Gut microbiota-driven immunomodulation in tuberculosis: targeting dysbiosis to overcome drug resistance

Tuberculosis (TB) remains a major global health threat, hampered by the escalating prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Managing these resistant infections demands protracted, intricate, and frequently hepatotoxic drug regimens with poor efficacy, toxicity, and adherence issues. This landscape underscores an urgent need to move beyond a purely antimicrobial-focused paradigm. Converging lines of evidence now firmly position the gut microbiota-a pivotal orchestrator of systemic immunity, metabolic homeostasis, and drug metabolism-as a central determinant in both TB pathogenesis and therapeutic success. Our review describes a vicious cycle at the heart of contemporary TB management. A critical and often overlooked trigger is the profound and persistent gut microbiota dysbiosis induced by the anti-TB medications themselves. Far from an incidental side effect, this dysbiosis is strongly implicated as a pathological driver in preclinical models and observational studies. It undermines pulmonary host defense through the gut-lung axis, aggravates anti-tuberculosis drug-induced liver injury (ATB-DILI), and cultivates a systemic state of chronic inflammation coupled with metabolic dysregulation (such as impaired lipid metabolism). Paradoxically, this host environment fosters Mycobacterium tuberculosis persistence and disease progression. In drug-resistant TB, this vicious cycle is amplified, is associated with therapeutic failure and may contribute to the selection of resistance in correlative studies. To disrupt this cycle, we assess the translational promise of interventions targeting the microbial ecosystem. This encompasses a multi-pronged strategy: employing probiotics, prebiotics, and tailored dietary modifications to restore ecological balance; utilizing fecal microbiota transplantation (FMT) for more profound restoration; and pioneering the development of novel, narrow-spectrum antimicrobials designed to preserve commensal flora. We contend that the integration of microbiome stewardship into TB care is an indispensable evolution in our approach. By concurrently targeting the pathogen and fortifying the host's intrinsic microbial defenses, this holistic strategy presents a transformative pathway to surmount drug resistance, alleviate treatment-related toxicity, and improve patient outcomes.