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Randomised clinical trial: Gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome

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Abstract

BackgroundA low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h.AimTo determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy.Methods In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (≥50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention).ResultsThirty-three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 ± 0.2 (SEM) episodes/day vs. 1.7 ± 0.4, P < 0.05]. Compared to baseline (1.4 ± 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism.Conclusions In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy.ClinicalTrials.gov identifier: NCT01339117.

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... Several studies have attempted to understand differential responses to a low FODMAP diet. Differentiation of individuals into response types has been based on gut microbiota (Bennet et al., 2018;Chumpitazi et al., 2015;Colomier et al., 2022;Valeur et al., 2018;Vervier et al., 2021;Zhang et al., 2021), metabolite patterns (Nybacka et al., 2021), colonic methane and SCFA production (Eetemadi & Tagkopoulos, 2021), hydrogen production (Schindler et al., 2021), fecal volatile organic compounds (Rossi et al., 2018), intake of FODMAP at baseline (Böhn et al., 2015), and psychological and nutritional factors (Colomier et al., 2022). However, results from these studies are inconsistent, and even in some cases point in opposite directions: For example, a higher proportion of saccharolytic bacteria at baseline has been observed in both response and non-response of IBS symptoms after dietary interventions (Bennet et al., 2018;Chumpitazi et al., 2015;Zhang et al., 2021). ...
... Differentiation of individuals into response types has been based on gut microbiota (Bennet et al., 2018;Chumpitazi et al., 2015;Colomier et al., 2022;Valeur et al., 2018;Vervier et al., 2021;Zhang et al., 2021), metabolite patterns (Nybacka et al., 2021), colonic methane and SCFA production (Eetemadi & Tagkopoulos, 2021), hydrogen production (Schindler et al., 2021), fecal volatile organic compounds (Rossi et al., 2018), intake of FODMAP at baseline (Böhn et al., 2015), and psychological and nutritional factors (Colomier et al., 2022). However, results from these studies are inconsistent, and even in some cases point in opposite directions: For example, a higher proportion of saccharolytic bacteria at baseline has been observed in both response and non-response of IBS symptoms after dietary interventions (Bennet et al., 2018;Chumpitazi et al., 2015;Zhang et al., 2021). In addition, other studies have not been able to identify differential responses to FODMAPs (Halmos et al., 2015;Staudacher et al., 2020). ...
... There is currently also no universal data-analytical framework for identification of differential response to dietary interventions. Both univariate (Böhn et al., 2015;Colomier et al., 2022;Halmos et al., 2015;Schindler et al., 2021;Valeur et al., 2018) and machine learning algorithms (Algera et al., 2022;Bennet et al., 2018;Chumpitazi et al., 2015;Nybacka et al., 2021;Rossi et al., 2018;Staudacher et al., 2020;Vervier et al., 2021;Zhang et al., 2021) have been applied in IBS and dietary trials, using the predictors mentioned above. Robust machine learning algorithms (Saccenti et al., 2014) could overcome the issue with multiple testing in univariate models, known to be problematic in analyzing large-scale omics data (Saccenti et al., 2014). ...
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Introduction There is large variation in response to diet in irritable bowel syndrome (IBS) and determinants for differential response are poorly understood. Objectives Our aim was to investigate differential clinical and molecular responses to provocation with fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) and gluten in individuals with IBS. Methods Data were used from a crossover study with week-long interventions with either FODMAPs, gluten or placebo. The study also included a rapid provocation test. Molecular data consisted of fecal microbiota, short chain fatty acids, and untargeted plasma metabolomics. IBS symptoms were evaluated with the IBS severity scoring system. IBS symptoms were modelled against molecular and baseline questionnaire data, using Random Forest (RF; regression and clustering), Parallel Factor Analysis (PARAFAC), and univariate methods. Results Regression and classification RF models were in general of low predictive power (Q² ≤ 0.22, classification rate < 0.73). Out of 864 clustering models, only 2 had significant associations to clusters (0.69 < CR < 0.73, p < 0.05), but with no associations to baseline clinical measures. Similarly, PARAFAC revealed no clear association between metabolome data and IBS symptoms. Conclusion Differential IBS responses to FODMAPs or gluten exposures could not be explained from clinical and molecular data despite extensive exploration with different data analytical approaches. The trial is registered at www.clinicaltrials.gov as NCT03653689 31/08/2018.
... The overall GI symptoms and abdominal pain severity in both IBS and non-IBS subgroups were lower than baseline but did not reach statistical significance. The number of high FODMAPs diet items in both IBS and non-IBS subgroups significantly decreased from baseline and was not different between groups (IBS patients: 11 [7][8][9][10][11][12][13][14] items to 5 [3][4][5][6][7][8] items; non-IBS patients: 10 [6][7][8][9][10][11][12][13][14][15] items to 5 [4][5][6][7] items; both P < 0.05). ...
... The overall GI symptoms and abdominal pain severity in both IBS and non-IBS subgroups were lower than baseline but did not reach statistical significance. The number of high FODMAPs diet items in both IBS and non-IBS subgroups significantly decreased from baseline and was not different between groups (IBS patients: 11 [7][8][9][10][11][12][13][14] items to 5 [3][4][5][6][7][8] items; non-IBS patients: 10 [6][7][8][9][10][11][12][13][14][15] items to 5 [4][5][6][7] items; both P < 0.05). ...
... 9 Two studies identified that the low FODMAP diet responders had a higher amount of fecal saccharolytic bacteria, for example, Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii than non-responders. 10 However, there were heterogeneities among these studies due to multiple ethnicities, diet consumption, and age. In addition, bacterial identification is costly and inconvenient. ...
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Background/Aims An increase in postprandial intestinal gas plays a role in bloating symptoms. We aim to study the utility of spot breath hydrogen (H2) level in predicting the response to a low fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) diet. Methods Patients with functional gastrointestinal disorders diagnosed by Rome IV criteria with bothersome bloating for > 6 months were prospectively enrolled. Patients completed 7-day food diaries and collected a breath sample 2 hours after their usual lunch at baseline and 4 weeks after low FODMAPs dietary advice by a dietitian. The responder was defined as an improvement of ≥ 30% bloating scores in the fourth week. Results Thirty-eight patients (32 female, 52.6 ± 13.8 years; 22 irritable bowel syndrome) completed the study. Twenty-one patients (55%) were classified as responders. Baseline global gastrointestinal symptoms, bloating, abdominal pain scores, and numbers of high FODMAPs items were similar between responders and non-responders. Both groups significantly decreased high FODMAPs items intake with similar numbers at the follow-up. The area under the curve for predicting low FODMAPs responsiveness using baseline H2 levels was 0.692 (95%CI, 0.51-0.86; P < 0.05), with the best cutoff at 8 parts per million (sensitivity 66.7%, specificity 82.4%). 66% of responders had baseline H2 level > 8 parts per million vs 17% of non-responders (P < 0.05). The baseline spot hydrogen level in responders was 9.5 (3.3-17.3) vs 4.5 (3.3-6.3) in non-responders (P < 0.05). Conclusions A higher baseline breath hydrogen level was associated with bloating improvement after low FODMAPs dietary advice. A spot breath test after lunch, a simple point-of-care test, is possibly helpful in managing patients with bloating.
... Of those, 15 clinical trials met the inclusion and exclusion criteria and were selected for the present systematic review. In specific, six studies evaluated the efficacy of a low-FODMAP diet [36][37][38][39][40][41][42], five evaluated the efficacy of FRD/LRD [28,[43][44][45][46], three trials evaluated the efficacy of the GFD [47][48][49], and one evaluated the efficacy of the MD [50]. The flowchart of the eligible studies is shown in Figure 1. ...
... In total, six relevant studies were found in pediatrics: three studies evaluated the effect of a low-FODMAP diet on GI outcomes in IBS patients [36][37][38], and three studies assessed its effect on FAP, FC, or FD [39,40,42]. Four studies were RCTs [36,38,40,42], and ...
... In total, six relevant studies were found in pediatrics: three studies evaluated the effect of a low-FODMAP diet on GI outcomes in IBS patients [36][37][38], and three studies assessed its effect on FAP, FC, or FD [39,40,42]. Four studies were RCTs [36,38,40,42], and ...
Article
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Functional gastrointestinal disorders (FGIDs) are common in children and adolescents. In recent years, interest in the role of diet in the treatment of FGIDs has increased. Currently, interest focuses on the low-FODMAP diet (LFD), the fructose- or lactose-restricted diet (FRD or LRD), the gluten-free diet (GFD), and the Mediterranean diet (MD). In this review, we focus on the role of these dietary patterns in the FGIDs most commonly diagnosed in clinical practice, namely irritable bowel syndrome (IBS), functional abdominal pain (FAP), functional dyspepsia (FD), and functional constipation (FC). Fifteen clinical trials were systematically reviewed (both RCTs and single-arm clinical trials). We demonstrated the lack of high-quality intervention trials. Based on current evidence, low-FODMAP diet, LRD, FRD, and GFD have no place in daily clinical practice for the management of children and adolescents with FGIDs. Nevertheless, some patients with IBS or RAP may experience some benefit from the use of a low-FODMAP diet or FRD/LRD. Limited data suggest that MD may be promising in the management of FGIDs, especially in IBS patients, but more data are required to investigate the mechanisms of its protective effects.
... Of those, 15 clinical trials met the inclusion and exclusion criteria and were selected for the present systematic review. In specific, 6 studies evaluated the efficacy of a low-FODMAP diet [36][37][38][39][40][41][42], 5 the efficacy of FRD/LRD [28,[43][44][45][46], 3 trials the efficacy of the GFD [47][48][49] and 1 the efficacy of the MD [50]. The flowchart is shown in Figure 1. ...
... In total, 6 relevant studies were found in pediatrics; 3 studies evaluated the efficacy of a low-FODMAP diet on GI outcomes in IBS patients [36][37][38] and 3 studies assessed its role on FAP or FC or FD [39,40,42]. Four studies were RCTs [36,38,40,42] and 2 studies were non-randomized clinical trials [37,39]. ...
... In total, 6 relevant studies were found in pediatrics; 3 studies evaluated the efficacy of a low-FODMAP diet on GI outcomes in IBS patients [36][37][38] and 3 studies assessed its role on FAP or FC or FD [39,40,42]. Four studies were RCTs [36,38,40,42] and 2 studies were non-randomized clinical trials [37,39]. FGIDs diagnosis was based on Rome III criteria in 4 studies [36,37,39,40] and in Rome IV in 2 studies [38,42]. ...
