Impact of microbiome alterations on fracture healing and nonunion: a narrative review

Fracture healing is a complex biological process determined by mechanical stability, vascular supply, and systemic physiological factors. Despite advances in fracture management, nonunion remains an important clinical challenge. Emerging evidence indicates that the gut microbiome is a key regulator of bone metabolism and fracture repair through immune modulation, nutrient digestion, and microbial signaling pathways.

We conducted a narrative review synthesizing experimental and clinical evidence on the impact of gut microbiome alterations on fracture healing and nonunion. Literature searches were performed in PubMed, Google Scholar, and Scopus for studies published between 2013 and 2026. A total of 107 records were initially screened by title and abstract, and 11 studies meeting inclusion criteria were included in the final synthesis. Many screened articles focused on osteoporosis, general bone metabolism or outcomes related to microbiome that didn't evaluate fracture healing, non-union, delayed union, or complications related to fractures, therefore they were excluded.

The gut microbiome emerges as an important regulator of bone metabolism and fracture repair. Microbial metabolites, particularly short-chain fatty acids, are associated with enhanced osteoblast activity, suppressed osteoclast-mediated bone resorption, and improved calcium absorption, collectively supporting bone mineral density and trabecular integrity. Dysbiosis impairs fracture healing by promoting gut barrier dysfunction, increasing intestinal permeability, and elevating systemic inflammation. Elevated pro-inflammatory cytokines, including IL-17a, are linked to reduced callus mineralization and delayed bone regeneration. Evidence also suggests a reciprocal interaction, where fracture events can alter gut microbiome composition and function. Microbiome-targeted interventions, such as probiotic and prebiotic supplementation, show therapeutic potential by improving bone microarchitecture, stimulating osteogenic signaling, and mitigating inflammation. Clinically, microbial dysregulation, particularly in infection-associated states, correlates with prolonged healing times and increased bone loss.

The gut microbiome is an emerging systemic regulator of bone metabolism and may influence fracture healing and nonunion risk through mechanisms that include immune modulation, microbial metabolites, and nutrient metabolism. Dysbiosis may impair bone regeneration and increase the risk of delayed union or nonunion. Microbiome-targeted therapies are promising, but more human studies are needed to confirm their clinical relevance. These findings highlight the interconnected roles of the microbiome, immune function, and metabolism in bone healing, underscoring the need for further research.