Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition.

Background: The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. Results: Here we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. Conclusion: We provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention.

Targeted LC-MS/MS Profiling of Bile Acids in Various Animal Tissues.

Bile acids are being increasingly investigated in humans and laboratory animals as markers for various diseases in addition to their important functions, such as promoting the emulsification in fat digestion and preventing gallstone formation. In humans and animals, primary bile acids are formed from cholesterol in the liver, converted in the intestine into various secondary bile acids by the intestinal microbiota and reabsorbed in the terminal ileum, and partially returned to the liver. A universal high-throughput workflow, including a simple workup, was applied as a tool for bile acid analysis in animal studies. The complex bile acid profiles in various tissues, organs, and body fluids from different animals were mapped using a newly developed comprehensive liquid chromatography-tandem mass spectrometry method. The method can also be used in screening food to obtain information about the nutritional content of bile acids. This could be relevant to investigations on various animal diseases and on the bioavailability of bile acids that pass through the gastric tract.

Development of a Highly Sensitive Ultra-High-Performance Liquid Chromatography Coupled to Electrospray Ionization Tandem Mass Spectrometry Quantitation Method for Fecal Bile Acids and Application on Crohn's Disease Studies.

In addition to their important role in fat digestion, bile acids are increasingly being used as markers for various diseases. The large diversity of bile acids results from the conversion of primary and conjugated bile acids into secondary bile acids by deconjugation and dehydroxylation reactions mediated by the intestinal microbiota. Here, we describe a fast and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for absolute quantitation of 45 bile acids in human or mouse feces in combination with a simple workup and extraction procedure. Method validation outlined excellent limits of detection and quantitation, linearity, selectivity, recovery, extraction loss, and precision. To investigate the connection between microbiome alterations and bile acid metabolism, the method was applied on a Crohn's disease study including patients with histologically documented active disease or remission as well as on a model using humanized mice. As the complex mechanism including genetic and environmental factors leading to the development of Crohn's disease is so far not completely understood, the study investigates the microbial metabolism of bile acids and the potential use of bile acid profiles to predict disease state.

Integrated microbiota and metabolite profiles link Crohn's disease to sulfur metabolism.

Gut microbial and metabolite alterations have been linked to the pathogenesis of inflammatory bowel diseases. Here we perform a multi-omics microbiome and metabolite analysis of a longitudinal cohort of Crohn's disease patients undergoing autologous hematopoietic stem cell transplantation, and investigational therapy that induces drug free remission in a subset of patients. Via comparison of patients who responded and maintained remission, responded but experienced disease relapse and patients who did not respond to therapy, we identify shared functional signatures that correlate with disease activity despite the variability of gut microbiota profiles at taxonomic level. These signatures reflect the disease state when transferred to gnotobiotic mice. Taken together, the integration of microbiome and metabolite profiles from human cohort and mice improves the predictive modelling of disease outcome, and allows the identification of a network of bacteria-metabolite interactions involving sulfur metabolism as a key mechanism linked to disease activity in Crohn's disease.