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The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-β-muricholic acid (T-β-MCA). T-β-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr -null ( Fxr ΔIE ) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr ΔIE mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs. Tempol is an antioxidant that reduces the body weight of mice on a high-fat diet. Li et al. now provide a mechanistic link by demonstrating that tempol affects the intestinal microbiota, which leads to a change in the composition of bile acids and suppression of FXR signalling.

The human gut microbiota impacts host metabolism and has been implicated in the pathophysiology of obesity and metabolic syndromes. However, defining the roles of specific microbial activities and metabolites on host phenotypes has proven challenging due to the complexity of the microbiome-host ecosystem. Here, we identify strains from the abundant gut bacterial phylum Bacteroidetes that display selective bile salt hydrolase (BSH) activity. Using isogenic strains of wild-type and BSH-deleted Bacteroides thetaiotaomicron, we selectively modulated the levels of the bile acid tauro-β-muricholic acid in monocolonized gnotobiotic mice. B. thetaiotaomicron BSH mutant-colonized mice displayed altered metabolism, including reduced weight gain and respiratory exchange ratios, as well as transcriptional changes in metabolic, circadian rhythm, and immune pathways in the gut and liver. Our results demonstrate that metabolites generated by a single microbial gene and enzymatic activity can profoundly alter host metabolism and gene expression at local and organism-level scales. The microbiome, the collection of bacteria that live in and on human bodies, has a strong influence on how well the body works. However, the diversity of the microbiome makes it difficult to untangle exactly how it has these effects. For example, it is poorly understood how the hundreds of species of bacteria that live in the gut affect metabolism – the chemical processes that make life possible. But they are known to influence how metabolic diseases like diabetes and obesity develop. When we eat a meal, the body releases compounds called bile acids to help to digest the food. Once the bile acids reach the colon, the bacteria residing there use enzymes to chemically modify the compounds. Imbalances in the resulting pool of over 50 different bile acids may accelerate how quickly people develop metabolic disorders. It is not clear, however, which bile acids have helpful or harmful effects on metabolism. Yao et al. first identified a selective version of a prevalent gut bacterial enzyme called a bile salt hydrolase. This enzyme was then deleted from a common gut bacterium using genetic tools. Finally, Yao et al. colonized mice lacking any bacteria (i.e., germ-free mice) with either the original bacterium or the hydrolase-deleted bacterium. Mice colonized with the hydrolase-deleted bacteria gained less weight on a high fat diet and had lower levels of fat in their blood and liver. These mice also shifted to burning fats instead of carbohydrates for energy. The changes in the bile acid pool produced in mice colonized with hydrolase-deleted bacteria did not only affect metabolism. Yao et al. found differences in the activity of genes important for other biological processes as well, such as those that control circadian rhythms and immune responses. Further research is needed to investigate whether limiting the activity of the bile salt hydrolase enzyme has similar effects in humans. If so, developing drugs or probiotics that target the enzyme could lead to new treatments for people with metabolic diseases like obesity and fatty liver disease. Investigating the biological effects of other bacterially modified bile acids may identify other possible treatments as well.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein–coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on 75Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Objective Bile acids may play a role in the pathogenesis of IBS. We investigated the potential effects of bile acids entering the colon and its role in the symptom pattern in IBS. Design We measured 75Se-labelled homocholic acid-taurine (75SeHCAT) retention, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor (FGF) 19 in patients with IBS (n=141) and control subjects (75SeHCAT n=29; C4 and FGF19 n=435). In patients with IBS stool frequency and form, as well as GI symptom severity were registered, and in a proportion of patients colonic transit time and rectal sensitivity were measured (n=66). An 8-week open-label treatment with colestipol was offered to patients with 75SeHCAT <20%, and the effect of treatment was evaluated with IBS severity scoring system and adequate relief of IBS symptoms. Results Compared with controls, patients with IBS had lower 75SeHCAT values (p=0.005), higher C4c levels (C4 corrected for cholesterol) (p<0.001), but similar FGF19 levels. Abnormal 75SeHCAT retention (<10%) was seen in 18% of patients, whereas 23% had elevated C4c levels. Patients with IBS with 75SeHCAT retention <10% had more frequent stools, accelerated colonic transit time, rectal hyposensitivity, a higher body mass index, higher C4c and lower FGF19 levels. Colestipol treatment improved IBS symptoms (IBS severity scoring system 220±109 vs 277±106; p<0.01), and 15/27 patients fulfilled criteria for treatment response (adequate relief ≥50% of weeks 5–8). Conclusions Increased colonic bile acid exposure influences bowel habit and colonic transit time in patients with IBS. A high response rate to open label treatment with colestipol supports this, but placebo-controlled studies are warranted.

Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD. Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR. FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01). These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

This study examines the validity of measuring faecal bile acids (FBA) in a single stool sample as a diagnostic tool for bile acid diarrhoea (BAD) by direct comparison to the 75 selenium-homotaurocholic acid (SeHCAT) scan. A prospective observational study was undertaken. Patients with chronic diarrhoea (> 6 weeks) being investigated for potential BAD with SeHCAT scan provided stool samples for measurement of FBA, using an enzyme-linked immunosorbent assay. Patients were characterised into four groups: SeHCAT negative control group, post-cholecystectomy, idiopathic BAD and post-operative terminal ileal resected Crohn’s disease. Stool samples were collected at baseline and 8-weeks post treatment to determine whether FBA measurement could be used to monitor therapeutic response. 113 patients had a stool sample to directly compare with their SeHCAT result. FBA concentrations (μmol/g) and interquartile ranges in patients in the control group (2.8; 1.6–4.2), BAD (3.6; 1.9–7.2) and post-cholecystectomy cohort 3.8 (2.3–6.8) were similar, but all were significantly lower (p < 0.001) compared to the Crohn’s disease cohort (11.8; 10.1–16.2). FBA concentrations in patients with SeHCAT retention of < 15% (4.95; 2.6–10.5) and < 5% (9.9; 4.8–15.4) were significantly higher than those with a SeHCAT retention > 15% (2.6; 1.6–4.2); (p < 0.001 and p < 0.0001, respectively). The sensitivity and specificity using FBA cut-off of 1.6 μmol/g (using ≤ 15% SeHCAT retention as diagnostic of BAD) were 90% and 25% respectively. A single random stool sample may have potential use in diagnosing severe BAD or BAD in Crohn’s patients. Larger studies are now needed to confirm the potential efficacy of this test to accurately diagnose BAD in the absence of SeHCAT testing.

Bile salt hydrolase (BSH) activity against the bile acid tauro-beta-muricholic acid (T-β-MCA) was recently reported to mediate host bile acid, glucose, and lipid homeostasis via the farnesoid X receptor (FXR) signaling pathway. An earlier study correlated decreased Lactobacillus abundance in the cecum with increased concentrations of intestinal T-β-MCA, an FXR antagonist. While several studies have characterized BSHs in lactobacilli, deconjugation of T-β-MCA remains poorly characterized among members of this genus, and therefore it was unclear what strain(s) were responsible for this activity. Here, a strain of L. johnsonii with robust BSH activity against T-β-MCA in vitro was isolated from the cecum of a C57BL/6J mouse. A screening assay performed on a collection of 14 Lactobacillus strains from nine different species identified BSH substrate specificity for T-β-MCA only in two of three L. johnsonii strains. Genomic analysis of the two strains with this BSH activity revealed the presence of three bsh genes that are homologous to bsh genes in the previously sequenced human-associated strain L. johnsonii NCC533. Heterologous expression of several bsh genes in E. coli followed by enzymatic assays revealed broad differences in substrate specificity even among closely related bsh homologs, and suggests that the phylogeny of these enzymes does not closely correlate with substrate specificity. Predictive modeling allowed us to propose a potential mechanism driving differences in BSH activity for T-β-MCA in these homologs. Our data suggests that L. johnsonii regulates T-β-MCA levels in the mouse intestinal environment, and that this species may play a central role in FXR signaling in the mouse.

Background Bile acid malabsorption (BAM) and bile acid-related diarrhea represent an under-recognized cause of chronic diarrhea mainly because of limited guidance on appropriate diagnostic and laboratory tests. We aimed to perform a systematic review of the literature in order to identify and compare the diagnostic accuracy of different diagnostic methods for patients with BAM, despite a proven gold standard test is still lacking. Methods A PubMed literature review and a manual search were carried out. Relevant full papers, evaluating the diagnostic accuracy of different methods for BAM, were assessed. Available data were analyzed to estimate the sensitivity and specificity of each published test. Results Overall, more than one test was considered in published papers on BAM. The search strategy retrieved 574 articles; of these, only 16 were full papers (with a total of 2.332 patients) included in the final review. Specifically, n  = 8 studies used 75 Selenium-homotaurocholic-acid-test ( 75 SeHCAT) with a < 10% retention threshold; n = 8 studies evaluated fasting serum 7-α-hydroxy-4-cholesten-3-one (C4); n  = 3 studies involved total fecal bile acid (BA) excretion over 48 h; n  = 4 studies assessed fibroblast growth factor 19 (FGF19). 75 SeHCAT showed an average sensitivity and specificity of 87.32 and 93.2%, respectively, followed by serum C4 (85.2 and 71.1%) and total fecal BA (66.6 and 79.3%). Fasting serum FGF19 had the lowest sensitivity and specificity (63.8 and 72.3%). All the extracted data were associated with substantial heterogeneity. Conclusions Our systematic review indicates that 75 SeHCAT has the highest diagnostic accuracy for BAM, followed by serum C4 assay. The diagnostic yield of fecal BA and FGF19 assays is still under investigation. Our review reinforces the need for novel biomarkers aimed to an objective detection of BAM and therefore improving the management of this condition.