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Functional gastrointestinal disorders (FGIDs) are common in children and adolescents. In recent years, interest in the role of diet in the treatment of FGIDs has increased. Currently, interest focus-es on the low-FODMAP diet (LFD), the fructose- or lactose-restricted diet (FRD or LRD), the glu-ten-free diet (GFD), and the Mediterranean diet (MD). In this review, we focus on the role of these dietary patterns in the FGIDs most commonly diagnosed in clinical practice, namely irritable bowel syndrome (IBS), functional abdominal pain (FAP), functional dyspepsia (FD), and func-tional constipation (FC). Fifteen clinical trials were systematically reviewed (both RCTs and sin-gle arm clinical trials). We demonstrated the lack of high-quality intervention trials. Based on current evidence, low-FODMAP diet, LRD, FRD, or GFD have no place in daily practice for the management of children and adolescents with FGIDs. Nevertheless, some patients with IBS or RAP may have some benefit from the use of a low-FODMAP diet or FRD/LRD. Limited data sug-gest that MD may be promising in the management of FGIDs, especially in IBS patients, but more data are required to investigate the mechanisms of its protective effects.
... Responders were those with alleviation of inflammatory bowel disease (IBS)-symptom severity following low-FODMAP diet intervention. Their baseline taxonomic characteristics exhibited higher relative abundances of Phascolarctobacterium [49], Bacteroides, Ruminococcaceae, and Faecalibacterium parusnitzii [50] (Table 1). Furthermore, overweight participants with lower abundances of Lactobacillus, Leuconostoc, and Pediococcus at baseline showed less weight loss and rapidly regained weight after an energy-restricted diet and normal diet, respectively. ...
... More recently, differences in the effects of specific diets according to the baseline gut microbiota have been observed in participants with gastrointestinal diseases. For example, studies have reported that patients with IBS have different responsiveness depending on the baseline status of specific gut microbiota after consuming a low-FODMAP diet [49,50]. Higher abundances of Phascolarctobacterium, Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii were associated with the alleviation of IBS symptom severity after low-FODMAP diet intervention in individuals with IBS [49,50]. ...
... For example, studies have reported that patients with IBS have different responsiveness depending on the baseline status of specific gut microbiota after consuming a low-FODMAP diet [49,50]. Higher abundances of Phascolarctobacterium, Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii were associated with the alleviation of IBS symptom severity after low-FODMAP diet intervention in individuals with IBS [49,50]. These bacterial taxa may be capable of fermenting nondigestible carbohydrates. ...
Article
Short-chain fatty acids (SCFAs), such as butyrate, propionate, and acetate produced by the gut microbiota have been implicated in physiological responses (defense mechanisms, immune responses, and cell metabolism) in the human body. In several types of cancers, SCFAs, especially butyrate, suppress tumor growth and cancer cell metastasis via the regulation of the cell cycle, autophagy, cancer-related signaling pathways, and cancer cell metabolism. In addition, combination treatment with SCFAs and anticancer drugs exhibits synergistic effects, increasing anticancer treatment efficiency and attenuating anticancer drug resistance. Therefore, in this review, we point out the importance of SCFAs and the mechanisms underlying their effects in cancer treatment and suggest using SCFAproducing microbes and SCFAs to increase therapeutic efficacy in several types of cancers.
... These studies compared the efficacy of a low-FODMAP diet to that of BDA, NICE, BRD, TACD, and a high-FODMAP diet. Most studies showed symptomatic improvement in patients on a low-FODMAP diet [8,[29][30][31][32][33][34][35][36][37][45][46][47][48][49], although a few studies did not show any improvement in symptoms on a low-FODMAP diet [26][27][28]50]. Most studies had smaller sample sizes (< 100 patients). ...
... A study by Zahedi et al. showed symptomatic improvement in both groups of patients, although the improvement was significantly greater in the low-FODMAP diet group [8]. Several studies have demonstrated the superiority of a low-FODMAP diet over a traditional, NICE, BDA, or high-FODMAP diet [29][30][31][33][34][35][36][37][45][46][47][48][49][50]. The studies by Ankersen et al., Bohn et al., and Grubel et al. showed no difference in symptom improvement between the two groups [26][27][28]. ...
Article
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Irritable bowel syndrome (IBS) is frequently observed in clinical practice and affects people from different parts of the world. The pathogenesis and aetiology are not well-defined or fully understood; however, altered bowel movements, psychological factors, and visceral hypersensitivity may contribute to symptoms via a pathway mediated by serotonin and other enteric neurotransmitters. Altered bowel movements, including diarrhoea and constipation, abdominal pain relieved by passing flatus, and bloating are the main salient features of this condition. This systematic review and meta-analysis aimed to determine the effectiveness and efficacy of a low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (low­FODMAP) diet in these patients. Systematic searches were conducted on PubMed, Medline, Google Scholar, and Cochrane Library. Randomised controlled trials (RCTs), systematic trials and cohort studies that included keywords about IBS and a low-FODMAP diet were included. Exclusion criteria included studies that were not in the English language, not relevant to IBS, diet-related to inflammatory bowel disease, or not pertinent to the subject. A total of 41 studies were included in this systematic review and meta-analysis. There was significant heterogeneity among the RCTs; hence, a random-effects model was used. The systematic review included a total of 8460 patients across 36 studies, with follow-up durations ranging from 11 to 16 months. Specifically, the meta-analysis included 15 RCTs with 1118 participants and follow-up durations from two days to nine weeks and six cohort studies including 292 patients with follow-up durations from two weeks to two years. The risk ratio (RR) was 1.21 (95% confidence interval= 0.98-1.51), and the I2 value was 63% for global symptom improvement with a low-FODMAP diet using a random-effects model. There was a low risk of bias in the RCTs. Five studies were included evaluating the effect of a low­FODMAP diet on quality of life, and these studies did not show any statistically significant benefit of a low­FODMAP diet on quality of life, although a mean difference of 4.59 (95% CI 1.50-7.67) was observed. The risk of bias was moderate to severe in the observational studies included in this review. Food intolerance is increasingly recognised as a contributory factor in IBS, and its role in the pathogenesis and precipitation of symptoms is being explored. Specific mechanisms include the fermentation of FODMAPs by the gut microbiota, leading to gas production and subsequent
... Složení mikrobiomu by tedy mohlo být i indikátorem účinnosti low-FODMAP diety. (3) Ve studii Dogan et al. bylo 60 dětí s diagnózou IBS náhodně rozděleno do dvou skupin: 30 dětí na low-FODMAP dietě a 30 dětí na obecné zdravé dietě. Ta byla definována jako strava bez čokolády, kofeinu, kyselých a pikantních jídel a bez potravin s vysokým obsahem tuku. ...
... Data týkající se makro-a mikronutrientů během low-FODMAP diety pocházející z pediatrických studií jsou omezená. V dostupných studiích můžeme nalézt jak údaje o sníženém příjmu celkové energie, proteinů, sacharidů, vlákniny, vitaminu B 12 , folátu, sodíku a vápníku, tak i výsledky, kde k rozdílům v příjmu makroa mikronutrientů nedocházelo.(3,11,12) Obecně lze zatím říct, že low-FODMAP dieta pod dohledem nutričního terapeuta nezpůsobuje významné nedostatky v příjmu živin. ...
... Subsequent studies have consistently confirmed the efficacy of the low FODMAP diet. Most of these studies demonstrated that the low FODMAP diet had a positive effect on IBS symptoms compared to habitual diets [27], typical diets [28,29], a high FODMAP diet [30], or a sham diet [26], and several studies found its equivalent treatment efficacy to standard dietary advice [31] or general dietary guidelines [32]. However, the quality of evidence was rated as low due to potential bias stemming from a lack of double-blinding and inadequate reporting of suboptimal adverse events [4]. ...
... The fecal microbiota has been analyzed by a "GA-map Dysbiosis Test" to create a "Dysbiosis Index" score, which provides a numerical score indicating how an individual's bacterial composition compares to a healthy reference population, with some bacteria having higher abundance than others, including Bacteroides stercoris, Acinetobacter, Pseudomonas, and genus Desulfitispora [58]. Children with IBS who responded to the low FODMAP diet had a higher abundance of certain bacteria at baseline, such as Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii, which are known to have great saccharolytic metabolic capacity [29,59]. Moreover, a recent study stratified IBS patients based on gut microbiota species and metabolic genetic characteristics, identifying two distinct microbiota profiles for IBS pathogenic-like and IBS health-like subtypes [60]. ...
Article
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Background According to national guidelines, a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) is a second-line therapy option for irritable bowel syndrome (IBS) and improves functional intestinal symptoms. Numerous noteworthy results have been published in this field over the past fifteen years. This study aims to analyze the global research trend and hotspot of the low FODMAP diet research, and provide a comprehensive perspective and direction for researchers. Methods The Science Citation Index-Expanded of the Web of Science Core Collection (WoSCC) was used to identify low FODMAP diet-related articles and reviews. Three bibliometric programs (CiteSpace, VOSviewer, Scimago Graphic) were utilized to analyze and visualize the annual publications, authors, countries, institutions, journals, citations, and keywords. Results In total, 843 documents related to the low FODMAP diet research were published in 227 journals by 3,343 authors in 1,233 institutions from 59 countries. The United States, which was the most engaged nation in international collaboration, had the largest annual production and the fastest growth. The most productive organization was Monash University, and the most fruitful researcher was Gibson PR. Nutrients ranked first in terms of the number of published documents. The article “A diet low in FODMAPs reduces symptoms of irritable bowel syndrome” (Halmos EP, 2014) received the most co-citations. Keywords that appear frequently in the literature mainly involve two main aspects: the clinical efficacy evaluation and mechanism exploration of the low FODMAP diet. The term “gut microbiota” stands out as the most prominent keyword among the burst keywords that have remained prevalent till date. Conclusion The restriction stage of the low FODMAP diet is superior to other dietary therapies for IBS in terms of symptom response, but it has a negative impact on the abundance of gut Bifidobacteria and diet quality. Identification of biomarkers to predict response to the low FODMAP diet is of great interest and has become the current research hotspot.
... The baseline microbiome composition of those who responded significantly to the diet appears to be different from that of those who did not, with a higher saccharolytic capacity. Future studies may clarify whether gut microbiome analysis can help IBS patients receive individualized reduced FODMAP or other dietary intervention treatment [28]. ...
... TDA, LFD, and GFD are effective approaches in non-constipated IBS. The TDA diet places a focus on regular eating habits with a lowered intake of fatty and spicy meals, caffeine, alcohol, and other foods that frequently cause symptoms [28]. A study conducted by Rej et al. found that TDA is the most patient-friendly in terms of cost and convenience. ...
