Fecal Bile Acid Concentrations Research Articles

The effects of brewers’ spent grain on high-fat diet-induced fatty liver

Obesity drives nonalcoholic fatty liver disease (NAFLD). This study investigated the effects of dietary brewers’ spent grain (BSG) supplementation on obesity-induced NAFLD. Mice fed a high-fat diet supplemented with 30% BSG (HFD30) had reduced body weight and decreased plasma total cholesterol (TC) concentrations compared with HFD-fed mice. Retroperitoneal white adipose tissue (RWAT) and liver weights were reduced. Consistent with reduced hepatic triacylglycerol, TC, and non-esterified fatty acid concentrations, HFD30-fed mice showed reduced hepatic steatosis. 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor genes were increased, whereas carnitine palmitoyltransferase 1 alpha, ATP-binding cassette subfamily A member 1 (Abca1), and cholesterol 7 alpha-hydroxylase genes were upregulated in the liver of HFD30-fed mice. Abca1 gene expression was also increased in epididymal WAT and RWAT of HFD30-fed mice. BSG supplementation increased and decreased fecal fat and bile acid concentrations, respectively. Taken together, BSG supplementation reduced HFD-induced hepatic lipid accumulation by increasing fatty acid oxidation and bile acid synthesis in the liver as well as decreasing lipid absorption in the intestine.

Impact of elobixibat on serum and fecal bile acid levels and constipation symptoms in patients with chronic constipation.

Background and AimElobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group.MethodsHealthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once‐daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms.ResultsFecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation‐related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects.ConclusionsDespite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.

From Chihuahua to Saint-Bernard: how did digestion and microbiota evolve with dog sizes

Health and well-being of dogs are of paramount importance to their owners. Digestion plays a key role in dog health, involving physicochemical, mechanical and microbial actors. However, decades of breeding selection led to various dog sizes associated with different digestive physiology and disease sensitivity. Developing new products requires the consideration of all the multi-faceted aspects of canine digestion, the evaluation of food digestibility, drug release and absorption in the gut. This review paper provides an exhaustive literature survey on canine digestive physiology, focusing on size effect on anatomy and digestive parameters, with graphical representation of data classified as “small”, “medium” and “large” dogs. Despite the huge variability between protocols and animals, interesting size effects on gastrointestinal physiology were highlighted, mainly related to the colonic compartment. Colonic measurements, transit time permeability, fibre degradation, faecal short-chain fatty acid concentration and faecal water content increase while faecal bile acid concentration decreases with body size. A negative correlation between body weight and Proteobacteria relative abundance was observed suggesting an effect of dog body size on faecal microbiota. This paper gathers helpful in vivo data for academics and industrials and supports the development of new food and pharma products to move towards canine personalized nutrition and health.

1017. Gut Microbiota Diversity and Beneficial Metabolite Production is Reduced in Liver Transplant Recipients and Associated with Post Operative Infection

