Gut microbiota-mediated Th17/Treg regulation in osteoporotic fracture: from postmenopausal dysbiosis to callus repair

Abstract

Osteoporotic fractures are traditionally regarded as severe clinical consequences of low bone mass and impaired bone strength, but fracture risk and repair outcomes are also shaped by systemic inflammation, intestinal barrier integrity, microbial metabolism, and osteoimmune regulation. Increasing evidence indicates that gut dysbiosis associated with postmenopausal osteoporosis is accompanied by increased lipopolysaccharide exposure, altered microbial metabolites, enhanced pro-inflammatory cytokine signaling, and dysregulation of T helper 17 and regulatory T cells. These changes may promote bone resorption before fracture and create an unfavorable immune background for subsequent repair. Fracture studies further show that interleukin-17 signaling, gut-derived T helper 17 cells, γδ T cells, and regulatory T cells participate in callus inflammation, progenitor recruitment, cartilage-to-bone transition, mineralization, and remodeling in a stage- and context-dependent manner. Microbial metabolites, particularly short-chain fatty acids such as butyrate, tryptophan-derived indoles, and bile acid metabolites, can modulate T helper 17/regulatory T-cell homeostasis through immunometabolic and receptor-dependent pathways, whereas trimethylamine N-oxide and polyamines may further modify inflammatory and bone-remodeling responses. These effects vary according to metabolite identity, target-cell type, receptor signaling, and the local inflammatory context. This review summarizes current evidence linking gut microbiota dysbiosis, microbial metabolites, T helper 17/regulatory T-cell regulation, and osteoporotic fracture risk and repair. Microbiota-targeted approaches, including probiotics and prebiotics, together with engineered oral delivery and local immunoregulatory strategies, may provide opportunities to improve the osteoimmune environment. However, direct clinical evidence that these approaches prevent osteoporotic fractures or improve fracture healing remains limited. Direct evidence connecting gut microbiota-dependent T helper 17/regulatory T-cell responses with postmenopausal osteoporotic fracture healing is still scarce, and most conclusions are inferred from bone-loss models, standard fracture models, microbiota intervention studies, and bone regeneration models. Future studies should integrate microbiota profiling, barrier assessment, metabolite analysis, bone marrow and callus immune phenotyping, callus mineralization, and mechanical healing endpoints in osteoporotic fracture-specific models.