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Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal (GI) disorders in the world. Although IBS does not affect a person's life span, it can significantly influence their quality of life. The treatment of IBS should be tailored to each patient's specific symptomatology because it can often be difficult to manage. Given that the pathogenesis of IBS is not well understood, it places a tremendous load on healthcare resources. Over the years, IBS has been described as either a simple GI disorder or a more complex multi-symptomatic gut-brain axis disorder. Many persons with IBS have psychological issues in addition to gastrointestinal symptoms, offering the door to non-pharmacological therapies such as cognitive behavioral therapy, gut-directed hypnosis, or psychodynamic interpersonal therapy. Non-pharmacological therapies with no side effects should be used as first-line therapy. Diet, exercise, microbiota-targeted therapies, and psychological treatments are among the most significant interventions. This review goes into the details of all the non-pharmacological interventions that can be used to treat IBS.
... The studies reported conflicting results. A randomized double-blind cross over clinical trial by Chumpitazi et al. including 33 children demonstrated a significantly lower number of daily episodes of abdominal pain after 48 hours of a low FODMAP diet compared to children on a typical American diet (9). ...
... The study also suggested microbiome composition may play a role in responsiveness to the diet with children who responded having a baseline microbiome composition enriched with taxa known to have greater saccharolytic metabolic capacity (Bacteroides, Ruminococcaceae and Faecalibacterium prausnitzii) than non-responders (9). Another double-blind randomized controlled single center trial conducted in Poland included 27 patients with FAP and found that children randomized to a low FODMAP diet had a trend towards improvement in abdominal symptoms compared to children randomized to the control diet [the control diet was based on the National Institute for Health and Care Excellence guidelines (NICE)] but the difference did not reach statistical significance (10). ...
Article
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Functional abdominal pain disorders (FAPDs) affect up to 25% of children in the United States. These disorders are more recently known as disorders of “brain-gut” interaction. The diagnosis is based on the ROME IV criteria, and requires the absence of an organic condition to explain the symptoms. Although these disorders are not completely understood, several factors have been involved in the pathophysiology including disordered gut motility, visceral hypersensitivity, allergies, anxiety/stress, gastrointestinal infection/inflammation, as well dysbiosis of the gut microbiome. The pharmacologic and non-pharmacologic treatments for FAPDs are directed to modifying these pathophysiologic mechanisms. This review aims to summarize the non-pharmacologic interventions used in the treatment of FAPDs including dietary modifications, manipulation of the gut microbiome (neutraceuticals, prebiotics, probiotics, synbiotics and fecal microbiota transplant) and psychological interventions that addresses the “brain” component of the brain-gut axis (cognitive behavioral therapy, hypnotherapy, breathing and relaxation techniques). In a survey conducted at a large academic pediatric gastroenterology center, 96% of patients with functional pain disorders reported using at least 1 complementary and alternative medicine treatment to ameliorate symptoms. The paucity of data supporting most of the therapies discussed in this review underscores the need for large randomized controlled trials to assess their efficacy and superiority compared to other treatments.
... This has been studied in the use of the low "FODMAP" (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, where microbiome differences have been associated with symptomatic response to a low-FODMAP diet in both children and adults, however with heterogeneous results. 10,11 There is a relative paucity of data addressing the microbiome and IBS treatments that are not diet-related despite the increasing interest in the gut-brain-microbiome axis. Specifically, there have been no microbial studies in relation to neuromodulation. ...
... 44 This supports that microbial fermentative activity may be associated with bloating and triggering of IBS symptoms which has also been speculated by the association of increased saccharolytic pathways with symptomatic response to a low-FODMAP diet. 11 We found an increase in pathways related to the biosynthesis of heme and vitamin K2 (a menaquinone). Increased vitamin and organic compound biosynthesis have been reported in children with IBS, and some of the associated enzymatic reactions were related to menaquinone biosynthesis. ...
Article
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Background Irritable bowel syndrome (IBS), a disorder of the gut–brain axis, is affected by the microbiome. Microbial studies in pediatric IBS, especially for centrally mediated treatments, are lacking. We compared the microbiome between pediatric IBS patients and healthy controls (HC), in relation to symptom severity, and with percutaneous electrical nerve field stimulation (PENFS), a non‐invasive treatment targeting central pain pathways. Methods We collected a stool sample, questionnaires and a 1–2 week stool and pain diary from 11 to 18 years patients with IBS. A patient subset completed 4 weeks of PENFS and repeated data collection immediately after and/or 3 months after treatment. Stool samples were collected from HC. Samples underwent metagenomic sequencing to evaluate diversity, composition, and abundance of species and MetaCyc pathways. Key Results We included 27 cases (15.4 ± 2.5 year) and 34 HC (14.2 ± 2.9 year). Twelve species including Firmicutes spp., and carbohydrate degradation/long‐chain fatty acid (LCFA) synthesis pathways, were increased in IBS but not statistically significantly associated with symptom severity. Seventeen participants (female) who completed PENFS showed improvements in pain (p = 0.012), disability (p = 0.007), and catastrophizing (p = 0.003). Carbohydrate degradation and LCFA synthesis pathways decreased post‐treatment and at follow‐up (FDR p‐value <0.1). Conclusions and Inferences Firmicutes, including Clostridiaceae spp., and LCFA synthesis pathways were increased in IBS patients suggesting pain‐potentiating effects. PENFS led to marked improvements in abdominal pain, functioning, and catastrophizing, while Clostridial species and LCFA microbial pathways decreased with treatment, suggesting these as potential targets for IBS centrally mediated treatments.
... The results demonstrated that IBS patients treated with a low-FODMAP diet had significantly reduced GI symptoms compared with patients consuming a typical Australian diet or subjects consuming their own habitual diet, such as abdominal pain and bloating. In recent years, many research organizations [66] have suggested that a low-FODMAP diet can be considered a first-line therapy for treating IBS based on six different random clinical trials' [58,65,[67][68][69] analyses. Although all six trials have faced varying degrees of criticism regarding placebo selection, the number of study participants, the success rate of blinding, and the duration of the intervention, the consistent results indicate the positive nature of this diet. ...
Article
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Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder characterized by chronic abdominal pain, bloating, and altered bowel habits. Low-FODMAP diets, which involve restricting fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, have emerged as an effective dietary intervention for alleviating IBS symptoms. This review paper aims to synthesize current insights into the impact of a low-FODMAP diet on the gut microbiome and its mechanisms of action in managing IBS. We explore the alterations in microbial composition and function associated with a low-FODMAP diet and discuss the implications of these changes for gut health and symptom relief. Additionally, we examine the balance between symptom improvement and potential negative effects on microbial diversity and long-term gut health. Emerging evidence suggests that while a low-FODMAP diet can significantly reduce IBS symptoms, it may also lead to reductions in beneficial microbial populations. Strategies to mitigate these effects, such as the reintroduction phase and the use of probiotics, are evaluated. This review highlights the importance of a personalized approach to dietary management in IBS, considering individual variations in microbiome responses. Understanding the intricate relationship between diet, the gut microbiome, and IBS symptomatology will guide the development of more effective, sustainable dietary strategies for IBS patients.
... 10 However, not all prior studies have yielded positive results. A double-blind crossover trial of 33 children with IBS revealed that 8 (24.2%) were responders, 15 (45.5%) were nonresponders, and 10 (30.3%) were "placebo-responders." 11 Similarly, a second doubleblind, placebo-controlled trial in 29 children with FAP, showed an improvement trend that did not reach statistical significance, reflecting our finding that LFD is less effective for those patients with pain, but no diarrhea. 12 Implementing restrictive diets, especially in pediatric patients, is challenging. ...
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Objectives Disorders of gut–brain interaction (DGBIs), including irritable bowel syndrome (IBS), are common among children. Although a diet that is low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) has been proven to help adults with IBS, there is conflicting evidence of its efficacy in pediatric patients. Methods This was a retrospective chart review of pediatric patients with DGBIs diagnosed by a pediatric gastroenterologist between December 2018 and April 2022 and referred to a dietician for low FODMAP diet (LFD). The diagnosis was based on Rome IV criteria, and the chart review was based on International Classification of Diseases 10 diagnosis codes for DGBIs. Subjective historical assessment was used to define symptom improvement. The causative FODMAP Monash group(s) were identified during the reintroduction phase based on a symptom diary. Results A total of 58 patients were initially identified (38 females), 47 of whom completed the LFD and followed up. This included 24 patients with IBS‐diarrhea predominant (IBS‐D), 10 patients with IBS‐mixed type (IBS‐M), 6 patients with IBS‐constipation predominant (IBS‐C), and 7 patients with functional abdominal pain (FAP) or functional dyspepsia (FD). Symptom improvement occurred in 22 (91.6%) of IBS‐D, 7 (70%) of IBS‐M, 3 (50%) of IBS‐C, and 3 (42.8%) of FAP/FD. Fructans, garlic, onions, and lactose were the most common offenders. Conclusion LFD improves symptoms in most patients with DGBIs, particularly those with IBS‐D.
... Therefore, further comprehensive research is essential to unravel the intricate interplay between intestinal microbiota and endometriosis. In fact, the multifactorial nature of endometriosis links it to an elevated risk of irritable bowel syndrome, for which dietary interventions have shown efficacy [78]. Further investigation is needed into the disappearance of A. muciniphila observed in mice with the largest lesions, particularly regarding its potential protective effects, akin to those of a probiotic. ...
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Background Endometriosis, affecting 10% of women in their reproductive years, remains poorly understood. Both individual and environmental unexplained factors are implicated in this heterogenous condition. This study aims to examine the influence of a Western diet on endometriosis lesion development in mice and to uncover the mechanisms involved. Methods Mice were fed either a control diet or a Western diet (high in fatty acids and low in fiber) for 4 weeks. Endometriosis was then surgically induced, and lesion development was monitored by ultrasound. After 7 weeks, the mice were sacrificed for analysis of lesion characteristics through RT-qPCR, immunohistochemistry, and flow cytometry. Additionally, the intestinal microbiota was assessed using 16S rRNA gene sequencing. Results Mice on the Western diet developed lesions that were significantly twice as large compared to those on the control diet. These lesions exhibited greater fibrosis and proliferation, alongside enhanced macrophage activity and leptin pathway expression. Changes in the intestinal microbiota were significantly noted after endometriosis induction, regardless of diet. Notably, mice on the Western diet with the most substantial lesions showed a loss of Akkermansia Muciniphila in their intestinal microbiota. Conclusions A Western diet significantly exacerbates lesion size in a mouse model of endometriosis, accompanied by metabolic and immune alterations. The onset of endometriosis also leads to substantial shifts in intestinal microbiota, suggesting a potential link between diet, intestinal health, and endometriosis development. Graphical Abstract
... While we noted improvements in gut microbiota composition and inflammatory markers in response to dietary interventions, these results were not uniformly observed across all included studies, suggesting a complex interaction influenced by individual patient microbiomes and dietary compliance. This complexity is echoed in the work of Chumpitazi et al. [18], which found that responses to dietary interventions could vary significantly based on baseline microbiota profiles, pointing to the need for personalized dietary management strategies in IBS treatment. Such findings indicate a move toward more individualized therapeutic approaches in the gastroenterological field, highlighting the importance of tailoring treatments to the specific biological and clinical profiles of IBS patients [28]. ...
