Gut microbiome-based strategies for HIV prevention and therapy, current challenges and future prospects

The gut microbiome has become a primary controller of host immunity as well as the pathogenesis of human immunodeficiency virus (HIV) infection. Commensal microbes in healthy persons keep the intestinal and other body barriers intact and regulate mucosal and systemic immune responses and generate metabolites, including short-chain fatty acids and indole derivatives that suppress inflammation and stimulate epithelial healing. These functions are impaired by HIV infection via depletion of gut CD4 + T cells, damage caused to epithelium, microbial translocation, and microbiota disruption. In this review article, we summarize recent studies suggesting that a balanced microbiome can mitigate HIV susceptibility and progression by preserving mucosal defenses, limiting systemic immune activation, and generating antiviral compounds. Other interventions, including probiotics, prebiotics, dietary modulation, and fecal microbiota transplantation (FMT), have been trialed with mixed outcomes in most cases, showing small but significant changes in the gut microbial composition and/or inflammatory markers. Current evidence highlights the potential of microbiome-targeted strategies to support HIV management; however, substantial gaps remain. Future research should focus on defining protective microbial signatures, developing next-generation live biotherapeutics, exploring metabolite-based therapies, and conducting large, mechanistically driven clinical trials. Harnessing the microbiome's protective functions could offer novel approaches to reducing HIV transmission, mitigating inflammation, and improving immune reconstitution in infected individuals.