Recipient microbiome-related features predicting metabolic improvement following fecal microbiota transplantation in adults with severe obesity and metabolic syndrome: a secondary analysis of a phase 2 clinical trial.

Microbial-based therapeutics in clinical practice are of considerable interest, and a recent study demonstrated fecal microbial transplantation (FMT) followed by dietary fiber supplements improved glucose homeostasis. Previous evidence suggests that donor and recipient compatibility and FMT protocol are key determinants, but little is known about the involvement of specific recipient factors. Using data from our recent randomized placebo-control phase 2 clinical trial in adults with obesity and metabolic syndrome, we grouped participants that received FMT from one of 4 donors with either fiber supplement into HOMA-IR responders (n = 21) and HOMA-IR non-responders (n = 8). We further assessed plasma bile acids using targeted metabolomics and performed subgroup analyzes to evaluate the effects of recipient parameters and gastrointestinal factors on microbiota engraftment and homeostatic model assessment of insulin resistance (HOMA2-IR) response. The baseline fecal microbiota composition at genus level of recipients could predict the improvements in HOMA2-IR at week 6 (ROC-AUC = 0.70). Prevotella was identified as an important predictor, with responders having significantly lower relative abundance than non-responders (p = .02). In addition, recipients displayed a highly individualized degree of microbial engraftment from donors. Compared to the non-responders, the responders had significantly increased bacterial richness (Chao1) after FMT and a more consistent engraftment of donor-specific bacteria ASVs (amplicon sequence variants) such as Faecalibacillus intestinalis (ASV44), Roseburia spp. (ASV103), and Christensenellaceae spp. (ASV140) (p < .05). Microbiota engraftment was strongly associated with recipients' factors at baseline including initial gut microbial diversity, fiber and nutrient intakes, inflammatory markers, and bile acid derivative levels. This study identified that responders to FMT therapy had a higher engraftment rate in the transplantation of specific donor-specific microbes, which were strongly correlated with insulin sensitivity improvements. Further, the recipient baseline gut microbiota and related factors were identified as the determinants for responsiveness to FMT and fiber supplementation. The findings provide a basis for the development of precision microbial therapeutics for the treatment of metabolic syndrome.

Dichotomous effect of dietary fiber in pediatrics: a narrative review of the health benefits and tolerance of fiber.

Dietary fibers are associated with favorable gastrointestinal, immune, and metabolic health outcomes when consumed at sufficient levels. Despite the well-described benefits of dietary fibers, children and adolescents continue to fall short of daily recommended levels. This gap in fiber intake (i.e., "fiber gap") might increase the risk of developing early-onset pediatric obesity and obesity-related comorbidities such as type 2 diabetes mellitus into adulthood. The structure-dependent physicochemical properties of dietary fiber are diverse. Differences in solubility, viscosity, water-holding capacity, binding capability, bulking effect, and fermentability influence the physiological effects of dietary fibers that aid in regulating appetite, glycemic and lipidemic responses, and inflammation. Of growing interest is the fermentation of fibers by the gut microbiota, which yields both beneficial and less favorable end-products such as short-chain fatty acids (e.g., acetate, propionate, and butyrate) that impart metabolic and immunomodulatory properties, and gases (e.g., hydrogen, carbon dioxide, and methane) that cause gastrointestinal symptoms, respectively. This narrative review summarizes (1) the implications of fibers on the gut microbiota and the pathophysiology of pediatric obesity, (2) some factors that potentially contribute to the fiber gap with an emphasis on undesirable gastrointestinal symptoms, (3) some methods to alleviate fiber-induced symptoms, and (4) the therapeutic potential of whole foods and commonly marketed fiber supplements for improved health in pediatric obesity.

Effects of dietary fibre on metabolic health and obesity.

Obesity and metabolic syndrome represent a growing epidemic worldwide. Body weight is regulated through complex interactions between hormonal, neural and metabolic pathways and is influenced by numerous environmental factors. Imbalances between energy intake and expenditure can occur due to several factors, including alterations in eating behaviours, abnormal satiation and satiety, and low energy expenditure. The gut microbiota profoundly affects all aspects of energy homeostasis through diverse mechanisms involving effects on mucosal and systemic immune, hormonal and neural systems. The benefits of dietary fibre on metabolism and obesity have been demonstrated through mechanistic studies and clinical trials, but many questions remain as to how different fibres are best utilized in managing obesity. In this Review, we discuss the physiochemical properties of different fibres, current findings on how fibre and the gut microbiota interact to regulate body weight homeostasis, and knowledge gaps related to using dietary fibres as a complementary strategy. Precision medicine approaches that utilize baseline microbiota and clinical characteristics to predict individual responses to fibre supplementation represent a new paradigm with great potential to enhance weight management efficacy, but many challenges remain before these approaches can be fully implemented.

