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Cited by 163Gut microbiota and healthGastrointestinal motility and disordersProbiotics and Fermented Foods

The gut Microbiome in adult and pediatric functional gastrointestinal disorders

Open access
Shin, Andrea, Preidis, Geoffrey A., Shulman, Robert, Kashyap, Purna C.·2019·Clinical Gastroenterology and Hepatology
DOI 10.1016/j.cgh.2018.08.054PMC PMC6314902
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Abstract

The importance of gut microbiota in gastrointestinal (GI) physiology was well described, but our ability to study gut microbial ecosystems in their entirety was limited by culture-based methods prior to the sequencing revolution. The advent of high-throughput sequencing opened new avenues, allowing us to study gut microbial communities as an aggregate, independent of our ability to culture individual microbes. Early studies focused on association of changes in gut microbiota with different disease states, which was necessary to identify a potential role for microbes and generate novel hypotheses. Over the past few years the field has moved beyond associations to better understand the mechanistic implications of the microbiome in the pathophysiology of complex diseases. This movement also has resulted in a shift in our focus toward therapeutic strategies, which rely on better understanding the mediators of gut microbiota-host cross-talk. It is not surprising the gut microbiome has been implicated in the pathogenesis of functional gastrointestinal disorders given its role in modulating physiological processes such as immune development, GI motility and secretion, epithelial barrier integrity, and brain-gut communication. In this review, we focus on the current state of knowledge and future directions in microbiome research as it pertains to functional gastrointestinal disorders. We summarize the factors that help shape the gut microbiome in human beings. We discuss data from animal models and human studies to highlight existing paradigms regarding the mechanisms underlying microbiota-mediated alterations in physiological processes and their relevance in human interventions. While translation of microbiome science is still in its infancy, the outlook is optimistic and we are advancing in the right direction toward precise mechanism-based microbiota therapies.

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Crossref · 10.1016/j.cgh.2018.08.054

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  • Premisecitation

    The interaction of diet, gut microbiome, and symptoms in FGIDs has not been well studied.

    “The interaction of diet, gut microbiome, and symptoms in FGIDs (reviewed in 30) has not been well studied”
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  • Premisecitation

    Microbial abundance and community structure in the proximal intestine are affected by gastric acid, pancreaticobiliary secretions, and fast transit.

    “Microbial abundance and community structure in the proximal intestine is affected by gastric acid, pancreaticobiliary secretions, and fast transit45.”
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    No consistent microbial signature has been associated with FGIDs.

    “While no consistent “microbial signature” has been associated with FGIDs, several lines of evidence support a role for gut microbes in the development of FGID symptoms7.”
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  • Premisecitation

    Short- and long-term dietary patterns have a major impact on the gut microbiome.

    “The impact of both short23 and long term dietary patterns24 on the gut microbiome cannot be overstated25, 26.”
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  • Premisecitation

    Several lines of evidence support a role for gut microbes in the development of FGID symptoms.

    “While no consistent “microbial signature” has been associated with FGIDs, several lines of evidence support a role for gut microbes in the development of FGID symptoms7.”
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    Premisecitation

    GI motility and the gut microbiota have reciprocal effects, indicating a bidirectional relationship.

    “GI motility and the gut microbiota have reciprocal effects (reviewed in 1), highlighting a bidirectional relationship (Figure 3).”
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    Premisecitation

    The effect size of host genetics on the gut microbiome is likely small because microbial-genetic association studies show environmental factors have substantially greater impact.

    “However, the effect size is likely small given recent microbial-genetic association studies showing environmental factors to have substantially greater impact on the gut microbiome than genetics22.”
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    Premisecitation

    Dietary intolerances are commonly reported in FGIDs and patients may alter or restrict diets based on perceived associations between symptoms and food.

    “The role of diet27 in microbial alterations is of significant interest in FGIDs as dietary intolerances are commonly reported in FGIDs and patients may alter or restrict their diets based on perceived associations between symptoms and food28, 29.”
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    Premisecitation

    Host genetics influence the gut microbiome, as shown by twin studies demonstrating shared community structures between related individuals and temporally stable heritable taxa.

    “Host genetic influence15,16,1718, 19,20 on the gut microbiome is apparent from studies of monozygotic and dizygotic twin pairs that demonstrate shared community structures between related individuals21 and temporally stable heritable taxa17.”
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    Bacterial density increases from proximal to distal GI sites.

    “Bacterial density increases from more proximal to distal sites44.”
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    Premisenone given

    The long-term effects on the gut microbiome of dietary interventions with reported benefit in IBS, such as psyllium fiber and low FODMAP diet, remain unknown.

    “the long term consequences of current dietary interventions with reported benefit in IBS, such as supplementation with psyllium fiber and the low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet31, 32, on the gut microbiome remain to be seen.”
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    Premisecitation

    The adult gut microbiota is relatively stable over time and resilient to temporary perturbations, but changes with age to a distinct and less diverse microbiome.

    “The adult gut microbiota is relatively stable over time and surprisingly resilient to temporary perturbations, changing as we get older to a distinct and less diverse microbiome12.”
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    • cites [12] Claesson, 2011, Composition, variability, and temporal stability of the intestinal microbiota of the elderly, Proc Natl Acad Sci U S A source

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    Interpretationreasoning

    Disruption of the gut microbial equilibrium can alter host physiology and lead to disease states such as functional gastrointestinal disorders.

    “However, a disruption in this equilibrium can lead to alteration of host physiology resulting in disease states such as functional gastrointestinal disorders (FGIDs).”
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    Gut microbial composition and diversity are largely determined by host selection pressures such as genetics, habits, sex, and GI location, as well as environmental factors including diet.

