Non-prescription Therapeutics

Non-prescription microbiome-based therapeutics are of intense interest to patients and are popularly used for a myriad of potential health benefits. Non-prescription therapeutics have traditionally included prebiotics, probiotics, and synbiotics, with the more recent addition of postbiotics. Fermented foods are also of interest because of their potential health benefits, many of which may be mediated through their effect on the gut microbiota. In this study, we provide an overview of the mechanisms and effectiveness of non-prescription microbiome-based therapeutics for common gastrointestinal (GI) conditions. The International Scientific Association for Probiotics and Prebiotics has proposed definitions for microbiome-based therapeutics. Prebiotics consist of “a substrate that is selectively used by host micro-organisms conferring a health benefit (1).” Prebiotics include readily fermentable dietary fibers, fructosaccharides and galactosaccharides (FOSs and GOSs), inulin, human milk oligosaccharides (HMOs), and polyunsaturated fatty acids. Probiotics are defined as “live organisms, which when administered in adequate amounts, confer a health benefit on the host (1).” Probiotics have most commonly included lactic acid-producing bacteria such as Lactobacillus or Bifidobacteria species. Probiotics are most commonly considered to be food products and are listed either as Generally Regulated as Safe at the strain level by US Food and Drug Administration or with Qualified Presumption of Safety at the species level by the European Food Safety Authority. Because probiotics are considered food products, standardization of their viability and efficacy is limited. Synbiotics are a mixture comprising “live microorganisms and substrate(s) selectively utilized by host microorganisms that confers a health benefit on the host (2).” Postbiotics are defined as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host (3).” This definition is intended to include inactivated or killed organisms, but does not include purified microbial metabolites. Furthermore, this definition requires that the organisms have undergone molecular characterization, for example, by genome sequencing. As a result, this definition excludes fermented foods produced by an unknown or poorly defined set of microbes. By contrast, fermented foods have been defined as “foods made through desired microbial growth and enzymatic conversions of food components (4).” Some fermented foods are labelled as containing probiotic strains, but often without molecular characterization or quantification of the microorganisms present. For the purposes of this work, we will separately consider postbiotics (as well as probiotics) and fermented foods based on whether the organisms involved in the production of these substances are characterized. MECHANISMS Non-prescription therapeutics have been proposed to mediate their effects through several mechanisms, both by alterations to the native commensal microbiota and by directly affecting host physiology (Figure 1). Most probiotic species, such as Lactobacilli and Bifidobacteria species, generate lactate by anaerobic fermentation of sugars (5). In turn, lactate can alter the composition and/or metabolic potential of host commensal bacteria in humans and, in particular, drives an increase in fecal short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate (6). SCFAs have numerous positive effects on the host. For example, in animal models, SCFAs have been shown to act as an energy source for healthy colonocytes, promote GI motility, drive the proliferation of inflammation-controlling regulatory T cells, and inhibit colon carcinogenesis (7–9).Figure 1.: Mechanisms of prebiotics and probiotics in gastrointestinal health. Prebiotics, such as fiber, galacto-oligosaccharides (GOSs), fructo-oligosaccharides (FOSs), and human milk oligosaccharides (HMOs), foster the growth and metabolism of probiotics such as Lactobacilli and Bifidobacteria as well as native commensal microbes. In turn, probiotic species may directly affect health by suppression of pathogens, inhibition of inflammation, and improvement in epithelial permeability, or they may indirectly provide benefit through support of native microbiota, for example, by increasing production of short-chain fatty acids (SCFAs) by these native species. SCFA have been linked to decreased colon cancer risk, increased gut motility, and increased abundance of regulatory T cells (Tregs), and they serve as a major energy source for colonocytes. Lactobacilli and other lactic acid bacteria produce lactate during fermentation, which has also recently been linked to an increase in gut Tregs. Specific Lactobacilli also produce ligands for the aryl hydrocarbon receptor (AhR), which may be linked to improvements in gut barrier function and seem to increase the abundance of anti-inflammatory CD4+CD8αα+ intraepithelial lymphocytes (IELs). In addition to the above prebiotics, germinated barley and ursodeoxycholic acid (UDCA) may also serve as prebiotics by increasing native Eubacterium and Bifidobacteria species to control inflammation and inhibiting adenoma-associated microbial communities, respectively. Created with BioRender.com.Metabolites produced by probiotic bacteria, or found in fermented foods, may also directly affect host GI function. Lactate increases the abundance of intestinal regulatory T cells in mice, therefore decreasing inflammation (10). Several species of Lactobacillus also produce ligands for host aryl hydrocarbon receptors (AhR) (11). These AhR ligands, particularly ligands produced by L. reuteri, have been associated with decreased gut permeability and