1. Academic Validation
  2. 6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice

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

  • Gut. 2022 Jun 13;gutjnl-2021-326541. doi: 10.1136/gutjnl-2021-326541.
Kassem Makki 1 Harald Brolin 1 Natalia Petersen 2 Marcus Henricsson 1 Dan Ploug Christensen 2 Muhammad Tanweer Khan 1 Annika Wahlström 1 Per-Olof Bergh 1 Valentina Tremaroli 1 Kristina Schoonjans 3 Hanns-Ulrich Marschall 1 Fredrik Bäckhed 4
Affiliations

Affiliations

  • 1 The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 2 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 3 ETH Zurich, Zurich, Zürich, Switzerland.
  • 4 The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden fredrik.backhed@wlab.gu.se.
Abstract

Objective: Dietary 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.

Design: To 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.

Results: We 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.

Conclusion: Modulation 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.

Keywords

bile acid metabolism; diabetes mellitus; dietary fibre; glucagen-like peptides.

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