The Need for Fiber Addition in Symptomatic Heart Failure (FEAST-HF): A Randomized Controlled Pilot Trial.

Background: Preclinical and observational studies suggest that the gut microbiome plays a role in the pathogenesis of heart failure (HF); the gut microbiome may be modified by fermentable dietary fibre (FDF). The Need for Fiber Addition in Symptomatic Heart Failure (FEAST-HF) trial evaluated feasibility of recruitment and supplementation with FDF in HF and whether FDF (acacia), compared to control, reduced the level of N-terminal pro-b-type natriuretic peptide (NT-proBNP) and growth stimulation expressed gene 2 (ST2), and produced changes in the gut microbiome. Methods: Participants were randomly allocated 1:1:1 to either of the intervention arms (5 g/d or 10 g/d acacia) or to the control arm (10 g/d microcrystalline cellulose (MCC; nonfermentable active control). Adherence and tolerance were assessed, and clinical events were monitored for safety. All outcomes (NT-proBNP, ST2, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire scores, 6-minute walk test score, gut microbiome) were measured at baseline, and at 6 and 12 weeks. Results: Between September 13, 2018 and December 16, 2021, 51 patients were randomly allocated to either MCC (n = 18), acacia 5 g daily (n = 13), or acacia 10 g daily (n = 18). No differences occurred between either dose of acacia and MCC in NT-proBNP level, ST2, New York Heart Association class, or questionnaire scores over 12 weeks. Dietary treatment arms had a negligible impact on microbial communities. No safety, tolerability, or adherence issues were observed. Conclusions: Dietary supplementation with acacia gum was both safe and well tolerated in ambulatory patients with HF; however, it did not change NT-proBNP level, ST2, or the composition of the gut microbiome.ClinicalTrials.gov: NCT03409926.

Contexte: Des études précliniques et observationnelles donnent à penser que le microbiome intestinal joue un rôle dans la pathogenèse de l'insuffisance cardiaque (IC). Or, ce microbiome pourrait être modifié par la consommation de fibres alimentaires fermentescibles (FAF). L'essai pilote contrôlé avec répartition aléatoire FEAST-HF (pour The Need forFiberAddition inSymptomaticHeartFailure) visait à évaluer la possibilité d'administrer un supplément de FAF (l'acacia) et à déterminer si celui-ci entraîne une réduction du taux du propeptide natriurétique de type B N-terminal (NT-proBNP) et du récepteur ST2 (growth stimulation expressed gene 2) ou une modification du microbiome intestinal comparativement au placebo. Méthodologie: Les participants ont été répartis de façon aléatoire selon un rapport 1:1:1 dans l'un des groupes d'intervention (recevant 5 g/jour ou 10 g/jour d'acacia) ou dans le groupe témoin (recevant 10 g/jour de cellulose microcristalline [CMC], une fibre de référence non fermentescible). La tolérance et l'observance du traitement ont été évaluées, et les événements cliniques ont été surveillés pour évaluer l'innocuité. Tous les indicateurs (NT-proBNP, ST2, classe d'IC selon l'échelle de la New York Heart Association, score au questionnaire de cardiomyopathie de Kansas City, score à un test de marche de 6 minutes et microbiome intestinal) ont été évalués au début de l'étude, à la semaine 6 et à la semaine 12. Résultats: Entre le 13 septembre 2018 et le 16 décembre 2021, 51 patients ont pris, après répartition aléatoire, de la CMC (n = 18), 5 g d'acacia par jour (n = 13) ou 10 g d'acacia par jour (n = 18). Aucune différence n'a été observée quant au taux de NT-proBNP ou de ST2, à la classe d'IC selon la New York Heart Association ou aux scores au questionnaire entre les groupes prenant l'une ou l'autre des doses d'acacia et le groupe prenant la CMC au cours d'une période de 12 semaines. L'effet sur la flore microbienne était négligeable dans les groupes de traitement alimentaire. Par ailleurs, aucun problème lié à l'innocuité, à la tolérabilité ou à l'observance du traitement n'a été observé. Conclusions: Les suppléments alimentaires d'acacia (gomme arabique) sont sûrs et bien tolérés; toutefois, ces suppléments n'ont pas entraîné de changement dans les taux de NT-proBNP ou de ST2, ni dans la composition du microbiome intestinal.ClinicalTrials.gov : NCT03409926.