    “Gut microbial composition and diversity is largely the consequence of host selection pressures such as genetics, habits, sex, and location within the gastrointestinal (GI) tract as well as environmental factors including diet (Figure 1).”
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    Premisecitation

    Culture-independent molecular methods based on DNA sequence similarities allowed identification and characterization of microbial communities and improved the ability to culture previously unculturable bacteria.

    “gave way to culture-independent molecular approaches allowing us to not only identify and characterize microbial communities based on similarities in DNA sequences, but also provide knowledge that has significantly improved our ability culture bacteria that were previously considered unculturable6.”
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    Premisecitation

    Gut microbiota distribution and composition vary along the length of the GI tract and across the lumen, mucus layer, and epithelium.

    “The distribution and composition of the gut microbiota changes along the length of the GI tract (Figure 2) and across the lumen, mucus layer, and the epithelium42, 43.”
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    Premisecitation

    Women have increased relative abundance of Firmicutes and lower Bacteroidetes compared to men, and this may be influenced by body mass index.

    “Sex associations (Figure 1) with the gut microbiota have been characterized by increased relative abundance of Firmicutes and lower Bacteroidetes in women compared to men and may be further influenced by body mass index13, 14.”
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    • cites [13] Dominianni, 2015, Sex, body mass index, and dietary fiber intake influence the human gut microbiome, PLoS One source

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    Gut microbial diversity varies with age, with substantial differences at the extremes of life.

    “Gut microbial diversity varies with age, and substantial differences are seen at the extremes of life8.”
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    • cites [8] Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PLoS One source

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    Premisecitation

    Altered GI motility and transit have long been recognized in the pathobiology of FGIDs such as IBS and functional dyspepsia.

    “Altered GI motility and transit have long been recognized in the pathobiology of FGIDs such as IBS48 and functional dyspepsia (FD)49, 50.”
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    Premisecitation

    Psychological stress, physical activity, tobacco use, alcohol consumption, and antibiotic exposure are modifying factors for the gut microbiome.

    “Other modifying factors (Figure 1) include psychological stress33,34, physical activity35, tobacco use36, alcohol consumption37, and antibiotic exposure38, 39,40.”
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    Spatial niche partitioning of microbial populations can result from mucus from goblet cells and differential oxygen tolerance.

    “Spatial niche partitioning of microbial populations can also be a result of mucus from goblet cells 46 and differential oxygen tolerance47.”
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    Premisecitation

    Approximately 10% of IBS cases begin after an episode of infectious gastroenteritis.

    “An estimated 10% of IBS cases begin after an episode of infectious gastroenteritis3.”
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    • cites [3] Jalanka, 2015, Microbial signatures in post-infectious irritable bowel syndrome--toward patient stratification for improved diagnostics and treatment, Gut Microbes source

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    Premisenone given

    The role of gut bacteria in FGIDs such as irritable bowel syndrome has been well described.

    “The role for gut bacteria in FGIDs such as irritable bowel syndrome (IBS) has been well described.”
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    Premisenone given

    The human gut contains a complex microbial ecosystem of bacteria, fungi, viruses, and archaea that lives mutualistically with the host under homeostatic conditions.

    “The human gut is home to a complex microbial ecosystem with bacteria, fungi, viruses, and archaea which exist in a mutualistic relationship with the host in homeostatic conditions.”
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    Premisenone given

    After birth, gut microbiota assembly begins with colonization from environmental microbes such as maternal vaginal, fecal, and skin microbiota.

    “At birth, assembly of the gut microbiota begins with colonization from environmental microbes (e.g., maternal vaginal, fecal, skin microbiota).”
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    Premisecitation

    In the months to years after birth, gut microbial communities shift in response to life events such as solid food exposure, illnesses, and antibiotics, with gradual diversity increases and convergence to an adult-like microbiota.

    “In the subsequent months to years, gut microbial communities continue to shift in response to key life events (e.g., exposure to solid foods, illnesses, antibiotics) with gradual increases in diversity and convergence to an “adult-like” microbiota9–11.”
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    • cites [9] Koenig, 2011, Succession of microbial consortia in the developing infant gut microbiome, Proc Natl Acad Sci U S A source

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    • cites [10] Palmer, 2007, Development of the human infant intestinal microbiota, PLoS Biol source

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    • cites [11] Hollister, 2015, Structure and function of the healthy pre-adolescent pediatric gut microbiome, Microbiome source

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    Premisecitation

    In a population-level analysis, 69 factors correlated with gut microbiome community variation, and stool consistency was the most influential covariate.

    “In one population-level analysis of gut microbiome variation, 69 factors were shown to correlate with microbiome community variation, with stool consistency emerging as the most influential covariate 41.”
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    • cites [41] Falony, 2016, Population-level analysis of gut microbiome variation, Science source

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    Premisecitation

    The mucus layer is a reservoir of antimicrobial peptides and immunoglobulins and provides the first line of defense against gut bacteria.

    “The mucus layer overlaying the epithelium is a reservoir of antimicrobial peptides and immunoglobulins and provides the first line of defense against gut bacteria85.”
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    Premisecitation

    Microbes can directly alter expression of tight junction proteins such as claudin-3 and zonula occludens-1 or enhance expression of genes involved in tight junction signaling.

    “Microbes(Figure 3) can directly alter expression of tight junction proteins such as claudin-380 and zonula occludens-181 or enhance expression of genes involved in tight junction signaling82.”
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    • cites [80] Patel, 2012, Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function, Am J Pathol source

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    Interpretationnone given

    Translation of findings from animal models to humans can be challenging.

