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

Abstract 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 γδ T cells and type 3 innate lymphoid cells (ILC3s). This loss correlated with reduced expression of the transcription factors AhR and RORγt 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 γδ T cells and RORγt⁺ ILC3s and Vδ1 T cells, and was associated with reduced iFABP and zonulin levels. Our findings indicate that disruption of the AhR–RORγt–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. Competing Interest Statement The authors have declared no competing interest.