Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling

Ann Med. 2021 Dec;53(1):508-522. doi: 10.1080/07853890.2021.1900593.

Abstract

Background: Recent evidence indicates that host-gut microbiota crosstalk has nonnegligible effects on host skeletal muscle, yet gut microbiota-regulating mechanisms remain obscure.Methods: C57BL/6 mice were treated with a cocktail of antibiotics (Abx) to depress gut microbiota for 4 weeks. The profiles of gut microbiota and microbial bile acids were measured by 16S rRNA sequencing and ultra-performance liquid chromatography (UPLC), respectively. We performed qPCR, western blot and ELISA assays in different tissue samples to evaluate FXR-FGF15/19 signaling.Results: Abx treatment induced skeletal muscle atrophy in mice. These effects were associated with microbial dysbiosis and aberrant bile acid (BA) metabolism in intestine. Ileal farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling was inhibited in response to microbial BA disturbance. Mechanistically, circulating FGF15 was decreased, which downregulated skeletal muscle protein synthesis through the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway. Treating Abx mice with FGF19 (human FGF15 ortholog) partly reversed skeletal muscle loss.Conclusions: These findings indicate that the BA-FXR-FGF15/19 axis acts as a regulator of gut microbiota to mediate host skeletal muscle.

Keywords: FGF15/19; FXR; Gut microbiota; bile acid; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / adverse effects
  • Bile Acids and Salts / metabolism
  • Disease Models, Animal
  • Down-Regulation / genetics
  • Dysbiosis / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gastrointestinal Microbiome / genetics*
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Intestines / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / microbiology*
  • Muscular Atrophy / chemically induced
  • Muscular Atrophy / microbiology*
  • RNA, Ribosomal, 16S
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction / genetics

Substances

  • Anti-Bacterial Agents
  • Bile Acids and Salts
  • RNA, Ribosomal, 16S
  • Receptors, Cytoplasmic and Nuclear
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • Fibroblast Growth Factors

Grants and funding

This work was supported by the National Key Research and Development Program of China [2018YFC2002000], National Natural Science Foundation of China [81901408 and 82071581], Shanghai Sailing program [19YF1414500], Shanghai Medical Leadership Training Program [2019LJ09].