Journal Article

6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice

Khan, Muhammad Tanweer, Bäckhed, Fredrik, Makki, Kassem, Schoonjans, Kristina, Brolin, Harald, Petersen, Natalia, Henricsson, Marcus, Tremaroli, Valentina, Marschall, Hanns-Ulrich, Bergh, Per-Olof, Christensen, Dan Ploug, Wahlström, Annika

2023

Overview

ObjectiveDietary fibres are essential for maintaining microbial diversity and the gut microbiota can modulate host physiology by metabolising the fibres. Here, we investigated whether the soluble dietary fibre oligofructose improves host metabolism by modulating bacterial transformation of secondary bile acids in mice fed western-style diet.DesignTo assess the impact of dietary fibre supplementation on bile acid transformation by gut bacteria, we fed conventional wild-type and TGR5 knockout mice western-style diet enriched or not with cellulose or oligofructose. In addition, we used germ-free mice and in vitro cultures to evaluate the activity of bacteria to transform bile acids in the caecal content of mice fed with western-style diet enriched with oligofructose. Finally, we treated wild-type and TGR5 knockout mice orally with hyodeoxycholic acid to assess its antidiabetic effects.ResultsWe show that oligofructose sustains the production of 6α-hydroxylated bile acids from primary bile acids by gut bacteria when fed western-style diet. Mechanistically, we demonstrated that the effects of oligofructose on 6α-hydroxylated bile acids were microbiota dependent and specifically required functional TGR5 signalling to reduce body weight gain and improve glucose metabolism. Furthermore, we show that the 6α-hydroxylated bile acid hyodeoxycholic acid stimulates TGR5 signalling, in vitro and in vivo, and increases GLP-1R activity to improve host glucose metabolism.ConclusionModulation of the gut microbiota with oligofructose enriches bacteria involved in 6α-hydroxylated bile acid production and leads to TGR5-GLP1R axis activation to improve body weight and metabolism under western-style diet feeding in mice.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Acid production / Acids / Animal models / Animals / Antidiabetics / Bacteria / Bile / bile acid metabolism / Bile acids / Bile Acids and Salts - metabolism / Body Weight / Body weight gain / Cellulose / Diabetes / Diabetes mellitus / Diet / Diet, Western / Dietary fiber / Dietary Fiber - administration & dosage / dietary fibre / Dietary Supplements / Fibers / Gastrointestinal Microbiome / Gene expression / Germfree / glucagen-like peptides / Glucose / Glucose - metabolism / Gut Microbiota / Insulin / Intestinal microflora / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Mice, Knockout / Microbiota / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Small intestine