BackgroundLiver transplant (LT) recipients have abnormal microbiota before and after transplantation. (1,2) Associations between fecal microbiota, microbial metabolites, and clinical outcomes in liver transplantation are not well established. We correlated fecal microbiota composition and metabolite concentrations with early LT outcomes, including infection.MethodsIn a prospective observational study, we collected peri-transplant fecal samples and determined microbiota composition by 16S ribosomal RNA gene sequencing in LT recipients. Fecal short chain fatty acid (SCFA) and bile acid concentrations were measured by targeted GC- and LC-MS analyses, respectively. Inverse Simpson index was used to determine microbiota alpha-diversity in subjects and healthy controls. Clinical outcomes including length of stay, ICU admission, liver function, antibiotic use, immunosuppressive requirement and post-operative infection were correlated with microbiota composition.Results69 patients were enrolled, 70 liver transplants were performed and 307 peri-transplant fecal samples were collected and analyzed. Compared to healthy controls, the fecal microbiota of LT recipients had reduced alpha-diversity (p< 0.001). [Fig1] Bacteroidetes, Ruminococcaceae, and Lachnospiraceae, three taxa associated with a health-promoting microbiota, and their metabolites, SCFA and secondary bile acids, were markedly diminished 55% of LT patients.(3) Intestinal domination ( >30% frequency) by Enterococcus or Proteobacteria species was common and occurred in 36% of LT recipients. 76 post-operative infections occurred in 40 LT recipients, with Enterococci causing 52% and Proteobacteria 41% of bacterial infections. In subjects with fecal samples collected within 5 days of infection, 9/17 infections were caused by the organism dominating the microbiota. [Fig2]Microbiota Composition and Metabolite Production 16s gene sequencing color coded by taxonomy. Each bar represents one stool sample nearest to LT compared to healthy controls. Alpha diversity measured by inverse simpson index. Absolute values of microbial metabolites and ratio of primary to secondary bile acids.Comparison of Microbiota Composition and Post Operative Infection All bacterial infections captured with a microbiota sample within 5 days of infection.ConclusionMicrobiota diversity and microbially derived metabolites are markedly reduced in >50% of LT recipients. Intestinal domination and post-operative infections caused by antibiotic-resistant Enterococcus and Proteobacteria correlate with loss of Bacteroidetes, Ruminococcaceae, and Lachnospiraceae species, suggesting a potential role for microbiota reconstitution therapy in LT patients.Disclosures Eric G. Pamer, MD;FIDSA, Nothing to disclose

119 Awardee Talk: A Matter of the Heart: The Use of Pulses in Canine and Feline Nutrition

Abstract In the pet food industry, the popularity of plant-based protein sources has risen as consumer demand for grain-free and novel protein sources increase. However, minimal research has been conducted as regards use of pulses and their effects on acceptability and digestibility in canine and feline nutrition. In addition, market shift towards grain-free and pulse-rich diets has presented concerns about the suitability of pulses as viable protein sources. In July 2018, the FDA published a press release discussing a potential link between diets containing legumes and the development of dilated cardiomyopathy (DCM) in dogs. As such, part of our research program has focused on the 1) characterization of the macronutrient composition and protein quality of plant-based protein sources, 2) evaluation of the effects of plant-based protein sources in extruded canine and feline diets on macronutrient digestibility, and modulation of fecal microbiota and metabolites, and 3) determination of the longitudinal effects of high pulse inclusion in diets on taurine status in dogs. Pulse ingredients contained approximately 20% crude protein, and had methionine or tryptophan as the first-limiting amino acids using the precision-fed cecectomized rooster assay. When incorporated in canine and feline diets, pulses did not result in negative effects on macronutrient digestibility or fecal scores. However, shifts in fecal microbial and metabolites were observed in animals fed pulse-based in contrast with animal-based protein diets. The inclusion of 45% green lentils in extruded diets did not cause decreased plasma or whole blood taurine or methionine levels. Additionally, excess taurine was not depleted from these animals in the urine or feces. Taurine status was considered normal in these dogs, despite changes in fecal bile acid concentrations and microbiota. Although we are currently carrying out further research projects investigating potential association of pulse rich diets and canine DCM. Current research findings from our laboratory suggest the inclusion of pulses may not be the causative factor. The use of plant-based proteins as ingredients in canine and feline diets not only meet consumer demand but also provide a valuable, safe, and nutritionally adequate alternative to traditional protein sources.

Concentrations of Fecal Bile Acids in Participants with Functional Gut Disorders and Healthy Controls.