    “The translation of findings from animal models to humans can, however, be challenging.”
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    Premisecitation

    Disturbances in gastric motor and sensory function, including impaired gastric accommodation and increased intragastric pressure, may underlie FGIDs and are often related to food intake.

    “Disturbances in gastric motor and sensory function, including impaired gastric accommodation and increased intragastric pressure, may underlie FGIDs and are often related to food intake102.”
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    Premisecitation

    Microbial starvation, such as decreased fiber consumption, can increase microbial reliance on mucus polysaccharides, resulting in degradation of the mucus layer and increased susceptibility to opportunistic pathogens and inflammation.

    “Hence microbial starvation such as with decreased consumption of fiber can increase microbial reliance on the mucus polysaccharides resulting in degradation of the mucus layer and increasing susceptibility to opportunistic pathogens and inflammation27, 86.”
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    • cites [27] Desai, 2016, A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility, Cell source

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    Bile acid deconjugation and dehydroxylation by gut bacteria regulate the quantity and derivatives of bile acids in the colon.

    “while bile acid deconjugation and dehydroxylation by gut bacteria regulates the quantity and derivatives of bile acids in the colon.”
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    Premisecitation

    Secretory mechanisms are common therapeutic targets of medications used to treat FGIDs.

    “Secretory mechanisms are common therapeutic targets94, 95 of medications used to treat FGIDs.”
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    Premisecitation

    Bacterial lipopolysaccharide can improve survival of enteric neurons by activating TLR4.

    “bacterial lipopolysaccharide, which can improve survival of enteric neurons by activation of toll-like receptor 4 (TLR4)58.”
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    • cites [58] Anitha, 2012, Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling, Gastroenterology source

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    Premisecitation

    The gut microbiota can influence immune activation via effects on T-cell subset lineage differentiation, host-receptor mediated signaling such as L. reuteri activation of histamine H2 receptor signaling, and production of microbial metabolites.

    “The gut microbiota can also influence immune activation via effects on lineage differentiation of T-cell subsets91, host-receptor mediated signaling as seen with L. reuteri activation of histamine H2 receptor signaling92, and production of microbial metabolites (Table 1).”
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    • cites [91] Powell, 2017, The mucosal immune system: master regulator of bidirectional gut-brain communications, Nat Rev Gastroenterol Hepatol source

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    • cites [92] Gao, 2015, Histamine H2 receptor-mediated suppression of intestinal inflammation by probiotic Lactobacillus reuteri, MBio source

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    Premisecitation

    SCFAs are produced by gut bacterial fermentation of dietary starches or complex carbohydrates.

    “SCFAs are produced by fermentation of dietary starches or complex carbohydrates by gut bacteria54”
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    • cites [54] Roy, 2006, Short-chain fatty acids: ready for prime time?, Nutr Clin Pract source

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    Premisecitation

    Riba et al. demonstrated a correlation between visceral hypersensitivity and increased E. coli abundance, followed by induction of hypersensitivity in response to E. coli gavage in mice.

    “A recent study by Riba et al.67 demonstrated a correlation between visceral hypersensitivity and increase of Escherichia coli abundance followed by induction of hypersensitivity in response to E. coli gavage in mice.”
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    • cites [67] Riba, 2017, Paneth cell defects induce microbiota dysbiosis in mice and promote visceral hypersensitivity, Gastroenterology source

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    Premisecitation

    The intestinal epithelium and overlaying mucus layer protect the host by providing a physical and immunological barrier against pathogens while regulating fluid and nutrient absorption.

    “The intestinal epithelium and the overlaying mucus layer serve a key role in protecting the host by providing a physical and immunological barrier against potentially harmful pathogens while also regulating fluid and nutrient absorption77.”
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    • cites [77] Bischoff, 2014, Intestinal permeability--a new target for disease prevention and therapy, BMC Gastroenterol source

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    Premisecitation

    Disruption of the gut microbiota in early life is associated with long-term changes in visceral sensitivity, emphasizing the importance of the gut microbiome in neurodevelopment of pain pathways.

    “Disruption of the gut microbiota in early-life also has been associated with longterm changes in visceral sensitivity, emphasizing the importance of the gut microbiome in neurodevelopment of pain pathways68.”
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    • cites [68] O'Mahony, 2014, Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats, Neuroscience source

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    Premisecitation

    A combination of three bifidobacteria resolved abdominal pain and improved quality of life to a greater extent than placebo.

    “while the other reported that a combination of three bifidobacteria resolved abdominal pain and improved quality of life to a greater extent than placebo135.”
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    • cites [135] Giannetti, 2017, A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial, J Clin Gastroenterol source

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    Premisecitation

    Macrophages and monocytes are important in modulating adaptive immune responses and producing proinflammatory cytokines such as IL-6 and IL-8, which in some studies are increased in IBS patients.

    “Macrophages and monocytes are important in modulating the adaptive immune responses and producing proinflammatory cytokines such as IL-6 and IL-8 which in some studies are increased in IBS patients117.”
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    • cites [117] Scully, 2010, Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity, Am J Gastroenterol source

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    Premisecitation

    SIBO has been proposed to trigger symptoms in FD, although studies examining SIBO in FD are limited by inaccessibility of distal small intestine and concerns about accuracy and interpretation of SIBO testing.

    “SIBO has been proposed to trigger symptoms in FD142, although studies examining the role of SIBO in FD are limited by the relative inaccessibility of the more distal regions of the small intestine and concerns regarding accuracy and interpretation of available testing methods for the diagnosis of SIBO143.”
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    • cites [142] Tziatzios, 2017, Is small intestinal bacterial overgrowth involved in the pathogenesis of functional dyspepsia?, Med Hypotheses source

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    • cites [143] Aziz, 2017, Small intestinal bacterial overgrowth as a cause for irritable bowel syndrome: guilty or not guilty?, Curr Opin Gastroenterol source

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    The bidirectional microbiome-gut-brain axis represents reciprocal regulation of the gut microbiome and the central nervous system.