Chemotherapy-induced weight gain in early-stage breast cancer: a prospective matched cohort study reveals associations with inflammation and gut dysbiosis.

BACKGROUND: Early-stage breast cancer patients treated with chemotherapy risk the development of metabolic disease and weight gain, which can result in increased morbidity and reduced quality of life in survivorship. We aimed to analyze changes within the gastrointestinal microbiome of early-stage breast cancer patients treated with and without chemotherapy to investigate a potential relationship between dysbiosis, a systemic inflammatory response, and resultant anthropomorphic changes. METHODS: We undertook an a priori analysis of serially collected stool and plasma samples from 40 patients with early-stage breast cancer who underwent adjuvant endocrine therapy only, adjuvant chemotherapy only, or both. Gut microbiota were assessed by metagenomic comparison of stool samples following deep sequencing. Inflammatory biomarkers were evaluated by proteomic analysis of plasma and measurement of fecal calprotectin. Body composition was investigated by dual-energy X-ray absorptiometry to determine biomass indices. RESULTS: As opposed to treatment with endocrine therapy only, chemotherapy resulted in statistically and clinically significant weight gain and an increase in the android to gynoid ratio of fat distribution. Patients treated with chemotherapy gained an average of 0.15% total mass per month, as opposed to a significantly different loss of 0.19% in those patients who received endocrine-only therapy. Concurrently, a twofold increase in fecal calprotectin occurred after chemotherapy that is indicative of interferon-dependent inflammation and evidence of colonic inflammation. These anthropomorphic and inflammatory changes occurred in concert with a chemotherapy-dependent effect on the gut microbiome as evidenced by a reduction in both the abundance and variety of microbial species. CONCLUSIONS: We confirm the association of chemotherapy treatment with weight gain and potential deleterious anthropometric changes and suggest that alterations of bacterial flora may contribute to these phenomena through the induction of systemic inflammation. Consequently, the gut microbiome may be a future target for intervention in preventing chemotherapy-dependent anthropometric changes.

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease.

BACKGROUND: Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10-/-) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/- model. RESULTS: Viral preparations extracted from IL-10-/- weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4-97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10-/- spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vß-12 subsets, which were expanded in the IL-10-/- versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/- splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10-/- mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. CONCLUSIONS: This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis. Video Abstract.

Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis.

OBJECTIVE: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. DESIGN: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. RESULTS: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). CONCLUSION: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.

Immunometabolism and microbial metabolites at the gut barrier: Lessons for therapeutic intervention in inflammatory bowel disease.

The concept of immunometabolism has emerged recently whereby the repolarizing of inflammatory immune cells toward anti-inflammatory profiles by manipulating cellular metabolism represents a new potential therapeutic approach to controlling inflammation. Metabolic pathways in immune cells are tightly regulated to maintain immune homeostasis and appropriate functional specificity. Because effector and regulatory immune cell populations have different metabolic requirements, this allows for cellular selectivity when regulating immune responses based on metabolic pathways. Gut microbes have a major role in modulating immune cell metabolic profiles and functional responses through extensive interactions involving metabolic products and crosstalk between gut microbes, intestinal epithelial cells, and mucosal immune cells. Developing strategies to target metabolic pathways in mucosal immune cells through the modulation of gut microbial metabolism has the potential for new therapeutic approaches for human autoimmune and inflammatory diseases, such as inflammatory bowel disease. This review will give an overview of the relationship between metabolic reprogramming and immune responses, how microbial metabolites influence these interactions, and how these pathways could be harnessed in the treatment of inflammatory bowel disease.

