Dietary indoles influence the AHR-RORγt axis and mucosal immune homeostasis in ART-treated SIV infection

Authors

• Siva Thirugnanam, Tulane National Biomedical Research Center, Covington, LA
• Alison R. Van Zandt, Tulane National Biomedical Research Center, Covington, LA
• Alexandra B. McNally, Tulane National Biomedical Research Center, Covington, LA
• Victoria A. Hart, Tulane National Biomedical Research Center, Covington, LA
• Isabelle Berthelot, Tulane National Biomedical Research Center, Covington, LA
• Cecily C. Midkiff, Tulane National Biomedical Research Center, Covington, LA
• Lara A. Doyle-Meyers, Tulane National Biomedical Research Center, Covington, LA
• David A. Welsh, LSU Health Sciences Center - New OrleansFollow
• Robert V. Blair, Tulane National Biomedical Research Center, Covington, LA
• Andrew G. MacLean, Tulane National Biomedical Research Center, Covington, LA
• Namita Rout, Tulane National Biomedical Research Center, Covington, LA

Document Type

Article

Publication Date

4-2-2026

Publication Title

JCI Insight

Abstract

HIV infection rapidly impairs the gastrointestinal 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 1 month restored colonic AHR+ IL-22-producing γδ T cells, RORγt+ ILC3s, and Vδ1 T cells, and was associated with reduced iFABP and zonulin levels. Immunohistochemical analyses further demonstrated enrichment of AHR/RORγt-coexpressing cells in the colon of indole-supplemented animals during chronic SIV infection on ART. Collectively, these findings indicate that disruption of the AHR-RORγt axis is a key pathogenic mechanism underlying persistent IEBD in chronic SIV/HIV infection. Modulation of AHR and RORγt signaling pathways in the gut may therefore represent a promising therapeutic strategy to reinforce mucosal barrier function and mitigate chronic inflammation in people living with HIV.

PubMed ID

41926722

Volume

11

Issue

10

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Thirugnanam, Siva; Van Zandt, Alison R.; McNally, Alexandra B.; Hart, Victoria A.; Berthelot, Isabelle; Midkiff, Cecily C.; Doyle-Meyers, Lara A.; Welsh, David A.; Blair, Robert V.; MacLean, Andrew G.; and Rout, Namita, "Dietary indoles influence the AHR-RORγt axis and mucosal immune homeostasis in ART-treated SIV infection" (2026). School of Graduate Studies Faculty Publications. 591.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/591
10.1172/jci.insight.201258