Dietary Indoles Modulate Gut Barrier Integrity via the AhR-IL-22 Axis in ART-Treated SIV Infection

HIV infection rapidly impairs the gastrointestinal (GI) barrier, contributing to persistent mucosal immune dysfunction, microbial translocation, and systemic inflammation despite antiretroviral therapy (ART). Using SIV-infected rhesus macaques on long-term ART, we investigated mechanisms underlying impairment in gut barrier-protective IL-17/IL-22 responses and the potential modulation of this pathway by dietary indoles. Longitudinal profiling of colonic epithelial and lamina propria cells revealed a selective loss of IL-17/IL-22-producing {gamma}{delta} T cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AhR and ROR{gamma}t and was associated with elevated plasma markers of intestinal epithelial barrier disruption (IEBD), including intestinal fatty acid-binding protein (iFABP), zonulin, and LPS-binding protein (LBP). Targeting this transcriptional deficiency, dietary indole supplementation for one month restored colonic AhR IL-22-producing {gamma}{delta} T cells and ROR{gamma}t ILC3s and V{delta}1 T cells, and was associated with reduced iFABP and zonulin levels. Our findings indicate that disruption of the AhR-ROR{gamma}t-IL-17/IL-22 axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of gut AhR signaling may represent a potential approach to reinforce mucosal barrier function and reduce chronic inflammation that persists in people living with HIV.