Gut microbiota homeostasis alleviates mycobacterial granuloma pathology in zebrafish

Growing evidence links the gut microbiota to host immune regulation and tuberculosis (TB) progression; however, its specific impact on the formation and necrosis of TB granulomas remains poorly defined. In this study, we established an adult zebrafish model of antibiotic-induced gut microbiota dysbiosis followed by Mycobacterium marinum (M.m) infection to investigate how gut microbiota perturbation influences host resistance to mycobacterial infection. Our results demonstrated that antibiotic-induced gut microbiota dysbiosis significantly increased the mycobacterial burden in zebrafish, thereby compromising host resistance to mycobacterial infection. Dysbiosis also intensified infection-associated inflammatory responses, as reflected by the elevated expression of the pro-inflammatory cytokines tnf-α and il-1β, resulting in more severe systemic pathology characterized by enhanced granuloma formation and necrosis, together with remodeling of the immune cell composition within granulomatous lesions. Importantly, fecal microbiota transplantation (FMT) from healthy donors effectively reduced the bacterial burden and alleviated granuloma-associated pathological changes in infected zebrafish. These findings demonstrate that the gut microbiota critically modulates the granuloma immune microenvironment, providing a robust platform and mechanistic support for gut microecological interventions as a host-directed therapy for TB.