    “The bidirectional microbiome-gut-brain axis (Figure 3) represents the reciprocal regulation of the gut microbiome and the central nervous system (CNS).”
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    Premisecitation

    Colonic mucosal gene expression profiling of IBS patients found differential expression of genes associated with host immune responses against microbial invasion, suggesting immune activation may be shaped by microbial interactions.

    “Colonic mucosal gene expression profiling of IBS patients also has found differential expression of genes associated with host immune responses against microbial invasion, further suggesting that immune activation may be shaped by microbial interactions121.”
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    • cites [121] Aerssens, 2008, Alterations in mucosal immunity identified in the colon of patients with irritable bowel syndrome, Clin Gastroenterol Hepatol source

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    Premisereasoning

    The composition of the gut microbiome differs between children with IBS and age-matched healthy controls, despite lack of a uniform IBS-microbiota signature across studies.

    “Similar to adult studies, the composition of the gut microbiome differs between children with IBS and age-matched healthy controls, despite lack of a uniform “IBS-microbiota” signature across studies.”
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    Interpretationreasoning

    These data highlight the importance of investigating specific pathophysiologic disturbances beyond descriptive analyses of heterogeneous patient populations to elucidate the role of the gut microbiome in IBS.

    “These data highlight the importance of investigating specific pathophysiologic disturbances, beyond merely providing descriptive analyses of a heterogeneous patient populations in elucidating the role of the gut microbiome in IBS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite no uniform IBS-microbiota pattern, key observations include decreased α-diversity and altered relative abundance of specific taxonomic groups: increased Firmicutes to Bacteroidetes ratio, decreased Lactobacillus and Bifidobacterium, and increased Streptococcus and Ruminococcus spp.

    “Despite the lack of a uniform “IBS-microbiota” pattern, key observations include a decrease in α-diversity and alterations in relative abundance of specific taxonomic groups including an increased ratio of Firmicutes to Bacteroidetes, decreased Lactobacillus and Bifidobacterium, and increased Streptococcus and Ruminococcus spp.112.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Bhattarai, 2017, Irritable bowel syndrome: a gut microbiota-related disorder?, Am J Physiol Gastrointest Liver Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    De Palma et al. demonstrated that germ-free mice colonized with fecal microbiota from IBS-D patients exhibited faster GI transit, increased colonic permeability, increased anxiety-like behavior, and increased CD3+ T lymphocyte infiltration compared to mice colonized with healthy control microbiota.

    “De Palma et al.52 recently demonstrated that GF mice colonized with the fecal microbiota of diarrheapredominant IBS (IBS-D) patients exhibited faster GI transit, increased colonic permeability, increased anxiety-like behavior, and increased infiltration by CD3+ T lymphocytes compared to those colonized by microbiota from healthy controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] De Palma, 2017, Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Signals from the CNS can influence GI physiology while shaping the gut microbial fingerprint, as seen in early life stress rodent models with altered gut microbial community composition.

    “Signals from the CNS can influence GI physiology while simultaneously shaping the gut microbial fingerprint as seen in early life stress rodent models which exhibit alterations in gut microbial community composition109.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] O'Mahony, 2009, Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbial metabolites such as SCFAs and microbially-derived neurotransmitters such as GABA and 5-HT may impact brain function and mental health.

    “Microbial metabolites such as SCFAs and microbially-derived neurotransmitters such as GABA and 5-HT may further impact brain function and mental health108.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Cryan, 2012, Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour, Nat Rev Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fecal microbial community composition might predict which children with IBS are more likely to respond to a low-FODMAP diet; in two studies, responders had distinct baseline microbiome signatures compared to non-responders.

    “Fecal microbial community composition also might be used to predict which children with IBS are more likely to respond to a low-FODMAP diet: in two separate studies, responders had distinct baseline microbiome signatures compared to non-responders131, 132.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [131] Chumpitazi, 2014, Gut microbiota influences low fermentable substrate diet efficacy in children with irritable bowel syndrome, Gut Microbes source

      Not checked in the free run.

    • cites [132] Chumpitazi, 2015, Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome, Aliment Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absorption of SCFAs can influence the luminal bacterial population, which may be relevant in FD.

    “In addition, the absorption of SCFAs can also influence the luminal bacterial population which may be relevant in FD100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Kaji, 2015, SCFA transport in rat duodenum, Am J Physiol Gastrointest Liver Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with a probiotic containing Bifidobacterium lactis accelerates whole gut transit and improves symptoms in patients with constipation-predominant IBS.

    “Treatment with a probiotic containing Bifidobacterium lactis118 accelerates whole gut transit and improves symptoms in patients with constipation-predominant IBS (IBS-C)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Agrawal, 2009, Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation, Aliment Pharmacol Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Data on the gastroduodenal microbiome and its role in FD are sparse, but a few studies lay groundwork for future work.

    “Although data on the gastroduodenal microbiome and its particular role in FD are sparse, there are a few studies that lay the groundwork for future work investigating the role of microbial community alterations in FD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Bifidobacterium infantis 35624 alleviated symptoms and was associated with normalization of abnormal IL-10/IL-12 ratios in IBS patients.

    “A role for the gut microbiome in immune modulation was suggested by findings from the clinical trial wherein B. infantis 35624 alleviated symptoms and was associated with normalization of abnormal IL-10/IL-12 ratios in IBS patients120.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] O'Mahony, 2005, Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because IBS is heterogeneous with multiple putative mechanisms, a broad nontargeted approach without consideration of underlying physiological disturbance likely dilutes the overall impact and makes it difficult to ascertain the precise benefit of microbiota modulation.