Bile acids are metabolites involved in nutrient absorption and signaling with levels influenced by dietary intake, metabolic processes, and the gut microbiome. We aimed to quantify 23 bile acids in fecal samples to ascertain if concentrations differed between healthy participants and those with functional gut disorders. Fecal bile acids were measured using liquid chromatography-mass spectrometry (LC-MS) in the COMFORT (The Christchurch IBS cohort to investigate mechanisms for gut relief and improved transit) cohort of 250 participants with Rome IV IBS (IBS-constipation (C), IBS-diarrhea (D), IBS-mixed (M)), functional gut disorders (functional constipation (FC), functional diarrhea (FD)) and healthy controls (FC n = 35, FD n = 13, IBS-C n = 24, IBS-D n = 52, IBS-M n = 29, and control n = 97). Dietary information was recorded to ascertain three-day dietary intake before fecal samples were collected. Fecal bile acid concentrations, predominantly primary bile acids, were significantly different between all functional gut disorder participants and healthy controls (CDCA p = 0.011, CA p = 0.003) and between constipation (FC + IBS-C) and diarrhea (FD + IBS-D) groups (CDCA p = 0.001, CA p = 0.0002). Comparison of bile acids between all functional groups showed four metabolites were significantly different, although analysis of combined groups (FC + IBS-C vs. FD + IBS-D) showed that 10 metabolites were significantly different. The bile acid profiles of FD individuals were similar to those with IBS-D, and likewise, those with FC were similar to IBS-C. Individuals with a diarrhea phenotype (FD + IBS-D) had higher concentrations of bile acids compared to those with constipation (FC + IBS-C). Bile acid metabolites distinguish between individuals with functional gut disorders and healthy controls but are similar in constipation (or diarrhea) whether classified as IBS or not.

Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.

Western‐style high‐fat/high‐sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD‐induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild‐type (WT) and human‐like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography–tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD‐induced change of gut microbiota inhibited BA deconjugation and 7α‐dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human‐like hydrophobic BA composition.

Avocado Consumption Alters Gastrointestinal Bacteria Abundance and Microbial Metabolite Concentrations among Adults with Overweight or Obesity: A Randomized Controlled Trial

ABSTRACTBackgroundAvocados are rich in dietary fiber and monounsaturated fatty acids (MUFAs), nutrients that have been independently connected to metabolic health benefits and the gastrointestinal microbiota.ObjectivesWe aimed to evaluate the impact of avocado consumption on the gastrointestinal microbiota and microbial metabolites, secondary outcomes of the Persea americana for Total Health (PATH) study, and conduct exploratory analyses to assess relations between the fecal microbiota, fecal metabolites, and health markers.MethodsAdults [n = 163, 25–45 y, BMI (kg/m2) ≥ 25.0] were enrolled in the PATH study, a 12-wk investigator-blinded trial where participants were batch randomized to match the 2 groups by age, sex, visceral adiposity, and fasting glucose concentrations. Participants consumed isocaloric meals with or without avocado (175 g, men; 140 g, women) once daily for 12 wk. The fecal microbiota was assessed with 16S ribosomal RNA gene (V4 region) sequencing and analysis using DADA2 and QIIME2. Fecal fatty acid and bile acid concentrations were quantified using GC and LC-MS. Per-protocol (≥80% meal consumption) and intent-to-treat analyses were conducted using univariate ANOVA and Mann-Whitney U tests. Bivariate correlations were conducted between fecal microbiota, fecal metabolites, and health measures.ResultsThe avocado treatment increased ɑ diversity and enriched Faecalibacterium, Lachnospira, and Alistipes between 26% and 65% compared with the control group. The avocado group had 18% greater fecal acetate, 70% greater stearic acid, and 98% greater palmitic acid concentrations than the control group, while the concentrations of the bile acids cholic and chenodeoxycholic acid were 91% and 57% lower, respectively.ConclusionsDaily avocado consumption resulted in lower fecal bile acid concentrations, greater fecal fatty acid and SCFAs, and greater relative abundances of bacteria capable of fiber fermentation, providing evidence that this nutrient-dense food affects digestive physiology, as well as the composition and metabolic functions of the intestinal microbiota. This trial was registered at www.clinicaltrials.gov as NCT02740439.

Gastric bypass in Y-Roux (RYGB) promotes changes in the concentration of fecal bile acids, which may be involved in improving glycemic homeostasis in patients with obesity and type 2 diabetes: A metabolomic study

Rationale: The improvement in glycemic homeostasis could result due to the increase of certain plasma levels of BAs and a decrease in their excretion in the feces, a condition frequently observed after RYGB1,2.

Developmental stages in microbiota, bile acids, and clostridial species in healthy puppies.