Unfermented ß-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are affected by dietary factors, including nondigestible carbohydrates (fibers), which are fermented by colonic microbes. Fibers are overall beneficial, but not all fibers are alike, and some patients with IBD report intolerance to fiber consumption. Given reproducible evidence of reduced fiber-fermenting microbes in patients with IBD, we hypothesized that fibers remain intact in select patients with reduced fiber-fermenting microbes and can then bind host cell receptors, subsequently promoting gut inflammation. METHODS: Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with oligofructose (5 g/L), or fermentation supernatants (24-hour anaerobic fermentation) and immune responses (cytokine secretion [enzyme-linked immunosorbent assay/meso scale discovery] and expression [quantitative polymerase chain reaction]) were assessed. Influence of microbiota in mediating host response was examined and taxonomic classification of microbiota was conducted with Kraken2 and metabolic profiling by HUMAnN2, using R software. RESULTS: Unfermented dietary ß-fructan fibers induced proinflammatory cytokines in a subset of IBD intestinal biopsies cultured ex vivo, and immune cells (including peripheral blood mononuclear cells). Results were validated in an adult IBD randomized controlled trial examining ß-fructan supplementation. The proinflammatory response to intact ß-fructan required activation of the NLRP3 and TLR2 pathways. Fermentation of ß-fructans by human gut whole microbiota cultures reduced the proinflammatory response, but only when microbes were collected from patients without IBD or patients with inactive IBD. Fiber-induced immune responses correlated with microbe functions, luminal metabolites, and dietary fiber avoidance. CONCLUSION: Although fibers are typically beneficial in individuals with normal microbial fermentative potential, some dietary fibers have detrimental effects in select patients with active IBD who lack fermentative microbe activities. The study is publicly accessible at the U.S. National Institutes of Health database (clinicaltrials.gov identification number NCT02865707).

A randomized controlled trial of a multicomponent online stress reduction intervention in inflammatory bowel disease.

Background: Psychological stress negatively impacts inflammatory bowel disease (IBD) outcomes. Patients have prioritized access to online interventions; yet, the data on these have been limited by mixed in-person/online interventions, low adherence, and non-randomized controlled trial (RCT) design. Objectives: We assessed the efficacy of and adherence to a 12-week online multicomponent stress reduction intervention in IBD. Design: This is a RCT. Methods: Adult participants on stable IBD medical therapy with elevated stress levels from four centers were randomized to intervention or control groups. Intervention participants received a 12-week online program including a weekly yoga, breathwork and meditation video (target 2-3 times/week), a weekly cognitive behavioral therapy/positive psychology informed video activity, and weekly 10-min check-ins by a study team member. Control participants received weekly motivational messages by email. All patients received standard of care IBD therapy. The primary outcome was Cohen's Perceived Stress Scale (PSS). Secondary outcomes evaluated mental health, resilience, health-related quality of life (HRQoL), symptom indices, acceptability, adherence, and inflammatory biomarkers. Analysis of covariance was used to determine between-group differences. Results: Of 150 screened patients, 101 were randomized to the intervention (n = 49) and control (n = 52) groups (mean age: 42.5 ± 14.1 years; M:F 1:3, 48% with ulcerative colitis and 52% with Crohn's disease). The between-group PSS improved by 22.4% (95% confidence interval, 10.5-34.3, p < 0.001). Significant improvements were seen in mental health, resilience, and HRQoL measures, with a median satisfaction score of 89/100 at the end of the 12 weeks. In the 44/49 patients who completed the intervention, 91% achieved program adherence targets. Conclusion: This 12-week online intervention improved perceived stress, mental health, and HRQoL, but did not impact IBD symptom indices or inflammatory biomarkers. The program was readily adopted and adhered to by participants with high retention rates. After iterative refinement based on participant feedback, future studies will evaluate the impact of a longer/more intense intervention on disease course. Registration: ClinicalTrials.gov Identifier NCT03831750. Plain Language Summary: An online stress reduction intervention in inflammatory bowel disease patients improves stress, mental health, and quality of life People with inflammatory bowel disease (IBD) have high levels of stress, anxiety, and depression. Although IBD patients have expressed the need for online mental wellness interventions, the existing data to support these interventions in IBD are limited. In this trial, 101 IBD patients had the chance to participate in a 12-week online stress reduction intervention. In those patients randomly selected to participate in the online intervention, each week they received the following: a 20- to 30-min yoga, breathwork, and meditation video that they were asked to do 2-3 times a week, a 10- to 20-min mental wellness activity they were asked to do once during the week, and a 10-min telephone check-in with a study team member. Participants who were not selected to use the online intervention received a weekly motivational message by email. In all, 90 of the 101 participants (89%) completed the study with the mean age of participants being 43 years and the majority being females (75%). Ninety-one percent of participants who completed the intervention met the program target of doing the yoga, breathwork, and meditation video at least 2 times per week. Significant improvements were seen in perceived stress (by 22.4%), depression (by 29.5%), anxiety (by 23.7%), resilience (by 10.6%), and quality of life (by 8.9%). No changes were seen in IBD severity or in blood markers of inflammation. In conclusion, this study demonstrates evidence that a 12-week online stress reduction intervention had low dropout rates, high adherence and beneficial effects on stress, mental health, and quality of life measures. Continued feedback will be sought from study participants and our IBD patient partners to refine the intervention and assess the impact in future studies of patients with active IBD, as well as the impact of a longer/more intense intervention.

