Gut Microbiota-Derived Short-Chain Fatty Acids Mediate the Bone-Protective Effects of Metformin Against Postmenopausal Osteoporosis.

Authors

Zenglin Tan, Jingjing Zeng, Furong Huang, Fan Gao, Yangyang Hu, Lei Guo, Peng Guo, Lei Chen

Published in

European journal of pharmacology. Pages 179442. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

Dysbiosis-induced inflammation has been implicated in postmenopausal osteoporosis (PMOP). Although metformin has shown benefits for bone health, the exact role of the gut microbiota in the mechanism underlying this relationship remains unclear.
We hypothesised that metformin could alleviate systemic inflammation in PMOP by augmenting the synthesis of short-chain fatty acids (SCFAs) by gut microbes.
Micro-computed tomography (μCT) was used to analyse the femurs. Faecal samples were collected for 16S rRNA sequencing and SCFAs detection. Quantitative real-time PCR (qRT-PCR) and western blotting were used to detect mRNA and protein expression, respectively. Primary bone marrow mesenchymal stem cells (BMSCs) and bone marrow macrophages (BMMs) were isolated to explore the effects of SCFAs on bone cell activity following inflammatory stimulation.
Metformin improved trabecular bone microarchitecture in OVX mice, as shown by higher BV/TV, Tb.Th, and Tb.N, and reduced serum and tibial IL-1β and TNF-α. Metformin also increased the abundance of SCFA-producing genera, including Butyricimonas, Prevotella, Ruminococcus, Coprococcus, Oscillospira, and Sutterella, and elevated faecal propionate, butyrate, and valerate. Transplantation of metformin-adapted microbiota reproduced the bone-protective and anti-inflammatory effects, whereas GPR41/GPR43 deficiency abolished the benefits of metformin, propionate, and butyrate. In vitro, propionate and butyrate, but not valerate, promoted BMSC osteogenic differentiation and inhibited BMM-derived osteoclast differentiation under IL-1β/TNF-α-induced inflammation.
Metformin modulates the gut microbiota by increasing propionate and butyrate synthesis, thereby reducing dysbiosis-induced inflammation and regulating BMSC and BMM differentiation to protect against PMOP.

PMID:
42874908
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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