    “However, given the heterogenous nature of the disease with multiple putative mechanisms, our broad nontargeted approach without consideration for the underlying physiological disturbance likely dilutes the overall impact and makes it difficult to ascertain the precise benefit of microbiota modulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Factors affecting gut microbiota composition are akin to etiological factors in IBS, and probiotic interventions have a generally beneficial effect.

    “Moreover, factors affecting gut microbiota composition are akin to the etiological factors in IBS and probiotic interventions have a generally beneficial effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Gut microbiota have been shown to modulate the majority of these physiological functions.

    “As summarized above, gut microbiota have been shown to modulate the majority of these physiological functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent studies highlight a role of the gut microbiome in modulating brain-gut communication, which may significantly affect pathophysiology of symptoms associated with FGIDs.

    “Recent studies highlight the role of the gut microbiome in modulating brain-gut communication, which may significantly affect the pathophysiology of symptoms associated with FGIDs107,108.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [107] Drossman, 2018, Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a Rome Foundation Working Team Report, Gastroenterology source

      Not checked in the free run.

    • cites [108] Cryan, 2012, Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour, Nat Rev Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In children ages 7-12, pediatric IBS is associated with decreased relative abundance of Bacteroides spp. and increased relative abundance of Gammaproteobacteria, including Haemophilus parainfluenzae, along with increased abundance of novel taxa related to Ruminococcus.

    “One study enrolling children ages 7–12 years found pediatric IBS to be associated with decreased relative abundance of Bacteroides spp. and increased relative abundance of the class Gammaproteobacteria, including Haemophilus parainfluenzae, along with increased abundance of novel taxa related to the genus Ruminococcus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Saulnier, 2011, Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In studies focused specifically on FAP, Romano et al. reported reduced pain severity, and Weizman et al. and Maragkoudaki et al. both reported reduced pain severity and frequency in those treated with the probiotic compared with placebo.

    “In studies focused specifically on FAP, Romano et al.138 reported reduced pain severity and Weizman et al.139 and Maragkoudaki et al.140 both reported reduced pain severity and frequency in those treated with the probiotic compared with placebo.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [138] Romano, 2014, Lactobacillus reuteri in children with functional abdominal pain (FAP), J Paediatr Child Health source

      Not checked in the free run.

    • cites [139] Weizman, 2016, Lactobacillus reuteri DSM 17938 for the management of functional abdominal pain in childhood: a randomized, double-blind, placebo-controlled trial, J Pediatr source

      Not checked in the free run.

    • cites [140] Maragkoudaki, 2017, Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain, Acta Paediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that cohort, microbiota composition correlated with abdominal pain severity and frequency and could distinguish IBS-C from unsubtyped IBS.

    “In this cohort, microbiota composition correlated with abdominal pain severity and frequency, and could be used to distinguish IBS-C from unsubtyped IBS128.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Saulnier, 2011, Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Few human studies describe the gut microbiome in FD, so the precise role of the microbiota remains unknown.

    “There are few human studies describing the gut microbiome in patients with FD, hence the precise role of the microbiota remains unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These mast cell mediators may alter nociceptive pathways in IBS or increase intestinal permeability.

    “These mediators may alter nociceptive pathways in IBS115 or increase intestinal permeability116.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Wouters, 2016, Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome, Gastroenterology source

      Not checked in the free run.

    • cites [116] Barbara, 2011, The immune system in irritable bowel syndrome, J Neurogastroenterol Motil source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In children ages 11-18, IBS-D is associated with increased abundance of Veillonella, Prevotella, Lactobacillus, and Parasporobacterium, and decreased abundance of Bifidobacterium and Verrucomicrobium.

    “Another study of children ages 11–18 years found IBS-D to be associated with increased abundance of the genera Veillonella, Prevotella, Lactobacillus, and Parasporobacterium, and with decreased abundance of Bifidobacterium and Verrucomicrobium129.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Rigsbee, 2012, Quantitative profiling of gut microbiota of children with diarrhea-predominant irritable bowel syndrome, Am J Gastroenterol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Psyllium fiber reduced pain episodes in an RCT enrolling children with IBS without altering gut microbiota composition based on 16S rRNA analysis.

    “On the other hand, psyllium fiber reduced pain episodes in an RCT enrolling children with IBS without altering the composition of the gut microbiota based on 16S ribosomal RNA analysis136.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Shulman, 2017, Psyllium fiber reduces abdominal pain in children with irritable bowel syndrome in a randomized, double-blind trial, Clin Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cross-sectional analysis of extensively phenotyped cohorts revealed stool consistency is a significant contributor to gut microbiome compositional variation, while the contribution from IBS is much less.

    “Cross-sectional analysis of extensively phenotyped cohorts also has revealed that while stool consistency is a significant contributor to gut microbiome compositional variation, the contribution imparted by IBS was much less41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Falony, 2016, Population-level analysis of gut microbiome variation, Science source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Abdominal bloating and distension are common complaints among FGID patients and are among the most challenging symptoms to treat.

    “Abdominal bloating and distension are common complaints among patients suffering from FGIDs, and are among the most challenging symptoms to treat.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Severity of symptom responses to a standardized meal was positively correlated with mucosal bacterial load, which was inversely correlated with bacterial diversity.

    “Interestingly, severity of symptom responses to a standardized meal was positively correlated with mucosal bacterial load, which in turn was inversely correlated with bacterial diversity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Zhong, 2017, Dyspepsia and the microbiome: time to focus on the small intestine, Gut source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bloating symptoms have mostly been studied in IBS patients, where bloating and distension were typically secondary outcomes.

