Compromised Intestinal Barrier Resilience to Disruption in People with HIV [colon]

People living with HIV (PLWH) experience chronic intestinal barrier dysfunction (gut leakage), which persists despite viral suppression by antiretroviral therapy (ART) and contributes to chronic inflammation and its comorbidities. The mechanisms underlying this phenomenon remain unclear and are likely multifactorial. We hypothesize that living with HIV compromises the intestinal barrier’s resilience to injurious agents, increasing susceptibility to leakage upon exposure to common exogenous or endogenous disruptors, such as alcohol or pro-inflammatory cytokines, respectively. Using 3D intestinal organoids (colonoids and enteroids) derived from PLWH on ART and HIV-negative controls, we assessed the impact of alcohol and inflammatory cytokines on barrier integrity. Organoids from PLWH exhibited reduced resilience to disruption compared to controls, correlating with alterations in pathways critical to epithelial integrity, including epithelial-mesenchymal transition, DNA repair, and oxidative stress-related pathways. These findings reveal a novel mechanism underlying intestinal dysfunction in PLWH and highlight potential molecular targets to mitigate these complications.