increased anti-inflammatory CD4+CD8αα+ intraepithelial lymphocytes in mouse models (12,13). Probiotic microbes can also inhibit the growth and/or colonization of pathogens. In vitro, several Lactobacillus strains limit the ability of pathogens such as Salmonella to bind to epithelial cells (14). Many lactic acid bacteria produce antimicrobial peptides called bacteriocins, which can inhibit in vitro growth of Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes (15). L. reuteri stimulates mouse innate lymphoid cells to produce interleukin-22, thereby inhibiting Candida colonization (16). Prebiotic substances can promote the growth of probiotic species and directly alter commensal bacteria to benefit the host. Fiber and other plant-derived polysaccharides, such as FOSs and GOSs, support fermentation by probiotic Bifidobacteria and Lactobacilli cultured from human stool (17,18). FOSs and GOSs can also be directly used by commensal bacteria to produce SCFAs (19). HMOs, a component of breast milk, increase the abundance of Bifidobacteria in both infants and adults (20,21), and certain HMOs have been associated with a decrease in the risk of necrotizing enterocolitis (22). Prebiotics may also affect native commensal microbes. For example, ursodiol, which may inhibit growth of recurrent colonic adenomas in men (23), decreases the fecal abundance of tumor-associated bacteria in these patients (24). Germinated barley increases the abundance of native Bifidobacterium and Eubacterium species in human feces, which, in turn, is associated with decreased intestinal inflammation (25). EVIDENCE FOR PREBIOTICS, PROBIOTICS, AND SYNBIOTICS IN GI CONDITIONS Probiotics have been extensively studied for the treatment of conditions within and outside the GI tract and have a wider evidence base than prebiotics, synbiotics, and postbiotics. In general, the literature for non-prescription therapeutics is large but limited by methodologic quality of the studies as well as variation in the number and types of prebiotics and microorganisms studied, dose, and duration of therapy. The probiotic literature is hampered by the small number of studies for any individual probiotic species or strain and differences in combinations of microorganisms in the various studies, so drawing firm conclusions about the effectiveness of prebiotics and probiotics is difficult. In most studies, the intervention was not mechanistically targeted, and effects of the intervention on composition or function of the gut microbiome are not well characterized. Finally, characterization of potential harms is often limited. It is likely that effectiveness of any non-prescription therapeutic is dependent on the specific prebiotics and/or strain(s) and function(s) of probiotic microorganisms used as well as host factors including the existing microbiome, diet, age, comorbidities, medication use, and geographic region. For purposes of this review, we focus on studies for the more common GI conditions (Figure 2).Figure 2.: Summary of clinical evidence for non-prescription therapeutics in common gastrointestinal conditions. ? No current evidence of benefit, but further studies needed. X No evidence of benefit in several studies and/or meta-analyses. * Weak evidence of benefit in several studies and/or meta-analyses. ** Moderate evidence of benefit in several studies and/or meta-analyses.Acute infectious gastroenteritis Probiotics have been studied in children to reduce the duration and severity of diarrhea in acute infectious gastroenteritis. In a Cochrane review of studies at low risk of bias, the risk of diarrhea lasting ≥48 hours was similar in patients treated with probiotics compared with controls (relative risk [RR] 1.00, 95% confidence interval [CI] 0.91–1.09), with no difference in duration of diarrhea (mean difference 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer) (26). No difference was detected in analyses limited to specific strains including Lactobacillus rhamnosus GG and Saccharomyces boulardii. Most studies included in this meta-analysis reported no adverse events (AEs), although in the majority, the methods for detecting AEs were not well-described. Studies conducted in North America only also confirmed these findings (27). Overall, probiotics do not seem to reduce duration or severity of diarrhea in North American children with acute infectious diarrhea and cannot currently be recommended for this indication. Prebiotics, including FOS, cellulose, and gum arabic, have not been found to improve diarrhea duration in children with acute gastroenteritis. In 1 meta-analysis, the use of these prebiotics decreased the duration of diarrhea compared with placebo by 15.3 hours, but with a 95% CI of −12 to +42.8 hours (28). However, there may be potential benefit in using synbiotic combinations or postbiotic preparations of heat-killed Lactobacillus species. Synbiotics, including a variety of lactic acid bacteria along with FOSs and GOSs, were found in aggregate to decrease duration of diarrhea by 26.3 hours compared with placebo (95% CI −36.1 to −16.2 hours). In 1 meta-analysis, heat-killed L. acidophilus was associated with a significantly decreased duration of acute diarrhea compared with placebo (−20.31 hours, 95% CI −27.06 to −13.57 hours) while heat-killed L. paracasei was associated with significantly decreased risk of acute gastroenteritis vs placebo (RR 0.51, 95% CI 0.37–0.71) (29). Reporting of AEs was limited in the included studies, so conclusions about safety could not be made. Overall, because of limited evidence, prebiotics, synbiotics, and postbiotics cannot currently be recommended for the treatment of acute infectious diarrhea. Antibiotic-associated