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This systematic review synthesizes findings from 12 studies to evaluate the effectiveness of dietary interventions in managing irritable bowel syndrome (IBS), with a focus on low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diets, probiotics, and prebiotics. The review rigorously follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and includes studies selected through comprehensive database searches. In adults diagnosed with IBS, this review assesses how effective dietary interventions, specifically low-FODMAP diets, probiotics, and prebiotics, are compared to standard management or placebo in improving clinical outcomes, modifying gut microbiota composition, and reducing inflammatory markers. Our analysis reveals that low-FODMAP diets consistently alleviate IBS symptoms and improve quality of life. However, the effectiveness of probiotics and prebiotics varies, with outcomes dependent on specific strains and individual patient microbiota profiles. The studies demonstrate significant improvements in gastrointestinal symptoms and microbiota composition, highlighting the potential of dietary strategies to beneficially modify gut health. However, the research points to the necessity of personalizing dietary approaches based on individual responses and microbiota profiles to optimize treatment efficacy. The risk of bias was assessed using the Cochrane risk-of-bias 2 tool for randomized controlled trials (RCTs) and the AMSTAR 2 tool for systematic reviews, with varying degrees of bias across the studies. This review identifies gaps in the long-term efficacy of these interventions and calls for more extensive trials to explore their sustained impacts. Our findings suggest that dietary management should be integrated into routine IBS treatment protocols and emphasize the need for further research to establish standardized dietary recommendations tailored to patient-specific characteristics.
... In another double-blind, crossover trial involving 33 children with IBS (average age: 12 years), Chumpitazi et al. compared a low FODMAP diet with a regular childhood diet. The study found that children on the low FODMAP diet experienced fewer episodes of abdominal pain, while those on the regular childhood diet experienced a significant increase in abdominal pain when compared to baseline characteristics (Chumpitazi et al. 2015). It is important to note that while a low FODMAP diet can provide relief for some individuals with IBS, its impact on the intestinal microbiota over the long term in these patients requires further investigation. ...
Chapter
Exploration of the human gut microbiome has deepened the understanding of how microbial colonisation, development and imbalances contribute to different health-related ailments. The immense metabolic capabilities of gut microbes and their role in maintaining human physical condition have become increasingly evident, enabling new possibilities for using them as therapeutic agents to combat human gastrointestinal (GI) ailments. Microbiome therapeutics in different GI diseases involve interventions that aim to manipulate the gut microbiome using approaches such as adding, removing or modulating microbes and utilising antibiotics, prebiotics and postbiotics. This approach can potentially overcome traditional therapeutics’ limitations by offering personalised, coordinated, reliable and sustainable treatments. However, despite its promise, microbiome therapeutics are still in the early stages of development and face various regulatory and technical challenges that require further research, particularly in different GI disorders. This chapter provides an outline of the existing knowledge and landscape of microbiome therapeutics specifically using fecal microbiome transplantation (FMT), prebiotics, probiotics, postbiotics, antibiotics and synbiotics discussing the existing applications in different GI disorders and exploring potential future directions for modulating the microbiome-based treatments.
... In another double-blind, crossover trial involving 33 children with IBS (average age: 12 years), Chumpitazi et al. compared a low FODMAP diet with a regular childhood diet. The study found that children on the low FODMAP diet experienced fewer episodes of abdominal pain, while those on the regular childhood diet experienced a significant increase in abdominal pain when compared to baseline characteristics (Chumpitazi et al. 2015). It is important to note that while a low FODMAP diet can provide relief for some individuals with IBS, its impact on the intestinal microbiota over the long term in these patients requires further investigation. ...
Chapter
Exploration of the human gut microbiome has deepened the understanding of how microbial colonisation, development and imbalances contribute to different health-related ailments. The immense metabolic capabilities of gut microbes and their role in maintaining human physical condition have become increasingly evident, enabling new possibilities for using them as therapeutic agents to combat human gastrointestinal (GI) ailments. Microbiome therapeutics in different GI diseases involve interventions that aim to manipulate the gut microbiome using approaches such as adding, removing or modulating microbes and utilising antibiotics, prebiotics and postbiotics. This approach can potentially overcome traditional therapeutics’ limitations by offering personalised, coordinated, reliable and sustainable treatments. However, despite its promise, microbiome therapeutics are still in the early stages of development and face various regulatory and technical challenges that require further research, particularly in different GI disorders. This chapter provides an outline of the existing knowledge and landscape of microbiome therapeutics specifically using fecal microbiome transplantation (FMT), prebiotics, probiotics, postbiotics, antibiotics and synbiotics discussing the existing applications in different GI disorders and exploring potential future directions for modulating the microbiome-based treatments.
... Trials using a low FODMAP diet in children with AP-DGBI have provided some evidence to use a low FODMAP diet as the therapeutic modality. However, all these trials have problems such as inadequate children, using the diet for a shorter period, and other methodological flaws [110][111][112]. However, there is a tendency in these trials that a low FODMAP diet has some efficacy in relieving symptoms. ...
Article
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In 1958, Apley and Naish authored a groundbreaking paper in Archives of Disease in Childhood, elucidating the epidemiology and risk factors of recurrent abdominal pain in children—a subject that had confounded clinicians of their time. Surprisingly, even after 65 years, there are several unanswered questions regarding the etiology, pathophysiology, and management of pediatric abdominal pain. Contrary to the prevailing notion that children naturally outgrow functional abdominal pain, compelling evidence suggests it's possible these children develop a number of clinically significant psychological issues that could profoundly impact their quality of life and, consequently, future health and educational outcomes. In this light, we aimed to comprehensively review the current literature to update the knowledge of practicing clinicians on functional abdominal pain, summarizing the evidence from the last 65 years. Conclusion: The enduring unanswered questions surrounding childhood abdominal pain continue to challenge clinicians, resulting in unnecessary investigations, thereby contributing to substantial healthcare expenditures. It is also evident that children with long-standing symptoms would progress to adulthood with the potential to develop irritable bowel syndrome and many psychological disturbances. Several key interventions using pharmacological agents, such as amitriptyline, showed that some of these drugs are no more effective than the placebo in clinical trials. Several research during the recent past suggest that psychological interventions such as gut-directed hypnotherapy alleviate symptoms and ensure better prognosis in the long run. Therefore, clinicians and researchers must join hands to explore the pathophysiological mechanisms underpinning functional abdominal pain and novel therapeutic strategies to ensure the well-being of these children. What is Known: • Functional abdominal pain disorders are common among children, with a worldwide prevalence of 13.5% of children suffering from at least one of these disorders • These disorders contribute to a significant reduction in the quality of life of affected children and their families and lead to an array of psychological problems What is New: • The biological basis of functional abdominal pain is becoming more explicit, including complex interactions between altered microbiome, deranged motility, and psychological dysfunction with gut-brain interactions • Novel approaches giving minimal emphasis on pharmacological interventions and exploring psychological interventions are showing promising results
... A prospective cohort study was performed on 161 Dutch children fulfilling the Rome III criteria for abdominal-pain-related FGIDs [124]. SIBO Summary of evidence: A randomized double-blind, crossover trial evaluated the effect of a low FODMAPs diet on 33 children fulfilling Rome III criteria for IBS [125]. After 1-week baseline period, children were randomized to receive either a low fermentable oligo-, di-and monosaccharides, and polyols (FODMAPs) diet (containing 0.15 g/kg/day-maximum 9 g/day-of FODMAPs) or a typical American childhood diet [(TACD) containing 0.7 g/kg/day-maximum 50 g/day-of FODMAPs]. ...
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The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID), whose prevalence has widely increased in pediatric population during the past two decades. The exact pathophysiological mechanism underlying IBS is still uncertain, thus resulting in challenging diagnosis and management. Experts from 4 Italian Societies participated in a Delphi consensus, searching medical literature and voting process on 22 statements on both diagnosis and management of IBS in children. Recommendations and levels of evidence were evaluated according to the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was reached for all statements. These guidelines suggest a positive diagnostic strategy within a symptom-based approach, comprehensive of psychological comorbidities assessment, alarm signs and symptoms’ exclusion, testing for celiac disease and, under specific circumstances, fecal calprotectin and C-reactive protein. Consensus also suggests to rule out constipation in case of therapeutic failure. Conversely, routine stool testing for enteric pathogens, testing for food allergy/intolerance or small intestinal bacterial overgrowth are not recommended. Colonoscopy is recommended only in patients with alarm features. Regarding treatment, the consensus strongly suggests a dietary approach, psychologically directed therapies and, in specific conditions, gut-brain neuromodulators, under specialist supervision. Conditional recommendation was provided for both probiotics and specific fibers supplementation. Polyethylene glycol achieved consensus recommendation for specific subtypes of IBS. Secretagogues and 5-HT4 agonists are not recommended in children with IBS-C. Certain complementary alternative therapies, antispasmodics and, in specific IBS subtypes, loperamide and rifaximin could be considered.
... In recent years, the characterization of phylogeny and functional diversity has been shown as a key factor in bacterial community analysis. PICRUSt has long been a key tool for studying the functional capacity of bacterial communities in soils (Chen et al., 2016;Thelusmond et al., 2016), rivers and lakes (Abia et al., 2018;Koo et al., 2017) and gut microbiota (Chumpitazi et al., 2015). In this study, PICRUSt results showed that microbial addition accelerated bacterial community metabolism, favored microbial utilization and transformation of carbon sources, and promoted the degradation of macromolecular substances (Fig. 8). ...
... The potential predictors of treatment responses in the context of commencing a low FODMAP diet include the composition and richness of specific bacteria [122][123][124][125]. ...
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The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.
... The composition of the microbiota could potentially be used to predict the response of IBS patients to the low FODMAP diet. In a trial involving 33 children, it was observed that responders to the low FODMAP diet had higher levels of taxa such as Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii, known for their greater saccharolytic metabolic activity [84]. A recent study involving 611 patients with IBS showed that 10 bacterial markers had a positive predictive value of 76% in identifying individuals who would respond positively to the low FODMAP diet [85]. ...