Elevated IL-6 and IL-22 in Early Pregnancy Are Associated with Worse Disease Course in Women with Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD), including Ulcerative Colitis (UC) and Crohn's disease (CD), are inflammatory conditions of the intestinal tract that affect women in their reproductive years. Pregnancy affects Th1- and Th2-cytokines, but how these changes occur during pregnancy in IBD is unclear. We performed a longitudinal profiling of serum cytokines in a cohort of 11 healthy pregnant women and 76 pregnant women with IBD from the first trimester of pregnancy to the first 12 months post-partum. Participants were monitored for biochemical disease activity (C-reactive protein [CRP] and fecal calprotectin [FCP]) and clinical activities. Maternal cytokines were measured using ELISA. We identified changes in Th1 and Th17 cytokines throughout pregnancy in healthy pregnant women. During pregnancy, maternal serum cytokine expressions were influenced by IBD, disease activity, and medications. Active UC was associated with an elevation in IL-21, whereas active CD was associated with elevated IFN-γ, IL-6, and IL-21. Interestingly, T1 serum cytokine levels of IL-22 (>0.624 pg/mL) and IL-6 (>0.648 pg/mL) were associated with worse IBD disease activity throughout pregnancy in women with UC and CD, respectively. This shows serum cytokines in pregnancy differ by IBD, disease activity, and medications. We show for the first time that T1 IL-22 and IL-6 correlate with IBD disease course throughout pregnancy.

Anti-Inflammatory Diet Prevents Subclinical Colonic Inflammation and Alters Metabolomic Profile of Ulcerative Colitis Patients in Clinical Remission.

A relationship between ulcerative colitis (UC) and diet has been shown in epidemiological and experimental studies. In a 6-month, open-label, randomized, placebo-controlled trial, adult UC patients in clinical remission were randomized to either an "Anti-inflammatory Diet (AID)" or "Canada's Food Guide (CFG)". Menu plans in the AID were designed to increase the dietary intake of dietary fiber, probiotics, antioxidants, and omega-3 fatty acids and to decrease the intake of red meat, processed meat, and added sugar. Stool was collected for fecal calprotectin (FCP) and microbial analysis. Metabolomic analysis was performed on urine, serum, and stool samples at the baseline and study endpoint. In this study, 53 patients were randomized. Five (19.2%) patients in the AID and 8 (29.6%) patients in the CFG experienced a clinical relapse. The subclinical response to the intervention (defined as FCP < 150 µg/g at the endpoint) was significantly higher in the AID group (69.2 vs. 37.0%, p = 0.02). The patients in the AID group had an increased intake of zinc, phosphorus, selenium, yogurt, and seafood versus the control group. Adherence to the AID was associated with significant changes in the metabolome, with decreased fecal acetone and xanthine levels along with increased fecal taurine and urinary carnosine and p-hydroxybenzoic acid levels. The AID subjects also had increases in fecal Bifidobacteriaceae, Lachnospiraceae, and Ruminococcaceae. In this study, we found thatdietary modifications involving the increased intake of anti-inflammatory foods combined with a decreased intake of pro-inflammatory foods were associated with metabolic and microbial changes in UC patients in clinical remission and were effective in preventing subclinical inflammation.

Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice.

The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified Klebsiella aerogenes, carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.

Altered Gut Microbiome Composition and Function Are Associated With Gut Barrier Dysfunction in Healthy Relatives of Patients With Crohn's Disease.