BackgroundWe investigated ‘rare’ bile acids (BA) as potential markers in septic neonates.Methods‘Rare’ (C-6 hydroxylated BA) and ‘classical’ BA were determined in 102 neonates using high-performance liquid chromatography—high-resolution mass spectrometry (HPLC-HRMS). Four groups according to maturity (full term, FT vs. preterm, PT) and septic status (early-onset neonatal sepsis, EOS vs. CTR; non-septic controls) were formed: FT-CTR; (n = 47), PT-CTR (n = 22), FT-EOS (n = 20), PT-EOS (n = 13).ResultsFirstly, FT-CTR had a significant higher amount of ‘rare’ BA than PT (FT-CTR: 0.5 µmol/L, IQR: 0.3–1.3 vs. PT-CTR: 0.01 µmol/L, IQR 0.01–0.2; p < 0.01). The most common ‘rare’ BA in FT-CTR were tauro-γ- (TGMCA) and tauro-α-muricholic acid (TAMCA). Secondly, in EOS, absolute ‘rare’ BA levels were comparable in both gestational age groups (FT-EOS: 0.6 µmol/L, IQR: 0.1–1.6 and PT-EOS: 0.6 µmol/L, IQR: 0.2–1.5). Therefore, EOS had significantly higher median ‘rare’ BA values than non-septic PT neonates (p < 0.01). In PT and term neonates, the relative amount of tauro-ω-muricholic acid (TOMCA) within the ‘rare’ BA pool was significantly higher in EOS than in controls (FT-CTR vs. \"FT-EOS and PT-CTR vs. PT-EOS; p < 0.01). It was hence the predominant ‘rare’ BA in EOS.ConclusionTOMCA is an independent factor associated with EOS. It has diagnostic potential.

The link between antibiotic treatment and IF-associated liver disease (IFALD) is unclear. Here, we study the effect of antibiotic treatment on bile acid (BA) metabolism and investigate the involved mechanisms. The results showed that pediatric IF patients with cholestasis had a significantly lower abundance of BA-biotransforming bacteria than patients without cholestasis. In addition, the BA composition was altered in the serum, feces, and liver of pediatric IF patients with cholestasis, as reflected by the increased proportion of primary BAs. In the ileum, farnesoid X receptor (FXR) expression was reduced in patients with cholestasis. Correspondingly, the serum FGF19 levels decreased significantly in patients with cholestasis. In the liver, the expression of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), increased noticeably in IF patients with cholestasis. In mice, we showed that oral antibiotics (gentamicin, GM or vancomycin, VCM) reduced colonic microbial diversity, with a decrease in both Gram-negative bacteria (GM affected Eubacterium and Bacteroides ) and Gram-positive bacteria (VCM affected Clostridium , Bifidobacterium and Lactobacillus ). Concomitantly, treatment with GM or VCM decreased secondary BAs in the colonic contents, with a simultaneous increase in primary BAs in plasma. Moreover, the changes in the colonic BA profile especially that of tauro-beta-muricholic acid (TβMCA), were predominantly associated with the inhibition of the FXR and further altered BA synthesis and transport. In conclusion, the administration of antibiotics significantly decreased the intestinal microbiota diversity and subsequently altered the BA composition. The alterations in BA composition contributed to cholestasis in IF patients by regulating FXR signaling. Liver disease: Detrimental effects of antibiotics in intestinal failure Using antibiotics during intestinal failure in children may lead to the development of liver disease. Microbiota in the gut play vital roles in balancing the digestive system, including transforming bile acids (BAs) secreted by the liver into forms that help us digest food. Wai Cai and Ying Wang at Shanghai Jiao Tong University in China and co-workers examined samples from 46 children treated with antibiotics for intestinal failure. The patients who also had cholestasis – disrupted production and flow of bile – had far fewer BA-transforming bacteria in their gut than those without cholestasis. They also had altered expression of a crucial BA receptor protein. Experiments on mice showed that treatment with two different antibiotics reduced microbiota diversity, which in turn influenced BA receptor signaling and altered BA composition, contributing to cholestasis.