BackgroundThe fecal microbiota, fecal bile acid concentrations, and abundance of Clostridium perfringens and Clostridium difficile are altered in acute and chronic gastrointestinal disease in adult dogs. However, less is known in young puppies.Hypothesis/ObjectivesTo determine composition of the fecal microbiota, assess development of fecal bile acid profiles, and determine the abundance of Clostridial species in puppies, young adult dogs, and adult dogs.AnimalsHealthy puppies from a whelping kennel (n = 53) and healthy client‐owned dogs <1 year old (n = 20) were separated into 6 age groups, then compared to client‐owned dogs over 1 year of age (n = 13).MethodsProspective observational study. Naturally voided fecal samples were analyzed by quantitative polymerase chain reaction to measure bacterial abundances. Fecal bile acids were quantified using gas chromatography‐mass spectrometry.ResultsPuppies up to 5 to 6 weeks of age had increased Dysbiosis Index (median [min‐max]: 5.39 [1.32‐8.6], P < .001), increased abundance of C. difficile (4.1 [0.01‐4.85] log DNA, P < .001), decreased secondary bile acid concentrations (0.61 [0.28‐5.06] μg/mg, P = .006), and decreased abundance of C. hiranonis (0.84 [0.01‐6.71], P = .005) compared to adult dogs (−4.62 [−8.36 to −0.61], 0.01 [0.01‐0.01], 4.12 [0.32‐8.94], and 6.02 [5.06‐7.00], respectively). Secondary bile acid concentration positively correlated with C. hiranonis abundance (ρ = 0.77; P < .001).Conclusions and Clinical ImportanceThe increase in secondary bile acids and simultaneous decrease of C. difficile and C. perfringens after 5 to 6 weeks of age warrants further investigation into regulatory impacts that secondary bile acids could have on clostridial species in dogs.

Divergence in aerobic capacity impacts bile acid metabolism in young women.

Liver adaptations may be critical for regular exercise and high aerobic capacity to protect against metabolic disease, but mechanisms remain unknown. Bile acids (BAs) synthesized in the liver are bioactive and can putatively modify energy metabolism. Regular exercise influences BA metabolism in rodents, but effects in humans are unknown. This study tested whether female subjects screened for high aerobic capacity (Hi-Fit, n = 19) [peak oxygen consumption (V̇o2peak) ≥45 mL·kg-1·min-1] have increased hepatic BA synthesis and different circulating BA composition compared with those matched for age and body mass with low aerobic capacity (Lo-Fit, n = 19) (V̇o2peak ≤35 mL·kg-1·min-1). Diet patterns, activity level, stool, and blood were collected at baseline before participants received a 1-wk standardized, eucaloric diet. After the 1-wk standardized diet, stool and blood were again collected and an oral glucose tolerance test (OGTT) was performed to assess insulin sensitivity and postprandial BA response. Contrary to our hypothesis, serum 7α-hydroxy-4-cholesten-3-one (C4), a surrogate of BA synthesis, was not different between groups, whereas Hi-Fit women had lower fecal BA concentrations compared with Lo-Fit women. However, Lo-Fit women had a higher and more sustained rise in circulating conjugated BAs during the OGTT. Hi-Fit women showed a significant post-OGTT elevation of the secondary BA, lithocholic acid (a potent TGR5 agonist), in contrast to Lo-Fit women where no response was observed. A 1-wk control diet eliminated most differences in circulating BA species between groups. Overall, the results emphasize the importance of using a standardized diet when evaluating BAs and indicate that regular exercise and aerobic capacity modulate BA metabolism under postprandial conditions.NEW & NOTEWORTHY Women with contrasting exercise and aerobic capacity levels show clear differences in bile acid (BA) metabolism. Women with low aerobic capacity (Lo-Fit) have increased circulating conjugated BAs post oral glucose tolerance test (OGTT), whereas women with high aerobic capacity (Hi-Fit) display a transient increase. Hi-Fit women show an increase in the secondary BA, lithocholic acid, during the OGTT not seen in Lo-Fit women. Differences in circulating BA species between Hi- and Lo-Fit women possibly contribute to differences in insulin sensitivity and energy regulation via different signaling mechanisms.