diarrhea The effectiveness of probiotics for the prevention or treatment of antibiotic-associated diarrhea (AAD) in adults has been evaluated in several clinical trials and meta-analyses. A Cochrane review found a reduction in the risk of AAD in probiotics-treated participants (RR 0.58, 95% CI 0.48–0.73) (30). A more recent systematic review and meta-analysis of 42 studies evaluated the effect of probiotics coadministered with antibiotics for the prevention of AAD (31). The pooled RR of AAD was 0.63 (95% CI 0.54–0.73), but with statistically significant heterogeneity. In a subgroup analysis, L. acidophilus, L. bulgaricus, L. casei, L. paracasei, L. rhamnosus, Lactobacillus spp., S. boulardii, B. animalis ssp lactis, B. longum, B. lichenformis, B. subtilis, and Bacillus claussi seemed to be effective. The effect seemed to be limited to studies with a moderate-to-high baseline risk of AAD, defined as a risk of diarrhea in the control group of 11%–30% or ≥31%, respectively. No serious AEs (SAEs) were reported. A meta-analysis focused on adults had similar findings with a reduction in AAD (RR 0.62, 95% CI 0.51–0.74) (32). Probiotics may also be modestly effective in preventing AAD in children (RR 0.45, 95% CI 0.36–0.56), with greater effectiveness in high-dose (≥5 billion colony-forming units per day) vs low-dose (<5 billion colony-forming units per day) studies in a recent meta-analysis (33). Probiotics reduced the duration of diarrhea by almost 1 day (mean difference −0.91 days, 95% CI −1.38 to −0.44). Lactobacillus rhamnosus and Saccharomyces boulardii were the most commonly studied probiotic organisms, and both seemed to be effective. No SAEs were reported in this meta-analysis, with AEs including rash, nausea, flatulence, bloating, and constipation not reported more commonly in the probiotic-treated groups. Thus, current literature conditionally supports the use of specific strains of probiotics, including Lactobacillus and Bifidobacterium species as well as Saccharomyces boulardii, with modest benefit in preventing or reducing duration of AAD in adults and children and no significant increase in SAEs. There is only minimal evidence on the use of prebiotics or synbiotics for the prevention of AAD, and currently, these cannot be recommended for this indication. Clostridioides difficile infection Given the high morbidity and cost associated with Clostridioides difficile infection (CDI), there has been substantial interest in the use of probiotics to decrease its incidence in patients on antibiotics or to prevent recurrence. Nevertheless, high-quality studies in this area are lacking, leading to low certainty of evidence and conflicting recommendations. The most recent American College of Gastroenterology guideline on management of CDI recommends against probiotics for primary prevention of CDI in patients taking antibiotics (conditional recommendation, moderate quality of evidence) and against probiotics for the prevention of recurrence (strong recommendation, very low quality of evidence) (34). The American Gastroenterological Association (AGA) guideline on probiotics recommended their use in patients with CDI only in the context of a clinical trial and conditionally recommended certain strain combinations to prevent recurrence (low quality of evidence) (35). Potentially effective strains included single-agent Saccharomyces boulardii; a 2-strain combination of L. acidophilus CL1285 with L. casei LBC80R; a 3-strain combination of L acidophilus, L delbrueckii subsp. bulgaricus, and B. bifidum; or a 4-strain combination of L acidophilus, L delbrueckii subsp. bulgaricis, B. bifidum, and S. salivarius subsp. thermophilus. These recommendations are supported by a Cochrane review of 31 studies, which found a moderate reduction in CDI (RR 0.40, 95% CI 0.30–0.52) (33). Notably, the effect was limited to studies with a risk of CDI in the control group of >5%, with no reduction in risk in studies with lower baseline risk. No increase in SAEs with probiotics was seen. The most commonly reported AEs were nausea, abdominal cramping, flatulence, soft stools, and taste disturbance. The PLACIDE trial of 3,000 inpatients aged 65 years and older being treated with antibiotics used a multistrain preparation of Bifidobacteria and Lactobacillus acidophilus and found no difference in the risk of CDI (RR 0.71, 95% CI 0.34–1.47) (36). However, CDI was uncommon in this study (1.2% of participants in the placebo arm). Although no SAEs were reported, participants receiving the probiotic reported significantly more bloating than controls (58.3% vs 17.6%, P = 0.023). Thus, the overall benefit of probiotics for the primary prevention of CDI in patients on antibiotics is uncertain and may be limited to specific strains or strain combinations and to patients at high risk of CDI. The evidence for use of prebiotics or probiotics to prevent CDI recurrence is similarly limited. A Cochrane review included 4 studies and found insufficient evidence to recommend probiotics for this indication (37). The PICO trial randomized 33 patients to a 4-strain probiotic including 2 Lactobacillus and 2 Bifidobacteria species vs placebo and found no significant difference in the risk of CDI recurrence (38). No significant difference in AEs was reported. Two randomized controlled trials (RCTs) examined the use of prebiotics in the prevention of recurrent CDI. One study using that the of CDI recurrence was significantly lower than placebo study using not a significant decrease in the recurrence Thus, to there is no evidence to that probiotic use can reduce risk of CDI and the evidence for prebiotics is very limited. In of probiotics may of the gut microbiome to the often with