    “The majority of clinical studies investigating symptoms of bloating have been performed in IBS patients, with bloating and distension evaluated as secondary endpoints148.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Schmulson, 2011, Review article: the treatment of functional abdominal bloating and distension, Aliment Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Two trials, one of L. reuteri DSM 17938 and one of B. longum, found more frequent defecation, but the meta-analysis still judged evidence insufficient for probiotics in pediatric functional constipation.

    “Although two of the included studies, those evaluating L. reuteri DSM 17938165 and B. longum166, reported significantly increased defecation frequency in the treatment arm, the meta-analysis concluded that there is currently insufficient evidence to support the use of probiotics for pediatric FC167.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [165] Coccorullo, 2010, Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study, J Pediatr source

      Not checked in the free run.

    • cites [166] Guerra, 2011, Pediatric functional constipation treatment with Bifidobacterium-containing yogurt: a crossover, double-blind, controlled trial, World J Gastroenterol source

      Not checked in the free run.

    • cites [167] Wojtyniak, 2017, Systematic review: probiotics for functional constipation in children, Eur J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When mice treated with antibiotics received fecal microbiota from slow-transit constipation patients, their GI transit slowed and their SCFA and bile acid profiles changed.

    “The potential role of microbially-derived metabolites is further supported by findings of delayed GI transit and altered SCFA and bile acid profiles following transfer of fecal microbiota from patients with slow transit constipation to antibiotic-treated mice159.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Ge, 2017, Potential role of fecal microbiota from patients with slow transit constipation in the regulation of gastrointestinal motility, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Constipation-induced shifts in gut microbiota can themselves affect GI motility, pointing to feedforward regulation rather than a one-way cause-effect link.

    “Interestingly, gut microbiota changes resulting from constipation can further impact GI motility, suggesting a more complex interaction with feedforward regulation rather than a simple cause-effect relationship53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Touw, 2017, Mutual reinforcement of pathophysiological host-microbe interactions in intestinal stasis models, Physiol Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because GI transit and gut microbiota influence each other, a transit change that alters the microbiota may lead to a microbial community that keeps the transit abnormality going.

    “In summary, the reciprocal interactions between GI transit and gut microbiota suggest that even if changes in gut microbiota are initiated by a change in transit, the altered microbial community can perpetuate the alteration in GI transit, highlighting the adaptability of the gut microbial community.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The gut microbiome can affect mechanisms underlying FD similar to IBS, but microbial community composition of the stomach and small bowel remains elusive and much work is needed before targeting specific microbial mediators that drive FD symptoms.

    “In summary, the gut microbiome can affect mechanisms underlying FD similar to IBS, but the microbial community composition of the stomach and small bowel remain elusive and much work is needed before we can target specific microbial mediators that drive symptoms in FD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pathophysiologic mechanisms contributing to bloating are poorly understood, although SIBO and alterations in gut microbial communities have been hypothesized to play a role through microbial fermentation of dietary nutrients.

    “The pathophysiologic mechanisms contributing to bloating are poorly understood, although SIBO and alterations in gut microbial communities have been hypothesized148 to play a role through microbial fermentation of dietary nutrients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Schmulson, 2011, Review article: the treatment of functional abdominal bloating and distension, Aliment Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Igarashi et al. found that gastric fluid samples from FD patients had an increased Bacteroidetes to Proteobacteria ratio and absence of Acidobacteria, whereas healthy volunteers had a decreased ratio and presence of Acidobacteria.

    “Igarashi et al145 found that gastric fluid samples from patients with FD were characterized by an increased Bacteroidetes to Proteobacteria ratio and absence of Acidobacteria. In contrast, healthy volunteers had a decreased Bacteroidetes to Proteobacteria ratio and presence of Acidobacteria.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Igarashi, 2017, Alteration in the gastric microbiota and its restoration by probiotics in patients with functional dyspepsia, BMJ Open Gastroenterol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Because bloating is predominantly a subjective sensation, there are no animal models to mimic these symptoms.

    “As this is predominantly a subjective sensation, there are no animal models to mimic these symptoms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Probiotic effects on bloating are inconsistent, though certain strains-B. lactis DN-173118, Bifidobacterium animalis DN-173 010, and VSL#3-have shown benefit in some IBS studies.

    “Efficacy of probiotic administration for symptoms of bloating have been less consistently reported153 although some studies in IBS patients have suggested benefit with specific probiotic strains including B. lactis DN-173118, Bifidobacterium animalis DN-173 010154, and VSL#3155.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [153] Hungin, 2013, Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice -- an evidence-based international guide, Aliment Pharmacol Ther source

      Not checked in the free run.

    • cites [154] Guyonnet, 2007, Effect of a fermented milk containing Bifidobacterium animalis DN-173 010 on the health-related quality of life and symptoms in irritable bowel syndrome in adults in primary care: a multicentre, randomized, double-blind, controlled trial, Aliment Pharmacol Ther source

      Not checked in the free run.

    • cites [155] Kim, 2003, A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome, Aliment Pharmacol Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Weizman trial of L. reuteri DSM 17938, already noted for abdominal pain benefit, also found less perceived abdominal distention and bloating.

    “The trial noted previously by Weizman and colleagues139, which reported benefit for abdominal pain with the probiotic L. reuteri DSM 17938, also reported a lower incidence of perceived abdominal distention and bloating.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Weizman, 2016, Lactobacillus reuteri DSM 17938 for the management of functional abdominal pain in childhood: a randomized, double-blind, placebo-controlled trial, J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice that received microbiota from constipated patients, 5-HT levels were inversely related to transit time, with fewer Firmicutes and more Bacteroidetes.