The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota

Elobixibat, a novel inhibitor of apical sodium-dependent bile acid transporter for treating chronic constipation, increases colonic bile acid concentrations, stimulating bowel function. However, it is not clear which bile acids are altered, or whether altered gut microbiota are associated with functional effects that may alter bowel function. To investigate the effects of elobixibat on changes in the faecal concentrations of total and individual bile acids and in faecal microbiota. This was a prospective, single-centre study. After baseline period, patients received 10mg daily of elobixibat for 2weeks. We evaluated the effects on bowel function, changes in faecal bile acid concentrations and composition of gut bacteria, before and after elobixibat administration. In the 30 patients analysed, the frequency of pre- and post-treatment bowel movements per fortnight was 7 and 10 (P<0.001), respectively. The pre-treatment faecal bile acid concentration increased significantly from 10.9 to 15.0µg/g stool post-treatment (P=0.030), with a significant increase in faecal deoxycholic acid (pre-treatment 3.94µg/g stool to post-treatment 5.02µg/g stool, P=0.036) and in glycine-conjugated deoxycholic and chenodeoxycholic acids. Shannon index was significantly decreased, but there were no significant changes at the genus and phylum levels. Short term treatment with elobixibat increased the concentrations of total bile acids and deoxycholic acid and decreased the diversity of faecal microbiota. The biological effects of elobixibat are associated with its effects on secretory bile acids, rather than the structural changes of an altered faecal microbiota.

4444 The effect of early life antibiotics on gut microbiome and fecal bile acid concentrations in children

OBJECTIVES/GOALS: The current proposal seeks to investigate the effect of early life antibiotic use in the development of functional gastrointestinal (GI) disorders. We propose that infants exposed to antibiotics will present with gut microbial dysbiosis, changes in fecal bile acid concentrations and develop more GI symptoms compared to unexposed children. METHODS/STUDY POPULATION: We analyzed fecal samples from 174 subjects at 12 months of age, of whom 52 were exposed to antibiotics in their first year of life. Of these, 33 subjects were sampled again at 24 months of age. DNA from 200mg of frozen stool (−80C) was isolated with the Qiagen DNeasy PowerSoil kit. Shotgun libraries were generated using the NexteraXT kit and sequenced on the Illumina HiSeq 2500 using 2x125 bp chemistry. Sequence data were analyzed using the Sunbeam metagenomics pipeline. The abundance of bacteria was estimated using Kraken version 2.0.8. Fecal bile acids will be quantified by liquid chromatography–mass spectrometry (LC-MS). RESULTS/ANTICIPATED RESULTS: Overall bacterial community composition at 12 or 24 months was not associated with antibiotic exposure (PERMANOVA test, Bray-Curtis distance). An increase in Enterobacteriaceae, in particular Escherichia coli, is a signature of antibiotic-induced dysbiosis, but also of early infant gut. Children with antibiotic exposure had slightly higher abundance of Escherichia coli compared to those with no exposure (p = 0.03). At 24 months, the abundance of Bacteroides caccae, a commensal gut species, was decreased for children exposed to antibiotics in the first year of life (fdr = 0.02). We will perform further analysis of bile acid modifying bacteria, fecal bile acid concentrations and correlate to GI symptoms. DISCUSSION/SIGNIFICANCE OF IMPACT: Our findings suggest a significant but nuanced impact of early life antibiotic use on the composition of the gut microbiota. The association of antibiotic exposure with B. caccae and E. coli warrant further attention in the context of the rapidly developing early-life microbiome. CONFLICT OF INTEREST DESCRIPTION: The authors declare no conflicts of interest relevant to this work.

Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial

Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D. We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by invivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency. Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated. In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.

Associations between Dietary Patterns and Bile Acids-Results from a Cross-Sectional Study in Vegans and Omnivores.