BACKGROUND & AIMS: The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. We therefore aimed to assess whether alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn's disease. METHODS: We used the Crohn's and Colitis Canada Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn's disease. Gut barrier function was assessed using the urinary fractional excretion of lactulose-to-mannitol ratio (LMR). Microbiome composition was assessed by sequencing fecal 16S ribosomal RNA. The cohort was divided into a discovery cohort (n = 2472) and a validation cohort (n = 655). A regression model was used to assess microbial associations with the LMR. A random forest classifier algorithm was performed to assess microbial community contribution to barrier function. RESULTS: Individuals with impaired barrier function (LMR >0.025) had reduced alpha-diversity (Chao1 index, P = 4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R2 = 0.001, P = 1.0e-3) compared with individuals with an LMR ≤0.025. When taxa were assessed individually, we identified 8 genera and 52 microbial pathways associated with an LMR >0.025 (q < 0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and 8 pathways (including decreased biosynthesis of glutamate, tryptophan, and threonine) were replicated in the validation cohort. The random forest approach revealed that the bacterial community is associated with gut barrier function (area under the curve, 0.63; P = 1.4e-6). CONCLUSIONS: The gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.

No effect of triheptanoin in patients with phosphofructokinase deficiency.

Phosphofructokinase deficiency (PFKD) is a rare disorder of glycogen metabolism. The lack of phosphofructokinase activity blocks the oxidative pathway from glucose and glycogen to pyruvate. Patients suffer from myopathy, exercise intolerance, and myoglobinuria. Currently, there is no specific treatment for PFKD. We hypothesized that 2 weeks treatment with triheptanoin could improve oxidative metabolism during exercise by bypassing the blocked pyruvate generation in PFKD. The study was a randomized, double-blind, placebo-controlled crossover study. Three genetically verified patients completed two treatment periods of 14 days each with triheptanoin (0.3-1 g × kg-1 × day-1) or placebo liquid. Primary outcomes were heart rate, fatty acid and total oxidation measured via stable isotope and indirect calorimetry methodology during submaximal exercise. Triheptanoin did not improve the primary outcome heart rate during submaximal exercise compared to placebo. Palmitate oxidation was increased during submaximal exercise in one patient but did not increase in the two other patients during triheptanoin treatment. Palmitate production and palmitate utilization increased during exercise and increased to a greater extent with triheptanoin treatment in all three patients. This study suggests that triheptanoin treatment has no effect on heart rate or exercise performance despite increased palmitate production and utilization in patients with PFKD.

Roux-en-Y gastric bypass and sleeve gastrectomy induce substantial and persistent changes in microbial communities and metabolic pathways.

Bariatric surgery induces significant microbial and metabolomic changes, however, links between microbial and metabolic pathways have not been fully elucidated. The objective of this study was to conduct a comprehensive investigation of the microbial, metabolomic, and inflammatory changes that occur following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). A prospective clinical trial was conducted with participants undergoing RYGB, SG, and non-operative controls (CTRL). Clinical parameters, blood samples, and fecal samples were collected pre-intervention and at 3 and 9 months. A multi-omics approach was used to perform integrated microbial-metabolomic analysis to identify functional pathways in which weight loss and metabolic changes occur after surgery. RYGB led to profound microbial changes over time that included reductions in alpha-diversity, increased Proteobacteria and Verrucomicrobiota, decreased Firmicutes, and numerous changes at the genera level. These changes were associated with a reduction in inflammation and significant weight loss. A reduction in Romboutsia genera correlated strongly with weight loss and integrated microbial-metabolomic analysis revealed the importance of Romboutsia. Its obliteration correlated with improved weight loss and insulin resistance, possibly through decreases in glycerophospholipids. In contrast, SG was associated with no changes in alpha-diversity, and only a small number of changes in microbial genera. A cluster of Firmicutes genera including Butyriciccocus, Eubacterium ventriosum, and Monoglobus was decreased, which correlated with decreased weight, insulin resistance, and systemic inflammation. This work represents comprehensive analyses of microbial-metabolomic changes that occur following bariatric surgery and identifies several pathways that are associated with beneficial metabolic effects of surgery.

Metagenomics Versus Metatranscriptomics of the Murine Gut Microbiome for Assessing Microbial Metabolism During Inflammation.