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Endometriosis and irritable bowel syndrome (IBS) are chronic conditions affecting up to 10% of the global population, imposing significant burdens on healthcare systems and patient quality of life. Interestingly, around 20% of endometriosis patients also present with symptoms indicative of IBS. The pathogenesis of both these multifactorial conditions remains to be fully elucidated, but connections to gut microbiota are becoming more apparent. Emerging research underscores significant differences in the gut microbiota composition between healthy individuals and those suffering from either endometriosis or IBS. Intestinal dysbiosis appears pivotal in both conditions, exerting an influence via similar mechanisms. It impacts intestinal permeability, triggers inflammatory reactions, and initiates immune responses. Furthermore, it is entwined in a bidirectional relationship with the brain, as part of the gut–brain axis, whereby dysbiosis influences and is influenced by mental health and pain perception. Recent years have witnessed the development of microbiota-focused therapies, such as low FODMAP diets, prebiotics, probiotics, antibiotics, and fecal microbiota transplantation, designed to tackle dysbiosis and relieve symptoms. While promising, these treatments present inconsistent data, highlighting the need for further research. This review explores the evidence of gut dysbiosis in IBS and endometriosis, underscoring the similar role of microbiota in both conditions. A deeper understanding of this common mechanism may enable enhanced diagnostics and therapeutic advancements.
... Identifying the interactions between the host, the microbiome, and lifestyle exposures that influence lifestyle responses is the fundamental difficulty in realizing the potential of a microbiome-informed customized lifestyle. Whereas previous studies have demonstrated that the microbiome composition can be used to classify individuals into responders and non-responders on the basis of the health improvements from lifestyle interventions [48,49], predictive models of personalized microbiota response have not yet been developed. We demonstrated here that it is possible to develop a generic ML model covering diverse lifestyle exposures that predicts the scale of microbiome change using only the baseline microbiome composition. ...
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Background A growing body of evidence suggests that the gut microbiota is strongly linked to general human health. Microbiome-directed interventions, such as diet and exercise, are acknowledged as a viable and achievable strategy for preventing disorders and improving human health. However, due to the significant inter-individual diversity of the gut microbiota between subjects, lifestyle recommendations are expected to have distinct and highly variable impacts to the microbiome structure. Results Here, through a large-scale meta-analysis including 1448 shotgun metagenomics samples obtained longitudinally from 396 individuals during lifestyle studies, we revealed Bacteroides stercoris, Prevotella copri, and Bacteroides vulgatus as biomarkers of microbiota’s resistance to structural changes, and aromatic and non-aromatic amino acid biosynthesis as important regulator of microbiome dynamics. We established criteria for distinguishing between significant compositional changes from normal microbiota fluctuation and classified individuals based on their level of response. We further developed a machine learning model for predicting “responders” and “non-responders” independently of the type of intervention with an area under the curve of up to 0.86 in external validation cohorts of different ethnicities. Conclusions We propose here that microbiome-based stratification is possible for identifying individuals with highly plastic or highly resistant microbial structures. Identifying subjects that will not respond to generalized lifestyle therapeutic interventions targeting the restructuring of gut microbiota is important to ensure that primary end-points of clinical studies are reached. 2m7TsyyzrZ6DMn35dcSWgYVideo Abstract
... 2021 ). Similarl y, le vels of Faecalibacterium increased in children given a diet low in fermentable oligosacc harides, disacc harides, monosacc harides, and polyols (FODMAPs), and the abundance of bacteria in this taxon correlated with symptom improvement (Chumpitazi et al. 2015 ). The FODMAP diet contains reduced quantities of fermentable carbohydrates and has been effective in reducing gastrointestinal symptoms in adults with IBD and IBS, e v en if it decreases Faecalibacterium le v els (Hustoft et al. 2017, Cox et al. 2020. ...
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In humans, many diseases are associated with alterations in gut microbiota, namely increases or decreases in the abundance of specific bacterial groups. One example is the genus Faecalibacterium. Numerous studies have underscored that low levels of Faecalibacterium are correlated with inflammatory conditions, with inflammatory bowel disease (IBD) in the forefront. Its representation is also diminished in the case of several diseases, including colorectal cancer (CRC), dermatitis, and depression. Additionally, the relative presence of this genus is considered to reflect, at least in part, intestinal health status because Faecalibacterium is frequently present at reduced levels in individuals with gastrointestinal diseases or disorders. In this review, we first thoroughly describe updates to the taxonomy of Faecalibacterium, which has transformed a single-species taxon to a multispecies taxon over the last decade. We then explore the links discovered between Faecalibacterium abundance and various diseases since the first IBD-focused studies were published. Next, we examine current available strategies for modulating Faecalibacterium levels in the gut. Finally, we summarize the mechanisms underlying the beneficial effects that have been attributed to this genus. Together, epidemiological and experimental data strongly support the use of Faecalibacterium as a next-generation probiotic (NGP) or live biotherapeutic product (LBP).
... One study in adults with IBS suggests that having a certain faecal bacterial profile might predict non-response to a low FODMAP diet but not to BDA/NICE first-line advice (68) . Another study in children with IBS reported that those who responded to a low FODMAP diet had microbiomes with greater saccharolytic metabolic capacity at baseline, i.e. those able to ferment complex carbohydrates such as inulin which is an FODMAP (69) . Both studies report on the abundance of bacterial taxa but have opposing results with reference to prediction of response to a low FODMAP diet, indicating a need for further investigation in a more heterogeneous population. ...
Article
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A diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) improves functional bowel symptoms and is a second-line dietary management strategy for the treatment of irritable bowel syndrome (IBS). The diet is complex and involves three stages: restriction, reintroduction and personalisation and clinical effectiveness is achieved with dietitian-led education; however, this is not always available. The aim of this review is to provide an update on the evidence for using the low FODMAP diet, with a focus on the impact of FODMAP restriction and reintroduction considering long-term management of IBS in a clinical setting. Randomised controlled trials have assessed symptom response, quality of life, dietary intake and changes to the gut microbiota during FODMAP restriction. Systematic reviews and meta-analyses consistently report that FODMAP restriction has a better symptom response compared with control diets and a network analysis reports the low FODMAP diet is superior to other dietary treatments for IBS. Research focused on FODMAP reintroduction and personalisation is limited and of lower quality, however common dietary triggers include wheat, onion, garlic, pulses and milk. Dietitian-led delivery of the low FODMAP diet is not always available and alternative education delivery methods, e.g. webinars, apps and leaflets, are available but remove the personalised approach and may be less acceptable to patients and may introduce safety concerns in terms of nutritional adequacy. Predicting response to the low FODMAP diet using symptom severity or a biomarker is of great interest. More evidence on less restrictive approaches and non-dietitian-led education delivery methods are needed.
... The LFD is commonly used in the management of adults with lower FGIS with few studies assessing its use in children with IBS [17]. A small number of studies have shown the LFD to be a useful treatment for FGIS in adults with IBD [10], but none have evaluated its use in children with IBD. ...
Article
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The low FODMAP diet (LFD) is a dietary intervention developed for and used particularly for the management of functional GI symptoms (FGIS) in adults with irritable bowel syndrome (IBS). It has also been proposed to improve coincident functional gut symptoms in adults with inflammatory bowel disease (IBD). This report describes the outcomes of the LFD in a series of children with IBD with concurrent FGIS. This study included children aged between 7-14 years with quiescent IBD and overlapping FGIS. All participants received three dietetic consultations in line with best practice recommendations. The IBS Global Improvement Scale was used to assess symptom outcomes. Mean (standard deviation [SD]) and number (percentage) were calculated for continuous and categorical data. Seven (77.7%) of the nine children experienced GI symptom improvement after completing the LFD for four weeks. All seven children had recurrence of symptoms in response to challenge with fructans and three also experienced symptoms of lactose intolerance. The LFD may be considered as a dietary option to help alleviate overlapping FGIS in children with quiescent IBD when provided by a qualified paediatric gastroenterology dietitian. Further studies are now required to support these findings.
... 2014 wykazały, że zastosowanie diety ubogiej w FODMAPs wpłynęło na lepsze samopoczucie 70% pacjentów cierpiących na zespół jelita drażliwego, a już po tygodniu nastąpiło u nich znaczne zmniejszenie nasilenia objawów klinicznych. Również u dzieci wprowadzenie diety low-FODMAP przyczyniło się do zmniejszenia częstotliwości występowania bólu brzucha (Chumpitazi i in. 2015). ...
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Irritable bowel syndrome is a functional disorder of the gastrointestinal tract with a very complex etiopathogenesis. About 15-20% of the population suffers from it. The causes of the disease include many factors: disorders of the enteric nervous system, visceral hypersensitivity, intestinal motility disorders, as well as nutritional, psychogenic and genetic factors. Characteristic symptoms of the disease include abdominal pain, bloating, constipation and diarrhea. One effective way to treat the condition is to follow a proper diet.
... 33 At baseline, faecal propionate was higher and total SCFA showed a trend towards being higher in responders to the LFD. These findings may indicate impaired SCFA absorption in responders at baseline, alternatively, they also support previous research indicating that higher saccharolytic bacteria at baseline may be a driver of response, 35,36 with a previous analysis of data from multiple studies demonstrating high colonic methane and SCFA production was predictive of response to low FODMAP diet. 33 A microbiota rich in carbohydrate-fermenting microbes could feasibly be linked to IBS symptoms associated with gas production, as patients with IBS experience increased symptom intensity with peak colonic gas production. ...
Article
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Background The low FODMAP diet (LFD) leads to clinical response in 50%–80% of patients with irritable bowel syndrome (IBS). It is unclear why only some patients respond. Aims To determine if differences in baseline faecal microbiota or faecal and urine metabolite profiles may separate clinical responders to the diet from non‐responders allowing predictive algorithms to be proposed. Methods We recruited adults fulfilling Rome III criteria for IBS to a blinded randomised controlled trial. Patients were randomised to sham diet with a placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.8 g/d B‐galactooligosaccharide (LFD/B‐GOS), for 4 weeks. Clinical response was defined as adequate symptom relief at 4 weeks after the intervention (global symptom question). Differences between responders and non‐responders in faecal microbiota (FISH, 16S rRNA sequencing) and faecal (gas–liquid chromatography, gas‐chromatography mass‐spectrometry) and urine (¹H NMR) metabolites were analysed. Results At 4 weeks, clinical response differed across the 3groups with adequate symptom relief of 30% (7/23) in controls, 50% (11/22) in the LFD group and 67% (16/24) in the LFD/B‐GOS group (p = 0.048). In the control and the LFD/B‐GOS groups, microbiota and metabolites did not separate responders from non‐responders. In the LFD group, higher baseline faecal propionate (sensitivity 91%, specificity 89%) and cyclohexanecarboxylic acid esters (sensitivity 80%, specificity 78%), and urine metabolite profile (Q² 0.296 vs. randomised −0.175) predicted clinical response. Conclusions Baseline faecal and urine metabolites may predict response to the LFD.
