Indole-AhR-IL-22 pathway strengthens gut barrier in simian HIV infection 4482

Abstract Description Despite effective antiretroviral therapy (ART), HIV disrupts the intestinal barrier early on, causing mucosal immune dysfunction, microbial translocation, and chronic immune activation. Using the nonhuman primate model of treated HIV infection (SIV-infected rhesus macaques on long-term ART), we monitored the transcriptional phenotype and cytokine functions of colonic epithelial and lamina propria cells using flow cytometry and ELISPOT. Supplementation with dietary indoles was initiated during chronic infection, following the emergence of circulating IEBD biomarkers. The results showed that loss of IL-17/IL-22 production in gut mucosal γδT cells and type-3 innate lymphoid cells (ILC3) was associated with decreased expression of the transcription factors AhR and RORγt, and subsequent elevated levels of plasma iFABP, zonulin, and LBP. Notably, dietary indole supplementation to induce gut AHR signaling enhanced AHR expression in gut epithelial cells and RORγt/IL-17/IL-22 expression in lamina propria cells. Further, it reduced circulating levels of iFABP and zonulin. In summary, these findings suggest that impaired AHR-RORγt-IL22 axis is a key mechanism by which chronic SIV infection contributes to gut barrier disruption despite ongoing ART. These results underscore the potential of AHR ligands as targeted prebiotics to stabilize intestinal epithelial barrier function, offering a novel approach to managing gut dysfunction and related inflammatory diseases in HIV infection. Funding Sources Supported by NIH/NIDDK R01DK131930 Topic Categories Mucosal and Regional Immunology (MUC)