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

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.

Redox‐Dependent Effects in the Physiopathological Role of Bile Acids

“…This muscle dysfunction was associated with an altered profile of BA that reaches the portal blood circulation. This change induces the inhibition of ileal FXR signaling with the consequent decrease in serum levels of FGF15, an enterokine related to muscle wasting [ 113 ]. Considering the antecedents related to muscular TGR5, BA, and sarcopenia [ 44 , 54 ], it is impossible to discard this receptor's participation in the muscle dysfunction associated with alteration in the microbiota-BA axis.…”

Dysbiosis of the gut microbiome impairs mouse skeletal muscle adaptation to exercise

“…Although these authors found that streptomycin reduced muscle membrane permeability, it did not affect the amount of myofibre swelling using a dose 80-fold greater than that used in the current study (Hayao et al 2018). Most recently, Qiu and colleagues reported antibiotic-induced dysbiosis caused muscle atrophy which was shown to be mediated by a suppression of bile acid signalling to fibroblast growth factor 15; however, as with the aforementioned studies, these authors used antibiotic doses 100 time greater than those used in the current study (Qiu et al 2021). Finally, intraperitoneal injection of the antibiotic imipenem for five consecutive days did not affect muscle specific force (Owen et al 2019).…”

Sarcopenia Is a Cause and Consequence of Metabolic Dysregulation in Aging Humans: Effects of Gut Dysbiosis, Glucose Dysregulation, Diet and Lifestyle

“…The changes in gut microbiota are involved with skeletal muscle mass by changing SCFA and inflammatory cytokines to modulate the gut-muscle axis. Qui et al used an antibiotic cocktail to mostly eliminate the gut microbiota of 10-week-old C57BL/6 mice and determine the effects on body composition [80]. The antibiotic-treated mice experienced skeletal muscle atrophy linked to decreased ileal farnesoid X receptor (FXR)-FGF15 signaling and subsequently impaired skeletal muscle protein synthesis.…”