Article
Background Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific changes in the metabolome in IBS-P. Methods Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated. Findings Two distinct metabotypes were identified and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile rich in short chain fatty acids (SCFAs). After FODMAP restriction significant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly greater in IBS-P compared to IBS-H (p = 0.016 and p = 0.026, respectively). Using just five metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78–0.94), specificity 71.4% (95% CI: 0.55–0.88). Interpretation A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pro-nociceptive potential when produced in a specific IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best. Funding This research was co-funded by 10.13039/501100002927Addenbrooke's Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the 10.13039/501100018956NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
Chapter
The most frequent functional gastrointestinal disorders (FGID) in children include infantile colic, constipation, functional abdominal pain (FAP), and irritable bowel syndrome (IBS). Unfortunately, treatment options for FGID in children are limited, therefore many dietary interventions have been evaluated, including probiotics. This chapter summarizes currently available evidence and recommendations for probiotic use in the treatment of frequent FGIDs in children. The strongest evidence exists for the use of Limosilactobacillus (L.) reuteri DSM 17938 and Bifidobacterium animalis subsp. lactis BB-12 for the treatment of infantile colic in breastfed infants. Limited but yet encouraging evidence exists for Lacticaseibacillus rhamnosus GG (LGG) for the treatment of IBS and L. reuteri DSM 17938 for FAP.
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Functional Gastrointestinal Disorders (FGIDs), also recently referred to as disorders of gut-brain interaction, are common in the pediatric population and vary according to age groups, i.e., neonatal/toddler and child/adolescent FGIDs. Pediatric FGIDs tend to evolve and persist into adulthood, contributing to financial burdens and psychological problems. Despite several decades of progress and advancements in molecular biology and medical sciences, the exact pathophysiology remains unknown, although genetic, psychosocial, gut dysbiosis, visceral hypersensitivity, and neuroimmune causes have been implicated. The ROME IV criteria facilitate easier and earlier diagnosis of FGIDs, excluding organic causes while minimizing unnecessary investigations. Dietary, psychosocial, neuro-stimulatory, and pharmacological management methods exist, although fewer trials have focused on pediatric drug-based management. Early identification and appropriate treatment hold the potential for cure and improvement in quality of life.
Chapter
This chapter will present advances in the treatment of visceral pain. Various treatments for visceral pain have been described in detail in the previous sections (Chaps. 6, 7, 8, and 9), and this chapter will focus on the major discoveries and advances in clinical applications of treatments for visceral pain in recent years.
Article
Objectives Abdominal pain remains one of the most common referral reasons to pediatric gastroenterology. Dietary intolerances are often considered but due to various factors are hardly pursued. We observed that diet review in large number of children with abdominal pain was high in sugary foods which led to food intolerance investigation and dietary intervention. Methods A retrospective review was conducted of patients presenting with abdominal pain, diarrhea, or vomiting and negative GI evaluation, who underwent fructose breath testing. Patients younger than 20 years old who were seen between June 1, 2018 and March 1, 2021 were included. Statistical analysis was performed in R. Results There were 110 pediatric patients during the study period who underwent fructose breath testing, with 31% male and 69% female. The average age was 12.14 ± 4.01 years, and the average BMI was 21.21 ± 6.12. Abdominal pain was the most common presenting symptom (74.5%) followed by diarrhea and vomiting. Seventy‐seven patients (70%) had a positive fructose breath test and were diagnosed with dietary intolerance to fructose. The 56 (67.5%) of those patients experienced symptoms during the breath test. Forty‐three patients improved with dietary intervention. Twenty‐seven on low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet and 16 on other diets. Conclusions Based on analysis of our cohort of children with abdominal pain and high incidence of fructose intolerance as well as improvement in symptoms, following dietary changes, this condition should be considered and treated. Further investigation is needed to improve diagnostic testing but also into understanding mechanisms behind symptom presentation in this population.
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The gut microbiota is believed to be a critical factor in the pathogenesis of IBS, and its metabolic byproducts, such as short-chain fatty acids (SCFAs), are known to influence gut function and host health. Despite this, the precise role of SCFAs in IBS remains a topic of debate. In this study, we examined the bacterial community structure by 16S rRNA gene profiling and SCFA levels by UPLC-MS/MS in fecal samples from healthy controls (HC; n = 100) and non-constipated patients (IBS-D and IBS-M; NC-IBS; n = 240) enrolled in 19 hospitals in Italy. Our findings suggest a significant difference between the fecal microbiomes of NC-IBS patients and HC subjects, with HC exhibiting higher intra-sample biodiversity. Furthermore, we were able to classify non-constipated patients into two distinct subgroups based on their fecal SCFA levels (fecal catabotype “high” and “low”), each characterized by unique taxonomic bacterial signatures. Our results suggest that the fecal catabotype with higher SCFA levels may represent a distinct clinical phenotype of IBS that could have implications for its diagnosis and treatment. This study provides a new perspective on the intricate relationship between the gut microbiome and bowel symptoms in IBS, underscoring the importance of personalized strategies for its management.
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Background: The low FODMAP diet (LFD) has been associated with reduced symptomology in pediatric functional gastrointestinal disorders (FGIDs). The LFD is a complex dietary intervention that may be difficult to follow; thus, there is great interest in determining factors that contribute to adherence. Objective: To examine whether baseline abdominal pain, emotional/behavioral problems, and/or quality of life predict adherence to the LFD in children with FGIDs. Design: This was a single group pre-post intervention design within a larger randomized controlled trial. Participants/setting: Thirty 7-12-year-old children with FGIDs were recruited from pediatric GI and primary care settings throughout Texas from 2019-2021. Evaluated participants were randomized to an LFD intervention as part of a larger randomized controlled trial. Intervention: Participants received dietary counseling and followed the LFD for 3 weeks. Measures: Emotional/behavioral problems and quality of life were obtained via parent-report, and abdominal pain was measured via child-report. Adherence was assessed utilizing diet records and computed via a decrease in consumption of overall FODMAP intake. Statistical analyses performed: A hierarchical generalized linear mixed regression model examined factors associated with adherence. Results: Greater baseline quality of life was associated with better adherence to the LFD (beta coefficient β=-.02, p=.03), while baseline emotional/behavioral problems and abdominal pain complaints were not significantly associated with adherence (all ps>.28). Conclusions: Higher child quality of life as reported by parents was related to increased adherence to this complex dietary intervention.
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Irritable bowel syndrome (IBS) is a heterogeneous functional disorder with a multifactorial etiology that involves the interplay of both host and environmental factors. Among environmental factors relevant for IBS etiology, the diet stands out given that the majority of IBS patients report their symptoms to be triggered by meals or specific foods. The diet provides substrates for microbial fermentation, and since the composition of the intestinal microbiota is disturbed in IBS patients, the link between diet, microbiota composition and microbial fermentation products might play an essential role in IBS etiology. In this review, we summarize current evidence regarding the impact of diet and the intestinal microbiota on IBS symptoms as well as the reported interactions between diet and the microbiota composition. Based on the existing data we suggest pathways (mechanisms) by which diet components, via the microbial fermentation could trigger IBS symptoms. Finally, this review provides recommendations for future studies that would enable elucidation of the role of diet and microbiota and how these factors may be (inter)related in the pathophysiology of IBS.
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Objective A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial. Design Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with ≥21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed. Results Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs 9.83 (9.72 to 9.93) log10 copies/g; p<0.001) compared with the Australian diet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; p<0.001) and mucus-associated Akkermansia muciniphila (19.3; p<0.001), and reduced Ruminococcus torques. Conclusions Diets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation. Trial registration number ACTRN12612001185853.
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DNA-binding transcription factors (TFs) are essential components of transcriptional regulatory networks in Bacteria. LacI-family TFs (LacI-TFs) are broadly distributed among certain lineages of bacteria. The majority of characterized LacI-TFs sense sugar effectors and regulate carbohydrate utilization genes. The comparative genomics approaches enable in silico identification of TF-binding sites and regulon reconstruction. To study function and evolution of LacI-TFs, we performed genomics-based reconstruction and comparative analysis of their regulons. For over 1,300 LacI-TFs from over 270 bacterial genomes, we predicted their cognate DNA-binding motifs and identified target genes. Using the genome context and metabolic subsystem analyses of reconstructed regulons we tentatively assigned functional roles and predicted candidate effectors for 78% and 67% of the analyzed LacI-TFs, respectively. Nearly 90% of the studied LacI-TFs are local regulators of sugar utilization pathways, whereas the remaining 125 global regulators control large and diverse sets of metabolic genes. The global LacI-TFs include the previously known regulators CcpA in Firmicutes, FruR in Enterobacteria, and PurR in Gammaproteobacteria, and the three novel regulators, GluR, GapR, and PckR, that are predicted to control the central carbohydrate metabolism in three lineages of Alphaproteobacteria. Phylogenetic analysis of regulators combined with the reconstructed regulons provides a model of evolutionary diversification of LacI-TFs. The obtained genomic collection of in silico reconstructed regulons in Bacteria is available in the RegPrecise database (http://regprecise.lbl.gov). It provides a framework for future structural and functional classification of the LacI protein family and identification of molecular determinants of the DNA and ligand specificity. The inferred regulons can be also used for functional gene annotation and reconstruction of sugar catabolic networks in diverse bacteria.
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The intestinal microbiome is a unique ecosystem and an essential mediator of metabolism and obesity in mammals. However, studies investigating the impact of the diet on the establishment of the gut microbiome early in life are generally lacking, and most notably so in primate models. Here we report that a high-fat maternal or postnatal diet, but not obesity per se, structures the offspring's intestinal microbiome in Macaca fuscata (Japanese macaque). The resultant microbial dysbiosis is only partially corrected by a low-fat, control diet after weaning. Unexpectedly, early exposure to a high-fat diet diminished the abundance of non-pathogenic Campylobacter in the juvenile gut, suggesting a potential role for dietary fat in shaping commensal microbial communities in primates. Our data challenge the concept of an obesity-causing gut microbiome and rather provide evidence for a contribution of the maternal diet in establishing the microbiota, which in turn affects intestinal maintenance of metabolic health.