Bile acids play an active role in fat metabolism and, in high-fat diets, elevated concentrations of fecal bile acids may be related to an increased risk of colorectal cancer. This study investigated concentrations of fecal and serum bile acids in 36 vegans and 36 omnivores. The reduced rank regression was used to identify dietary patterns associated with fecal bile acids. Dietary patterns were derived with secondary and conjugated fecal bile acids as response variables and 53 food groups as predictors. Vegans had higher fiber (p < 0.01) and lower fat (p = 0.0024) intake than omnivores. In serum, primary and glycine-conjugated bile acids were higher in vegans than in omnivores (p ≤ 0.01). All fecal bile acids were significantly lower in vegans compared to omnivores (p < 0.01). Processed meat, fried potatoes, fish, margarine, and coffee contributed most positively, whereas muesli most negatively to a dietary pattern that was directly associated with all fecal bile acids. According to the pattern, fat intake was positively and fiber intake was inversely correlated with bile acids. The findings contribute to the evidence that, in particular, animal products and fat may play a part in higher levels of fecal bile acids.

Gut Microbiota Dysbiosis Is Associated with Altered Bile Acid Metabolism in Infantile Cholestasis.

The co-occurrence of gut microbiota dysbiosis and bile acid (BA) metabolism alteration has been reported in several human liver diseases. However, the gut microbiota dysbiosis in infantile cholestatic jaundice (CJ) and the linkage between gut bacterial changes and alterations of BA metabolism have not been determined. To address this question, we performed 16S rRNA gene sequencing to determine the alterations in the gut microbiota of infants with CJ, and assessed their association with the fecal levels of primary and secondary BAs. Our data reveal that CJ infants show marked declines in the fecal levels of primary BAs and most secondary BAs. A decreased ratio of cholic acid (CA)/chenodeoxycholic acid (CDCA) in infants with CJ indicated a shift in BA synthesis from the primary pathway to the alternative BA synthesis pathway. The bacterial taxa enriched in infants with CJ corresponded to the genera Clostridium, Gemella, Streptococcus, and Veillonella and the family Enterobacteriaceae and were negatively correlated with the fecal BA level and the CDCA/CA ratio but positively correlated with the serological indexes of impaired liver function. An increased ratio of deoxycholic acid (DCA)/CA was observed in a proportion of infants with CJ. The bacteria depleted in infants with CJ, including Bifidobacterium and Faecalibacterium prausnitzii, were positively and negatively correlated with the fecal levels of BAs and the serological markers of impaired liver function, respectively. In conclusion, the reduced concentration of BAs in the gut of infants with CJ is correlated with gut microbiota dysbiosis. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs.IMPORTANCE Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ.

The relationship between fecal bile acids and microbiome community structure in pediatric Crohn's disease.

Gut microbiome community structure is associated with Crohn's disease (CD) development and response to therapy. Bile acids (BAs) play a central role in modulating intestinal immune responses, and changes in gut bacterial communities can profoundly alter the intestinal BA pool. The liver synthesizes and conjugates primary bile acids (priBAs) that are then deconjugated, epimerized, and dehydroxylated by gut bacteria to produce secondary bile acids (secBAs). We investigated the relationship between the gut microbiome and the fecal BA pool in stool samples obtained from a well-characterized cohort of pediatric CD patients undergoing nutritional therapy to induce disease remission. We found that fecal BA composition was altered in a sub-group of CD patients who did not sustain remission. The microbial community structures associated with priBA and secBA-dominant profiles were distinct. In addition, the fecal BA concentrations were correlated with the abundance of distinct bacterial taxonomic groups. Finally, priBA dominant samples were associated with community-level decreases in enzymes for dehydroxylation but not deconjugation.

Cholecystectomy and Biliary Sphincterotomy Increase Fecal Bile Loss and Improve Lipid Profile in Dyslipidemia.