    “5-HT was negatively correlated with transit time and changes were accompanied by decreased relative abundance of the phylum Firmicutes and increased Bacteroidetes in mice receiving fecal microbiota from constipated patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Cao, 2017, Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine, Sci Rep source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    By 6 weeks of age, as many as one quarter of infants show infant colic.

    “Infant colic, a characteristic group of behaviors featuring prolonged crying, is present in up to 25% of infants at 6 weeks of life173”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Wolke, 2017, Systematic review and meta-analysis: fussing and crying durations and prevalence of colic in infants, J Pediatr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Gut microbes may influence bloating via fermentation products and by altering visceral sensation.

    “In summary, while gut microbes can potentially impact these symptoms both via fermentative end products and by their effect on visceral sensation, we need to better characterize the potential microbial mediators in order to develop relevant therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A multicenter randomized double-blind placebo-controlled crossover study reported that a combination of three probiotic bifidobacteria improved pain scores and quality of life among 48 children with IBS, but no benefit was observed among 25 enrolled children with FD, perhaps due to small numbers.

    “Although the previously highlighted multicenter, randomized, double blind, placebo controlled crossover study reported that a combination of three probiotic bifidobacteria improved pain scores and quality of life among 48 children with IBS, no benefit was observed among the 25 enrolled children who had FD, perhaps owing to the small number of patients treated135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Giannetti, 2017, A mixture of 3 bifidobacteria decreases abdominal pain and improves the quality of life in children with irritable bowel syndrome: a multicenter, randomized, double-blind, placebo-controlled, crossover trial, J Clin Gastroenterol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At genus level, mice given microbiota from constipated patients had less Clostridium, Lactobacillus, Desulfovibrio, and Methylobacterium and more Bacteroides and Akkermansia.

    “Genus level analyses further showed decreased relative abundance of Clostridium, Lactobacillus, Desulfovibrio and Methylobacterium and increased relative abundance of Bacteroides and Akkermansia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Cao, 2017, Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Healthy volunteers' microbiomes were richer in genes for carbohydrate, fatty acid, and lipid metabolism, while functional constipation patients had more genes tied to methanogenesis, hydrogen production, and glycerol.

    “Furthermore, healthy volunteers were found to have a gut microbiome enriched in genes involved in carbohydrate, fatty acid, and lipid metabolism while FC patients harbored a high abundance of genes involved in methanogenic pathways, hydrogen production, and glycerol162.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Mancabelli, 2017, Unveiling the gut microbiota composition and functionality associated with constipation through metagenomic analyses, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another multicenter trial of FMT capsules versus placebo in diarrhea-predominant IBS showed no significant symptom improvement at three months; a subgroup analysis suggested more benefit in post-infectious IBS (p=0.09).

    “On the other hand, a separate multicenter RCT189 comparing FMT capsules to placebo in patients with diarrhea-predominant IBS was unable to demonstrate significant symptom relief at three months with FMT, although subgroup analysis suggested patients with post-infectious IBS experienced greater improvement with FMT compared to placebo (p=0.09).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [189] Aroniadis, 2018, A double-blind, randomized, placebo-controlled trial of fecal microbiota transplantation capsules (FMTC) for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiome changes continuously over life, with distinctive features at different ages.

    “A comprehensive view of the gut microbiome in both pediatric and adult FGIDs is important in order to account for the dynamics of the gut microbiome as it exhibits a continuum across the lifespan, with hallmark characteristics in different phases of life192.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Kundu, 2017, Our gut microbiome: the evolving inner self, Cell source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The gut microbiome can be influenced by diet, demographic traits, body mass index, medications, and other variables.

    “There are several factors that can affect the gut microbiome including diet, demographics, body mass index, medication etc. as described above and hence these should be controlled before linking the microbiome with host outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fennel oil was the only other treatment with demonstrated efficacy for infant colic, whereas simethicone and changes to the mother's diet had inconsistent results.

    “Of note, the only other therapy to demonstrate efficacy in infant colic was fennel oil while often-recommended interventions including simethicone and maternal diet manipulation produced mixed results181.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Harb, 2016, Infant colic-what works: a systematic review of interventions for breast-fed infants, J Pediatr Gastroenterol Nutr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The gut microbiome plays a central role in FGID pathophysiology by affecting host physiology, though exact mechanisms are still being investigated.

    “It is now apparent that the gut microbiome is an integral player in the pathophysiology of FGIDs through its effects on host physiological processes even though the precise mechanisms underlying microbial regulation remain an area of active investigation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    A comprehensive view of the gut microbiome in pediatric and adult FGIDs is important to account for its dynamics across the lifespan.

    “A comprehensive view of the gut microbiome in both pediatric and adult FGIDs is important in order to account for the dynamics of the gut microbiome as it exhibits a continuum across the lifespan, with hallmark characteristics in different phases of life192.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Kundu, 2017, Our gut microbiome: the evolving inner self, Cell source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Genetically engineered bacterial strains that assess the gut environment, release metabolites at specific GI locations, and optimize drug metabolism appear to be on the horizon.

    “The use of genetically engineered bacterial strains to assess the gut environment, release metabolites of interest at specific locations within the GI tract, and optimize drug metabolism appears to be on the horizon190, 191.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [190] Kalantar-Zadeh, 2018, A human pilot trial of ingestible electronic capsules capable of sensing different gases in the gut, Nature Electronics source

      Not checked in the free run.

    • cites [191] Mimee, 2018, An ingestible bacterial-electronic system to monitor gastrointestinal health, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among patients with moderate-to-severe IBS, an RCT found FMT yielded more responses at three months (65% vs 43%, p=0.049) than placebo, but this difference disappeared by 12 months.