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Background & Aims Pharmacologic treatments for IBS and medical management of symptoms are increasingly based on IBS subtype, so it is important to accurately differentiate patients. Few studies have classified subtypes of pediatric IBS, and conclusions have been challenged by methodologic limitations. We performed a prospective study to investigate the distribution of IBS subtypes among children and adolescents based on stool diary information, and compared subtypes according to demographic and pain characteristics. Methods We studied 129 subjects, 7–18 y old (mean 11.4 ± 2.8 y old, 60.5% female, 69.0% Caucasian) who met Pediatric Rome III IBS criteria and were part of larger studies of children with functional gastrointestinal disorders, recruited from primary and tertiary care centers. Children completed daily pain and stool diaries for 2 weeks. Participants were assigned IBS subtypes based on their reported stool information, per adult Rome III criteria. IBS subtypes were compared for demographic variables and pain characteristics. Results IBS with constipation (IBC-C) was the most common subtype of the disorder (58.1% of subjects), whereas mixed IBS (IBS-M) was the least common (2.3% of subjects); 34.1% of subjects were unsubtyped (IBS-U) and 5.4% had IBS with diarrhea (IBS-D). The groups of different IBS subtypes did not differ significantly by sex, age, ethnicity, or pain characteristics. Conclusions In contrast to adults, IBS-C and IBS-U are the most common subtypes of IBS in children, whereas IBS-D and IBS-M are less common. Demographic and pain characteristics cannot distinguish subtypes.
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Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
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OBJECTIVES:The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the origin of these symptoms by magnetic resonance imaging (MRI) of the gut. A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500 ml of water containing 40 g of either glucose, fructose, inulin, or a 1:1 mixture of 40 g glucose and 40 g fructose. MRI scans were performed hourly for 5 h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H2) was measured and symptoms recorded after each scan.RESULTS:Data are reported as mean (s.d.) (95% CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0-5 h of SBWC to 71 (23) l/min, significantly greater than for glucose at 36 (11-132) l/min (P<0.001), whereas AUC SBWC after inulin, 33 (17-106) l/min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l/min (P=0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l/min, significantly greater than glucose and glucose+fructose (both P<0.05). Breath H2 rose more with inulin than with fructose. Glucose when combined with fructose significantly reduced breath H2 by 7,700 (3,121-12,300) p.p.m./min relative to fructose alone (P<0.01, n=13).CONCLUSIONS:Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers.Am J Gastroenterol advance online publication, 19 November 2013; doi:10.1038/ajg.2013.386.
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Profiling phylogenetic marker genes, such as the 16S rRNA gene, is a key tool for studies of microbial communities but does not provide direct evidence of a community's functional capabilities. Here we describe PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states), a computational approach to predict the functional composition of a metagenome using marker gene data and a database of reference genomes. PICRUSt uses an extended ancestral-state reconstruction algorithm to predict which gene families are present and then combines gene families to estimate the composite metagenome. Using 16S information, PICRUSt recaptures key findings from the Human Microbiome Project and accurately predicts the abundance of gene families in host-associated and environmental communities, with quantifiable uncertainty. Our results demonstrate that phylogeny and function are sufficiently linked that this 'predictive metagenomic' approach should provide useful insights into the thousands of uncultivated microbial communities for which only marker gene surveys are currently available.
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A 16S rRNA gene database (http://greengenes.lbl.gov) addresses limitations of public repositories by providing chimera screening, standard alignment, and taxonomic classification using multiple published taxonomies. It was found that there is incongruent taxonomic nomenclature among curators even at the phylum level. Putative chimeras were identified in 3% of environmental sequences and in 0.2% of records derived from isolates. Environmental sequences were classified into 100 phylum-level lineages in the Archaea and Bacteria.
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Carbohydrates occur across a range of foods regularly consumed including grains such as wheat and rye, vegetables, fruits, and legumes. Short-chain carbohydrates with chains of up to 10 sugars vary in their digestibility and subsequent absorption. Those that are poorly absorbed exert osmotic effects in the intestinal lumen increasing its water volume, and are rapidly fermented by bacteria with consequent gas production. These two effects alone may underlie most of the induction of gastrointestinal symptoms after they are ingested in moderate amounts via luminal distension in patients with visceral hypersensitivity. This has been the basis of the use of lactose-free diets in those with lactose malabsorption and of fructose-reduced diets for fructose malabsorption. However, application of such dietary approaches in patients with functional bowel disorders has been restricted to observational studies with uncertain efficacy. As all dietary poorly absorbed short-chain carbohydrates have similar and additive effects in the intestine, a concept has been developed to regard them collectively as FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) and to evaluate a dietary approach that restricts them all. In patients with irritable bowel syndrome, there is now an accumulating body of evidence, based on observational and comparative studies, and on randomized-controlled trials that supports the notion that FODMAPs trigger gastrointestinal symptoms in patients with functional bowel disorders, and that a diet low in FODMAPs offers considerable symptom relief in the majority of patients who use it.Am J Gastroenterol advance online publication, 16 April 2013; doi:10.1038/ajg.2013.96.
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Background Sub-acute ruminal acidosis (SARA) is a well-recognized digestive disorder found in particular in well-managed dairy herds. SARA can result in increased flow of fermentable substrates to the hindgut, which can increase the production of volatile fatty acids, alter the structure of the microbial community, and have a negative effect on animal health and productivity. However, little is known about changes in the structure of the microbial community and its relationship with fatty acids during SARA. Four cannulated primiparous (60 to 90 day in milk) Holstein dairy cows were assigned to two diets in a 2 × 2 crossover experimental design. The diets contained (on a dry matter basis): 40% (control diet, COD) and 70% (SARA induction diet, SAID) concentrate feeds. Samples of ruminal fluid and feces were collected on day 12, 15, 17 and 21 of the treatment period, and the pH was measured in the ruminal and fecal samples; the fecal microbiota was determined by pyrosequencing analysis of the V1–V3 region of amplified 16S ribosomal RNA (16S rRNA). Results SAID decreased ruminal and fecal pH and increased the propionate, butyrate and total volatile fatty acid (TVFA) concentration in feces when compared with the COD. A barcoded DNA pyrosequencing method was used to generate 2116 16S operational taxonomic units (OTUs). A total of 11 phyla were observed, distributed amongst all cattle on both diets; however, only 5 phyla were observed in all animals regardless of dietary treatment, and considerable animal to animal variation was revealed. The average abundance and its range of the 5 phyla were as follows: Firmicutes (63.7%, 29.1–84.1%), Proteobacteria (18.3%, 3.4–46.9%), Actinobacteria (6.8%, 0.4–39.9%), Bacteroidetes (7.6%, 2.2–17.7%) and Tenericutes (1.6%, 0.3–3%). Feeding the SAID resulted in significant shifts in the structure of the fecal microbial community when compared with the traditional COD. Among the 2116 OTUs detected in the present study, 88 OTUs were affected significantly by diet; and the proportion of these OTUs was 20.6% and 17.4% among the total number of sequences, respectively. Among the OTUs affected, the predominant species, including OTU2140 (G: Turicibacter), OTU1695 (G: Stenotrophomonas) and OTU8143 (F: Lachnospiraceae), were increased, while the abundance of OTU1266 (S: Solibacillus silvestris) and OTU2022 (G: Lysinibacillus) was reduced in the SAID group compared with the COD. Further, our results indicated that the fecal volatile fatty acid (VFA) concentrations were significantly related to presence of some certain species of Bacteroidetes and Firmicutes in the feces. Conclusions This is, to our knowledge, the first study that has used barcoded DNA pyrosequencing to survey the fecal microbiome of dairy cattle during SARA. Our results suggest that particular bacteria and their metabolites in the feces appear to contribute to differences in host health between those given SAID and traditional COD feeding. A better understanding of these microbial populations will allow for improved nutrient management and increased animal growth performance.
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Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat's signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81-99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.
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Bacteria that colonize the mammalian intestine collectively possess a far larger repertoire of degradative enzymes and metabolic capabilities than their hosts. Microbial fermentation of complex non-digestible dietary carbohydrates and host-derived glycans in the human intestine has important consequences for health. Certain dominant species, notably among the Bacteroidetes, are known to possess very large numbers of genes that encode carbohydrate active enzymes and can switch readily between different energy sources in the gut depending on availability. Nevertheless, more nutritionally specialized bacteria appear to play critical roles in the community by initiating the degradation of complex substrates such as plant cell walls, starch particles and mucin. Examples are emerging from the Firmicutes, Actinobacteria and Verrucomicrobium phyla, but more information is needed on these little studied groups. The impact of dietary carbohydrates, including prebiotics, on human health requires understanding of the complex relationship between diet composition, the gut microbiota and metabolic outputs.
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Kyoto Encyclopedia of Genes and Genomes (KEGG, http://www.genome.jp/kegg/ or http://www.kegg.jp/) is a database resource that integrates genomic, chemical and systemic functional information. In particular, gene catalogs from completely sequenced genomes are linked to higher-level systemic functions of the cell, the organism and the ecosystem. Major efforts have been undertaken to manually create a knowledge base for such systemic functions by capturing and organizing experimental knowledge in computable forms; namely, in the forms of KEGG pathway maps, BRITE functional hierarchies and KEGG modules. Continuous efforts have also been made to develop and improve the cross-species annotation procedure for linking genomes to the molecular networks through the KEGG Orthology system. Here we report KEGG Mapper, a collection of tools for KEGG PATHWAY, BRITE and MODULE mapping, enabling integration and interpretation of large-scale data sets. We also report a variant of the KEGG mapping procedure to extend the knowledge base, where different types of data and knowledge, such as disease genes and drug targets, are integrated as part of the KEGG molecular networks. Finally, we describe recent enhancements to the KEGG content, especially the incorporation of disease and drug information used in practice and in society, to support translational bioinformatics.
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This study describes and validates a new method for metagenomic biomarker discovery by way of class comparison, tests of biological consistency and effect size estimation. This addresses the challenge of finding organisms, genes, or pathways that consistently explain the differences between two or more microbial communities, which is a central problem to the study of metagenomics. We extensively validate our method on several microbiomes and a convenient online interface for the method is provided at http://huttenhower.sph.harvard.edu/lefse/.
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Investigating the size and mechanisms of the placebo response in clinical trials have relied on experimental procedures that simulate the double-blind randomized placebo-controlled design. However, as the conventional design is thought to elucidate drug rather than placebo actions, different methodological procedures are needed for the placebo response. We reviewed the respective literature for trials designs that may be used to elucidate the size of the placebo response and the mechanisms associated with it. In general, this can be done by either manipulation the information provided to the subjects, or by manipulation the timing of the drug applied. Two examples of each strategy are discussed: the "balanced placebo design" (BDP) and the "balanced cross-over design" (BCD) and their variants are based on false information, while the "hidden treatment" (HT) and the "delayed response test" (DRT) are based on manipulating the time of drug action. Since most such approaches include deception or incomplete information of the subjects they are suitable for patient only with authorized deception. Both manipulating the information provided to subjects (BDP, DCD) or manipulating the timing of drug application (HT, DRT) allows overcoming some of the restrictions of conventional drug trials in the assessment of the placebo response, but they are feasible mostly in healthy subjects for ethical reasons.
