparations, and many have important methodologic limitations, making it difficult to make unequivocal conclusions regarding efficacy, especially when compared with proven therapies. Furthermore, considerable differences exist in composition, doses, and biologic activity between various commercial preparations, so that results with one preparation cannot be applied to other probiotic preparations. Finally, costs to the patient may be considerable since no preparation is FDA approved and most are not reimbursed by insurers. Enthusiasm for use of probiotics has outpaced the scientific evidence. Large, well-designed multicenter controlled clinical trials with replication cohorts are needed to clarify the role of specific probiotics in different well-defined patient populations.

●The decision to use a probiotic rests mostly upon the degree of anticipated benefit, available alternatives, the clarity of the available data in showing a benefit, costs, and patient preferences. No probiotic strategy is currently considered to represent either the standard of care or primary treatment for any of the conditions described above. The following recommendations are based upon the author's overall appraisal of the quality and consistency of the available evidence.

•Pouchitis – Data from small, controlled trials suggest a benefit from the original (DeSimone) VSL#3 consortium in the primary and secondary prevention of pouchitis. Thus, this is a reasonable adjunctive option in addition to standard medical therapy, although long-term efficacy is uncertain and access to this preparation in the United States is difficult. (See 'Pouchitis' above.)

•Ulcerative colitis – Benefits of probiotics in ulcerative colitis remain unproven, but E. coli Nissle 1917 shows promise in maintaining remission and could be considered as an alternative to biologic approaches in patients with mild recurrent disease who are intolerant or resistant to 5-ASA preparations. The original VSL#3 preparation may have some efficacy in treating active disease as an adjunctive approach, but the quality of data is poor. No probiotic preparations have been validated for clinical use in ulcerative colitis. (See 'Ulcerative colitis' above.)

•Crohn disease – A benefit of standard probiotics in Crohn disease remains unproven. (See 'Crohn disease' above.)

•Infectious diarrhea – The use of probiotics in children with presumed acute infectious diarrheal illness has no benefit. Probiotic use in adults with acute infectious gastroenteritis is unproven. (See 'Infectious diarrhea' above.)

•Constipation – Limited randomized controlled trials suggest possible improvement in defecation frequency and stool consistency in adult and older adult patients with chronic constipation, but limited benefit in children. However, these studies are likely subject to publication bias and larger studies are needed before probiotics can be routinely recommended in the management of severe chronic constipation. (See 'Constipation' above.)

•Irritable bowel syndrome – Evidence remains unconvincing for benefits of probiotics for treating irritable bowel syndrome, probably due to marked heterogeneity in this disorder and variability between the agents studied. A definitive therapeutic role remains unproven and needs to be further investigated in defined patient subsets. (See 'Irritable bowel syndrome' above.)

•Lactose intolerance – A benefit of probiotics for lactose intolerance remains unproven. (See 'Lactose intolerance' above.)

•Hepatic encephalopathy – Initial studies were associated with an improvement in hepatic encephalopathy. However, a large meta-analysis has shown no demonstrable benefit with regard to clinically relevant outcomes (eg, mortality and quality of life). (See 'Hepatic encephalopathy' above and "Hepatic encephalopathy in adults: Treatment", section on 'Modification of colonic flora (prebiotics and probiotics)'.)

•Allergy – A definitive role of probiotics for allergic conditions remains unproven, although initial results in studies of children with a variety of preparations for atopic dermatitis are promising. (See 'Allergy' above and "Prebiotics and probiotics for prevention of allergic disease".)