recurrent CDI use of probiotics or prebiotics for primary or prevention or for the treatment of CDI is not currently prebiotics and probiotics have been studied for patients with studies have that probiotic strains including Lactobacillus acidophilus have been found to reduce associated with but not the Prebiotics may growth of that can In studies, have been shown to reduce of while increasing the of organisms including and AEs were not reported in these on current evidence, prebiotics or probiotics cannot be recommended for the treatment of There is substantial interest in the use of microbiome-based therapeutics for the to dietary and The literature in this area is with including of standardization of the of and definitions of In studies have included combinations of dietary prebiotics, probiotics, and Because of these evidence to support most microbiome-based therapeutics in is lacking, and the recent guideline no for use of probiotics in because of this (35). on the use of prebiotics in are limited. 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This was associated with an increased fecal abundance of Bifidobacterium and Eubacterium Overall, the evidence does not support the use of prebiotics to in The literature on synbiotics for is and has most commonly studied Bifidobacterium species with combinations of other organisms and prebiotics such as inulin, and GOSs There is of improvement in and in these studies, but current evidence does not support the use of synbiotics for Probiotics have also been studied for the treatment of combination of L. paracasei paracasei, L. L. acidophilus, L. delbrueckii bulgaricus, B. longum, B. B. and S. salivarius has modest benefit for prevention of an of or for of However, a small study not this probiotic combination to be in for patients with Thus, the effectiveness of probiotics for in clinical is enterocolitis enterocolitis is a in very and very low infants by intestinal on leading to and There is evidence that human breast milk to very and very low infants can prevent milk several potential most HMOs, which can increase the abundance of Bifidobacteria species in the colon One meta-analysis the use of HMOs in infants in that overall these prebiotics reduced the of and but not However, a study that infants milk with lower of 1 were more likely to compared with infants milk with of (22). This that specific HMOs within human milk are potential prebiotics that can reduce and in this However, a Cochrane review found that prebiotics not affect the risk of or with low certainty of evidence Probiotics may reduce the risk of (RR 95% CI and in infants (RR 95% CI There is evidence of strain and with the evidence for a combination of Lactobacillus and Bifidobacterium or B. animalis or L. reuteri or or L. rhamnosus or or (35). There is benefit for very and very low with reduction in the risk of (RR 95% CI and overall (RR 95% CI However, there was no benefit for and low infants Synbiotics containing Lactobacilli and/or Bifidobacteria and FOSs and/or GOSs have also been studied for prevention of HMOs were not included in these that synbiotics may reduce the risk of (RR 95% CI although with low certainty of evidence to methodologic with the included studies of probiotics in infants has not been because of about probiotic which to be most common in infants at reported to have included and Because probiotics are not commonly about safety of probiotics have the European of and to conditionally recommend only certain probiotic strains and only safety can be and the American of to recommend against use of probiotics in particularly with a has human as a of food and and fermented foods are in fermented foods include fermented such as or and A variety of microorganisms can be used to but most commonly are lactic acid acid and The mechanisms by which fermented foods improve human health are but are to include alterations of food to improve their of that may have health of the gut of the and metabolism of and poorly food components such as fermentable and a recent study that high of fermented foods in healthy patients was associated with decreased and other which was associated with an increase in fecal microbial Although studies have associated in fermented foods with health and of fermented foods in GI conditions are currently the common GI studies fermented milk products or and GI such as and diarrhea are in and and do not any firm conclusions about their of milk and milk products has been associated with risk of although the of fermented milk products in is However, was not associated with a significant reduction in overall cancer incidence or although there was a of a greater effect for cancer compared with colon cancer By contrast, of fermented foods has been associated with significantly increased risk of cancer in of studies In a small randomized study, was than milk in patients with with lower severity but no in abdominal and diarrhea In to for infection vs with effects of abdominal and no randomized studies of other fermented foods such as or are Because of the of of fermented foods, they cannot be recommended for use for the treatment for common GI conditions. Non-prescription microbial therapeutics for the treatment of GI but current studies have not defined the or microbial that are most effective. Given the of the gut microbiome, is likely that more of the of effect of microbial therapeutics is to to the individual In this studies both the and function of the gut microbiome with more of are to this of Specific and of and of This as of the on to support the have been to the for and from and and is supported by the the which to the of this and methods for of colon microbiota, US no of