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Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This 'additive model' is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in 'comparator' studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.
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Reduction of short-chain poorly absorbed carbohydrates (FODMAPs) in the diet reduces symptoms of irritable bowel syndrome (IBS). In the present study, we aimed to compare the patterns of breath hydrogen and methane and symptoms produced in response to diets that differed only in FODMAP content. Fifteen healthy subjects and 15 with IBS (Rome III criteria) undertook a single-blind, crossover intervention trial involving consuming provided diets that were either low (9 g/day) or high (50 g/day) in FODMAPs for 2 days. Food and gastrointestinal symptom diaries were kept and breath samples collected hourly over 14 h on day 2 of each diet. Higher levels of breath hydrogen were produced over the entire day with the high FODMAP diet for healthy volunteers (181 +/- 77 ppm.14 h vs 43 +/- 18; mean +/- SD P < 0.0001) and patients with IBS (242 +/- 79 vs 62 +/- 23; P < 0.0001), who had higher levels during each dietary period than the controls (P < 0.05). Breath methane, produced by 10 subjects within each group, was reduced with the high FODMAP intake in healthy subjects (47 +/- 29 vs 109 +/- 77; P = 0.043), but was not different in patients with IBS (126 +/- 153 vs 86 +/- 72). Gastrointestinal symptoms and lethargy were significantly induced by the high FODMAP diet in patients with IBS, while only increased flatus production was reported by healthy volunteers. Dietary FODMAPs induce prolonged hydrogen production in the intestine that is greater in IBS, influence the amount of methane produced, and induce gastrointestinal and systemic symptoms experienced by patients with IBS. The results offer mechanisms underlying the efficacy of the low FODMAP diet in IBS.
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Two strains of a gram-positively staining, obligately anaerobic, non-spore-forming, rod-shaped bacterium, designated strains 111-13A and 111-35T, were isolated from human faeces. Analysis of the 16S rRNA gene sequences indicated that these strains were members of the Clostridium coccoides rRNA group of organisms. The nearest relatives of the unknown bacterium were Eubacterium formicigenerans (having a sequence similarity of 94%) and an uncultured bacterium (similarity > 99%). Characterization studies indicated that the unidentified faecal bacterium was biochemically distinct from Eubacterium formicigenerans, members of the Clostridium coccoides group and all other described Eubacterium species. On the basis of the data from these studies, it is proposed that the hitherto unknown rod-shaped bacterium be designated a species of a novel genus, namely Dorea longicatena gen. nov., sp. nov., and that Eubacterium formicigenerans be transferred to this genus as Dorea formicigenerans gen. nov., comb. nov.
Article
Two strains of a gram-positively staining, obligately anaerobic, non-spore-forming, rod-shaped bacterium, designated strains 111-13A and 111-35T, were isolated from human faeces. Analysis of the 16S rRNA gene sequences indicated that these strains were members of the Clostridium coccoides rRNA group of organisms. The nearest relatives of the unknown bacterium were Eubacterium formicigenerans (having a sequence similarity of 94%) and an uncultured bacterium (similarity > 99%). Characterization studies indicated that the unidentified faecal bacterium was biochemically distinct from Eubacterium formicigenerans, members of the Clostridium coccoides group and all other described Eubacterium species. On the basis of the data from these studies, it is proposed that the hitherto unknown rod-shaped bacterium be designated a species of a novel genus, namely Dorea longicatena gen. nov., sp. nov., and that Eubacterium formicigenerans be transferred to this genus as Dorea formicigenerans gen. nov., comb. nov.
Article
Dietary fibre supplements have been advocated for the management of chronic constipation (CC) and irritable bowel syndrome (IBS). Recently, a fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) restricted diet has been recommended for IBS. To systematically examine recent evidence for dietary interventions with fibre in CC and IBS and FODMAP-restricted diet in IBS, and provide recommendations. We searched PUBMED, MEDLINE, OVID and COCHRANE databases from 2004 to 2014. Published studies in adults with CC and IBS and constipation-predominant IBS (IBS-C) that compared fibre with placebo/alternative and FODMAP-restricted diet with alternative were included. Of 550 potentially eligible clinical trials on fibre, 11 studies were found and of 23 potentially eligible studies on FODMAPs, six were found. A meta-analysis was not performed due to heterogeneity and methodological quality. Fibre was beneficial in 5/7 studies in CC and 3/3 studies in IBS-C. FODMAP-restricted diet improved overall IBS symptoms in 4/4 and IBS-C symptoms in 1/3 studies and three studies did not meet inclusion criteria. There were significant disparities in subject selection, interventions and outcome assessments in both fibre and FODMAPs studies. Fibre supplementation is beneficial in mild to moderate CC and IBS-C, although larger, more rigorous and long-term RCTs are needed (Fair evidence-Level II, Grade B). Although the FODMAP-restricted diet may be effective in short-term management of selected patients with IBS (Fair evidence-Level II, Grade C) and IBS-C (Poor evidence-Level III, Grade C), more rigorous trials are needed to establish long-term efficacy and safety, particularly on colonic health and microbiome. © 2015 John Wiley & Sons Ltd.
Article
Food intolerance is non-immunological and is often associated with gastrointestinal symptoms. To focus on food intolerance associated with gastrointestinal symptoms and critically appraise the literature in relation to aetiology, diagnosis, mechanisms and clinical evidence. A search using the terms and variants of food intolerance, lactose, FODMAP, gluten, food chemicals within Pubmed, Embase and Scopus was carried out and restricted to human studies published in English. Additionally, references from relevant papers were hand searched for other appropriate studies. Food intolerance affects 15-20% of the population and may be due to pharmacological effects of food components, noncoeliac gluten sensitivity or enzyme and transport defects. There have been significant advances in understanding the scientific basis of gastrointestinal food intolerance due to short-chain fermentable carbohydrates (FODMAPs). The most helpful diagnostic test for food intolerance is food exclusion to achieve symptom improvement followed by gradual food reintroduction. A low FODMAP diet is effective, however, it affects the gastrointestinal microbiota and FODMAP reintroduction to tolerance is part of the management strategy. There is increasing evidence for using a low FODMAP diet in the management of functional gastrointestinal symptoms where food intolerance is suspected. Exclusion diets should be used for as short a time as possible to induce symptom improvement, and should be followed by gradual food reintroduction to establish individual tolerance. This will increase dietary variety, ensure nutritional adequacy and minimise impact on the gastrointestinal microbiota. © 2014 John Wiley & Sons Ltd.
Article
Introduction: The importance of lactose malabsorption in irritable bowel syndrome (IBS) is not well defined and these patients often complain of lactose intolerance. To objectively measure lactose malabsorption, a hydrogen breath test (HBT) can be performed, but a discrepancy emerges between the results of the HBT and the symptomatic response during the HBT. Aims: To determine in a group of IBS patients whether self-perceived lactose intolerance and the symptomatic response to lactose HBT were conditioned by other factors besides the presence of lactose malabsorption. Materials and methods: Oral challenge to lactose (50 g) was tested in 51 IBS patients to assess HBT malabsorption and the symptomatic response to lactose intolerance was scored on a validated questionnaire. Allergological screening for common inhalants and food allergens (including cow's milk) was performed. The presence of psychological factors (e.g. anxiety, depression, fatigue) was evaluated using validated questionnaires. Results: A total of 21 out of 51 patients (41.1%) were self-perceived to be lactose intolerant, 24/51 (47%) had a positive HBT, and 14/51 (27.4%) presented with symptoms of lactose intolerance during HBT. The serological screening for inhalant and food allergens was positive in 6/21 (28.6%) and 4/21 (19%) of patients who self-perceived lactose intolerance and in 5/14 (37.5%) and 3/14 (21.4%) in intolerant patients symptomatic during HBT. Only 1/51 (1.9%) presented evidence of IgE-mediated hypersensitivity to cow's milk. Patients who experienced symptoms of lactose intolerance during HBT presented more severe IBS symptoms [326 (296-398) vs. 215 (126-295) P=0.05] and a higher score of anxiety, depression, and fatigue. Factors influencing the symptoms of lactose intolerance during HBT resulted in an increase in hydrogen produced and in the severity of IBS. Conclusion: In a cohort of 51 IBS patients, the symptoms of lactose intolerance during HBT were influenced by the capacity to absorb lactose and the severity of IBS. Other factors, such as the psychological status or an adverse reaction to milk, merit consideration as potential cofactors involved in lactose perception and tolerance.
Article
Members of the genus Bifidobacterium are commonly found in the gastrointestinal tracts of mammals, including humans, where their growth is presumed to be dependent on various diet- and/or host-derived carbohydrates. To understand transcriptional control of bifidobacterial carbohydrate metabolism, we investigated two genetic carbohydrate utilization clusters dedicated to the metabolism of raffinose-type sugars and melezitose. Transcriptomic and gene inactivation approaches revealed that the raffinose utilization system is positively regulated by an activator protein, designated RafR. The gene cluster associated with melezitose metabolism was shown to be subject to direct negative control by a LacI-type transcriptional regulator, designated MelR1, in addition to apparent indirect negative control by means of a second LacI-type regulator, MelR2. In silico analysis, DNA-protein interaction, and primer extension studies revealed the MelR1 and MelR2 operator sequences, each of which is positioned just upstream of or overlapping the correspondingly regulated promoter sequences. Similar analyses identified the RafR binding operator sequence located upstream of the rafB promoter. This study indicates that transcriptional control of gene clusters involved in carbohydrate metabolism in bifidobacteria is subject to conserved regulatory systems, representing either positive or negative control.
Article
Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disease with a substantial social and economic burden. Treatment options remain limited and research on the aetiology and pathophysiology of this multifactorial disease is ongoing. To discuss the potential role of gut microbiota in the pathophysiology of IBS and to identify possible interactions with pathophysiologic targets in IBS. Articles were identified via a PubMed database search ['irritable bowel syndrome' AND (anti-bacterial OR antibiotic OR flora OR microbiota OR microflora OR probiotic)]. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. The role of gut microbiota in IBS is supported by varying lines of evidence from animal and human studies. For example, post-infectious IBS in humans is well documented. In addition, certain probiotics and nonsystemic antibiotics appear to be efficacious in the treatment of IBS. Mechanisms involved in improving IBS symptoms likely go beyond mere changes in the composition of the gut microbiota, and accumulating animal data support the interplay of microbiota with other IBS targets, such as the gut-brain axis, visceral hypersensitivity, mucosal inflammation and motility. The role of the gut microbiota is still being elucidated; however, it appears to be one of several important factors that contributes to the aetiology and pathophysiology of the irritable bowel syndrome.