Microbial remodeling of gut tryptophan metabolism and indole-3-lactate production regulate epithelial barrier repair and viral suppression in human and simian immunodeficiency virus infections

Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are associated with mucosal barrier disruption and immune suppression. Administration of Lactiplantibacillus plantarum or Bifidobacterium longum subsp. infantis into the SIV-inflamed gut lumen in vivo resulted in rapid reprogramming of microbial TRP metabolism towards indole-3-lactic acid (ILA) production. This shift accelerated epithelial repair and enhanced anti-viral defenses through induction of IL-22 signaling in mucosal T cells and aryl hydrocarbon receptor activation. Additionally, ILA treatment of human colorectal tissue explants ex vivo inhibited HIV replication by reducing mucosal inflammatory cytokine production and cell activation. Our findings underscore the therapeutic potential of microbial metabolic reprogramming of TRP-to-ILA and mechanisms in mitigating viral pathogenic effects and bolstering mucosal defenses for HIV eradication.