Shotgun metagenomics studies have improved our understanding of microbial population dynamics and have revealed significant contributions of microbes to gut homeostasis. They also allow in silico inference of the metagenome. While they link the microbiome with metabolic abnormalities associated with disease phenotypes, they do not capture microbial gene expression patterns that occur in response to the multitude of stimuli that constantly ambush the gut environment. Metatranscriptomics closes that gap, but its implementation is more expensive and tedious. We assessed the metabolic perturbations associated with gut inflammation using shotgun metagenomics and metatranscriptomics. Shotgun metagenomics detected changes in abundance of bacterial taxa known to be SCFA producers, which favors gut homeostasis. Bacteria in the phylum Firmicutes were found at decreased abundance, while those in phyla Bacteroidetes and Proteobacteria were found at increased abundance. Surprisingly, inferring the coding capacity of the microbiome from shotgun metagenomics data did not result in any statistically significant difference, suggesting functional redundancy in the microbiome or poor resolution of shotgun metagenomics data to profile bacterial pathways, especially when sequencing is not very deep. Obviously, the ability of metatranscriptomics libraries to detect transcripts expressed at basal (or simply low) levels is also dependent on sequencing depth. Nevertheless, metatranscriptomics informed about contrasting roles of bacteria during inflammation. Functions involved in nutrient transport, immune suppression and regulation of tissue damage were dramatically upregulated, perhaps contributed by homeostasis-promoting bacteria. Functions ostensibly increasing bacteria pathogenesis were also found upregulated, perhaps as a consequence of increased abundance of Proteobacteria. Bacterial protein synthesis appeared downregulated. In summary, shotgun metagenomics was useful to profile bacterial population composition and taxa relative abundance, but did not inform about differential gene content associated with inflammation. Metatranscriptomics was more robust for capturing bacterial metabolism in real time. Although both approaches are complementary, it is often not possible to apply them in parallel. We hope our data will help researchers to decide which approach is more appropriate for the study of different aspects of the microbiome.

Post-neonatal Outcomes of Infants Born to Women with Active Trimester One Inflammatory Bowel Disease: A Pilot Study.

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are chronic inflammatory bowel diseases (IBD) that affect women in their childbearing years. Early pregnancy flare-up negatively impacts obstetrical and perinatal outcomes, but the impact on infants is unclear. AIM: To determine whether active IBD disease activity is associated with adverse post-neonatal outcomes post-partum. METHODS: This is a single-center cohort study of women with IBD who underwent serial monitoring of post-neonatal outcomes post-partum. Infant outcomes were collected via self-filled questionnaires, including perinatal outcomes, APGAR scores, infant weights, heights, feeding habits and comorbidities within the first year of life. RESULTS: There was a total of 98 women with IBD and 78 live births throughout the study: 50 women were enrolled during trimester one alone and 49 were included into the current study. Among the 49 analyzed, 32 were in remission and 17 were in relapse during trimester one. Trimester one disease activity was associated with more adverse obstetrical outcomes including emergency C-sections and reduced 1-min APGAR scores. At follow-up, infants born to women with T1-flare had reduced weight-for-age Z scores and length-for-age Z scores up to 6 months of age. CONCLUSIONS: Active IBD during trimester one is correlated with adverse post-neonatal outcomes, particularly decreased infant weight and height up to 6 months of age. This suggests disease control in first trimester is essential for optimizing infant growth and post-neonatal outcomes.

The effect of fecal microbial transplant on intestinal microbial composition in short-bowel neonatal piglets.

BACKGROUND: Short-bowel syndrome (SBS) in neonates is associated with microbial dysbiosis due to intestinal surgery, prolonged hospitalization, enteral nutrition, and repeated antibiotic exposure. Sepsis and liver disease, leading causes of morbidity and mortality in SBS, may relate to such intestinal dysbiosis. We investigated the safety and feasibility of fecal microbial transplant (FMT) to alter intestinal microbial composition in SBS piglets. METHODS: Following a 75% distal small-intestinal resection, piglets were fed parenteral nutrition with an elemental diet and randomized to saline (SAL; n = 12) or FMT (n = 12) treatments delivered by gastric tube on day 2 (d2). The FMT donor was a healthy adult pig. Comparisons were also made to healthy sow-fed littermate controls (SOW; n = 6). Stool samples were collected daily, and tissue samples were collected at baseline and termination. Microbial DNA was extracted from stool and analyzed using 16S ribosomal RNA sequencing. RESULTS: All piglets survived to the end point. On d2-d4, FMT piglets had some differences in microbiota composition compared with SAL, SOW, and donor counterparts. Between base and term, there were transitory changes to alpha and beta diversity in FMT and SAL. CONCLUSION: FMT treatment in postsurgical neonatal piglets with SBS appears safe, with no increase in sepsis and no mortality. In SBS piglets, FMT induced transient changes to the intestinal microbiota. However, these changes did not persist long-term.