    “In one RCT among patients with moderate-to-severe IBS, higher response (p=0.049) rates at three months, defined as a 75point improvement in the IBS severity scoring system, were observed in patients receiving FMT (65%) compared to those receiving placebo (43%). However, differences were no longer significant at 12 months followup188.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Johnsen, 2018, Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial, Lancet Gastroenterol Hepatol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Gnotobiotic models permit researchers to include varied diets and microbiomes resembling humans, transfer phenotypes to examine causality, and study complex two-way host-microbe interactions.

    “The use of gnotobiotic models allows inclusion of heterogeneity among gut microbiome and diet similar to human subjects, phenotype transfer to better understand cause-effect relationships, and complex reciprocal interactions among the host and microbiome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Rifaximin has been tested in functional dyspepsia, bloating, and flatulence, and is approved for treating adults with IBS-D.

    “Rifaximin has been studied in functional dyspepsia146, abdominal bloating, and flatulence150, and is approved for treatment of adults with IBS-D151.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [146] Tan, 2017, Randomised clinical trial: rifaximin versus placebo for the treatment of functional dyspepsia, Aliment Pharmacol Ther source

      Not checked in the free run.

    • cites [150] Sharara, 2006, A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence, Am J Gastroenterol source

      Not checked in the free run.

    • cites [151] Pimentel, 2011, Rifaximin therapy for patients with irritable bowel syndrome without constipation, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent study in nonconstipated IBS reported borderline changes in microbial richness and faster proximal colonic emptying, without clear changes in bowel function, permeability, or intraluminal metabolites.

    “with a recent study of patients with nonconstipated IBS showing borderline effects on microbial richness and increased rates of proximal colonic emptying but no clear effects on bowel function, permeability, or production of intraluminal metabolites119.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Acosta, 2016, Effects of rifaximin on transit, permeability, fecal microbiome, and organic acid excretion in irritable bowel syndrome, Clin Transl Gastroenterol source

      Not checked in the free run.

93 of 93

  • The paper relies on this without support.

    Knowledge about the gut microbiome in functional abdominal bloating in children is limited.

    “Little is known regarding the microbiome in functional abdominal bloating in children.”

  • The paper relies on this without support.

    Most knowledge about how gut microbiota affects peripheral constipation mechanisms, such as GI motility, comes from animal studies.

    “Most of our knowledge regarding the effects of the gut microbiota on peripheral mechanisms associated with constipation, such as GI motility, comes from animal studies.”

  • The paper relies on this without support.

    The mechanisms underlying infant colic are unclear, partly because small animal models are lacking.

    “Underlying mechanisms are unclear, due in part to a lack of small animal models.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Functional constipation patients have significantly lower abundance of Bifidobacterium and Lactobacilli than healthy controls.

    “Moreover, characteristic of lower abundance of Bifidobacterium and Lactobacilli, the gut flora in FC patients is significantly distinctive from that in healthy controls.8”

    From Efficacy in bowel movement and change of gut microbiota on adult functional constipation patients treated with probiotics-containing products: a systematic review and meta-analysis (2024) · cites this paper as [8]

    The functional-constipation section (page unavailable) reports that patients’ gut microbiota differs from that of controls, supporting the broader comparison. But it identifies reduced Bacteroides, Roseburia, and Coprococcus in patients—not reduced Bifidobacterium and Lactobacilli. Its report of reduced Lactobacillus concerns mice receiving microbiota from constipated patients, not a patient–control comparison. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The same microbiota-transfer study is described as using mice and rats

    Minor

    The visceral-hypersensitivity section attributes study 66 to germ-free mice, while the later IBS section describes the same study as using germ-free rats. Reference 66 also identifies rats as the recipients.

  • A methane study is cited as a rifaximin trial

    Minor

    The text includes reference 152 among placebo-controlled rifaximin treatment studies, but reference 152 is titled as a study of methane's effects on intestinal transit and contractile activity, not rifaximin treatment.

2 of 2

Cites

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Authors
Shin, A., Preidis, G. A., Shulman, R., & Kashyap, P. C.
Affiliations
  • Indiana University Indianapolis (US)
  • Baylor College of Medicine (US)
  • Mayo Clinic (US)
Corresponding author
Kashyap, Purna C.
ORCID
Venue
Clinical Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2019-01
Volume
17
Issue
2
Pages
256-274
ISSN
1542-3565 (ISSN-L)
DOI
10.1016/j.cgh.2018.08.054
PMC
PMC6314902
OpenAlex
W2888216390
Semantic Scholar
2ae3877f0a5e1ab18d34c70cd6ef284c838f2905
Cited by
163
References
220
Citations by year
2026: 12 · 2025: 13 · 2024: 19 · 2023: 26 · 2022: 33 · 2021: 24 · 2020: 25 · 2019: 9 · 2018: 1 · 2017: 1
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Gastroenterology and Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • National Institutes of Health (KL2TR001106, UL1TR001108, K08 DK113114, P30 DK056338, R01 NR013497, DK111850, DK114007)
  • National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award
  • AGA–Rome Foundation Functional GI and Motility Pilot Research Award
  • American Neurogastroenterology and Motility Society Research Grant
  • Ting Tsung and Wei Fong Chao Foundation
  • Daffy’s Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
Keywords
gut microbiota, functional gastrointestinal disorders, pediatric functional gastrointestinal disorders, microbiota-host interactions, intestinal motility, gut-brain axis, epithelial barrier integrity, immune system development
MeSH terms
Gastrointestinal Microbiome, Host Microbial Interactions, Animals, Disease Models, Animal, Gastrointestinal Diseases, Humans, Microbiota, Dysbiosis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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