Gut microbiome-induced metabolites promote the role of Silybin as adjunctive drug in HIV-positive immunological nonresponders

HIV-infected immunological nonresponders (INRs) endure persistent T-cell dysfunction and chronic inflammation, facing high risk of various complications and mortality, with no effective therapies available. Silybin, the principal constituent of a plant extract, possesses anti-inflammation and immunomodulatory properties. The gut microbiome has been shown to modulate the efficacy of immune therapies and drugs. We gave 54 INRs oral silybin for three months and used multi-omics to investigate the gut-related factors influencing the efficacy of silybin. Silybin raised CD4+ T cells counts in 52% of participants and an efficacy classification model based on baseline gut microbiome and metabolites was developed. Favorable gut bacteria produced anti-inflammatory metabolites that downregulated Ras/MAPK/PI3K-Akt signaling pathways also targeted by silybin. Our findings shed light on a novel therapeutic approach for addressing immune dysfunction in HIV-positive INRs and have important implications for personalized medical strategies in the management of HIV infection.