Bile is the only significant pathway for cholesterol elimination. Cholecystectomy (CS) increases fecal bile acid loss, and endoscopic biliary sphincterotomy (ES) is thought to have a similar effect. We speculated that a combined effect of ES + CS would further enhance fecal bile acid loss, potentially causing lipid profile changes in these patients. Fecal bile acids and sterols were determined using gas chromatography in cohorts of post-CS + ES, post-CS and in healthy controls. The effect of ES + CS on blood lipid profile was assessed retrospectively in a single-center cohort of post-CS + ES patients, using a computerized database. Parameters of interest included demographics, medical history, and lipid profiles. Fecal primary bile acid concentrations were increased after CS + ES compared to CS and controls (cholic acid [CA] 1.4ng/mg vs. 0.26ng/mg, p = 0.02 vs. 0.23ng/mg, p = 0.004, chenodeoxycholic acid [CDCA] 1.92ng/mg vs. 0.39ng/mg, p = 0.02 vs. 0.23ng/mg, p = 0.01, respectively). Fecal cholesterol excretion was similar in all three groups. Baseline serum lipid profile and subsequent changes following CS + ES were correlated. In patients with baseline hypercholesterolemia (total cholesterol (TC) > 200mg/dl), TC levels decreased by 28.5mg/dl, and LDL levels decreased by 21.5mg/dl. The effect was more pronounced in those with TC > 200mg/dl, despite of statin intake. In patients with hypertriglyceridemia [triglycerides (TG) > 200mg/dl], TG decreased by 67.8mg/dl following ES + CS. Among patients without dyslipidemia or dyslipidemia with adequate response to statins, the effect of ES + CS on lipid profile was minor. Fecal bile acid loss increases following CS + ES. The effect on blood lipid profile depends on baseline TC and TG levels. Lipid profile is improved in dyslipidemic patients, while the impact of CS + ES is minimal on the normolipemic population.

Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

BackgroundIrritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D.MethodsThis trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis.The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed.Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron.DiscussionThe TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond.Trial registrationISRCTN, ISRCTN17508514, Registered on 2 October 2017.

Comparison of diets enriched in stearic, oleic, and palmitic acids on inflammation, immune response, cardiometabolic risk factors, and fecal bile acid concentrations in mildly hypercholesterolemic postmenopausal women—randomized crossover trial

Direct comparisons between SFAs varying in chain length, specifically palmitic acid (16:0) and stearic acid (18:0), relative to the latter's metabolic product, oleic acid (18:1), on cardiometabolic risk factors are limited. The aim of this study was to determine the relative comparability of diets enriched in palmitic acid, stearic acid, and oleic acid on inflammation and coagulation markers, T lymphocyte proliferation/ex-vivo cytokine secretion, plasma cardiometabolic risk factors, and fecal bile acid concentrations. Hypercholesterolemic postmenopausal women (n=20, mean±SD age 64±7 y, BMI 26.4±3.4 kg/m2, LDL cholesterol≥2.8 mmol/L) were provided with each of 3 diets [55% energy (%E) carbohydrate, 15%E protein, 30%E fat, with ∼50% fat contributed by palmitic acid, stearic acid, or oleic acid in each diet; 5 wk/diet phase] using a randomized crossover design with 2-wk washouts between phases. Outcome measures were assessed at the end of each phase. Fasting LDL-cholesterol and non-HDL-cholesterol concentrations were lower after the stearic acid and oleic acid diets than the palmitic acid diet (all P<0.01). Fasting HDL-cholesterol concentrations were lower after the stearic acid diet than the palmitic acid and oleic acid diets (P<0.01). The stearic acid diet resulted in lower lithocholic acid (P=0.01) and total secondary bile acid (SBA) concentrations (P=0.04) than the oleic acid diet. All other outcome measures were similar between diets. Lithocholic acid concentrations were positively correlated with fasting LDL-cholesterol concentrations (r=0.33; P=0.011). Total SBA, lithocholic acid, and deoxycholic acid concentrations were negatively correlated with fasting HDL cholesterol (r=-0.51 to -0.44; P<0.01) concentrations and positively correlated with LDL cholesterol:HDL cholesterol (r =0.37-0.54; P<0.01) ratios. Dietary stearic acid and oleic acid had similar effects on fasting LDL-cholesterol and non-HDL-cholesterol concentrations and more favorable ones than palmitic acid. Unlike oleic acid, the hypocholesterolemic effect of stearic acid may be mediated by inhibition of intestinal hydrophobic SBA synthesis. These findings add to the data suggesting there should be a reassessment of current SFA dietary guidance and Nutrient Facts panel labeling.This trial was registered at clinicaltrials.gov as NCT02145936.