Phytomolecule and microbiota-modulation based therapeutic strategies for MDR-Tuberculosis: Mechanistic interplay and translational perspectives

Multidrug-resistant tuberculosis (MDR-TB) continues to represent a critical global health challenge due to resistance against first- and second-line anti-TB drugs. Emerging evidence highlights the pivotal role of the human microbiota in TB pathogenesis, immune regulation, and drug response. This review systematically explores the microbiota–MDR-TB axis, with a focus on phytomolecule-based therapeutic interventions. A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, Google Scholar, and Elsevier ScienceDirect following PRISMA guidelines, covering studies from January 2004 to August 2025. Included studies encompassed in vitro , in vivo , and clinical investigations elucidating microbiota alterations during TB infection and therapy, mechanistic insights into microbiota-derived metabolites (short-chain fatty acids, indoles), and their regulation of host immunity through AMPK–mTOR signaling, autophagy, and Treg/Th1 cell balance. Our analysis reveals that TB-associated gut and lung dysbiosis leads to SCFA depletion, epithelial barrier disruption, and systemic inflammation, weakening granuloma integrity and favoring M.tb persistence. Phytomolecules such as curcumin, emodin, resveratrol, and berberine exhibit dual actions by exerting direct antimycobacterial effects while simultaneously restoring the microbiota. These effects help reprogram immune responses through PRR, AHR, and AMPK pathways. Additionally, microbiota-sparing drug formulations, including ridinilazole, cadazolid, and lolamicin, along with probiotics, prebiotics, and synbiotics, demonstrate potential as adjunctive strategies to mitigate dysbiosis and enhance treatment outcomes. This review provides a mechanistic and translational framework for integrating phytomolecules and microbiome-modulating approaches into precision therapy, supporting the development of microbiota-informed host-directed therapies for MDR-TB. • Microbiota–MDR-TB Link: Gut–Lung Dysbiosis Drives TB Progression, Drug Resistance, and Immune Dysfunction. • Phytomolecules’ Dual Role : Natural compounds act as both antimycobacterial agents and microbiota modulators. • Mechanistic Insights: Key immune pathways (AMPK–mTOR, PRRs, autophagy) are influenced by microbiota and phytomolecules. • Clinical Evidence: Dysbiosis worsens MDR-TB, while probiotics and metformin improve host outcomes. • Therapeutic Advances: Probiotics, synbiotics, and microbiota-sparing drugs enhance TB therapy and limit resistance. • Future Outlook: Microbiome profiling and phytomolecule-based adjuncts support precision MDR-TB management.