Our study has identified that impaired peroxisome proliferator-activated receptor-α (PPARα) signaling and associated mitochondrial dysfunction is an important underlying mechanism for prolonged leaky gut barriers in HIV and Simian immunodeficiency virus (SIV) infections despite antiretroviral therapy. Using the intestinal loop model in SIV-infected rhesus macaques, we found rapid repair of gut epithelial barriers within 5 h of administering Lactobacillus plantarum into virally inflamed gut. The rapid recovery was driven by PPARα activation and occurred independent of mucosal CD4+ T cell recovery, highlighting a metabolic repair pathway that can be targeted for epithelial repair prior to complete immune recovery. Our findings provide translational insights into restoring gut mucosal immunity and function, both of which are essential to enable HIV cure efforts.

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4 T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the "leaky gut," which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)-inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4 T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.