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

Area of Science:

• Immunology
• Gastroenterology
• Virology

Background:

• HIV infection severely compromises the gastrointestinal (GI) barrier, leading to immune dysfunction and systemic inflammation even with antiretroviral therapy (ART).
• Impaired gut barrier function is linked to microbial translocation and chronic inflammation in HIV/SIV infection.
• The role of IL-17/IL-22 producing cells and their regulatory pathways in gut barrier integrity during chronic infection is not fully understood.

Purpose of the Study:

• To investigate the mechanisms of impaired gut barrier-protective IL-17/IL-22 responses in SIV-infected macaques on ART.
• To explore the potential of dietary indoles to modulate the AhR-RORγt-IL-17/IL-22 pathway and restore gut barrier function.

Main Methods:

• Longitudinal profiling of colonic epithelial and lamina propria cells in SIV-infected rhesus macaques on long-term ART.
• Analysis of immune cell populations, including IL-17/IL-22-producing γδ T cells and ILC3s.
• Measurement of transcription factors (AhR, RORγt) and plasma markers of intestinal epithelial barrier disruption (iFABP, zonulin, LBP).
• Intervention with dietary indole supplementation and assessment of its effects on immune cells and barrier markers.

Main Results:

• A selective loss of IL-17/IL-22-producing γδ T cells and ILC3s was observed, correlating with reduced AhR and RORγt expression.
• Elevated plasma markers of intestinal epithelial barrier disruption (IEBD) were associated with this immune cell loss.
• Dietary indole supplementation restored colonic AhR⁺ IL-22-producing γδ T cells and RORγt⁺ ILC3s.
• Indole treatment was associated with reduced levels of iFABP and zonulin, indicating improved barrier function.

Conclusions:

• Disruption of the AhR-RORγt-IL-17/IL-22 axis is a critical mechanism underlying persistent intestinal epithelial barrier disruption in chronic SIV/HIV infection.
• Dietary indole supplementation can restore key immune cells and improve gut barrier function.
• Modulating gut AhR signaling presents a potential therapeutic strategy to reinforce mucosal barrier function and reduce chronic inflammation in people living with HIV.