A new study led by investigators at the Kwon Lab and collaborators shows how energy use by gut immune cells can weaken the intestinal lining in people living with HIV, even when the virus is controlled by treatment. The work identifies a metabolic switch inside these cells as a promising target to help protect the gut and reduce inflammation.

Published in Cell today, the study focuses on CD8+ T cells that reside in the colon. Researchers compared these colon resident CD8+ T cells from people with HIV on antiretroviral therapy with those from people without HIV, then used patient derived colon organoids (3D mini gut)  and genetically engineered CD8+ T cells in mouse models to test cause and effect. They found that in people with HIV, these colon-resident CD8+ T cells dial down a key regulator called PPARγ—an internal “fuel switch” that helps cells store and burn fat—pushing the cells to pull fats from neighboring epithelial cells. This “fat scavenging” deprives the lining of resources, triggers epithelial cell death, and compromises barrier integrity.

When the team reactivated this metabolic switch with PPARγ agonists in lab models, T cells regained healthier fuel handling, epithelial damage fell, and barrier function improved. In mice engineered to switch off this pathway only in CD8+ T cells, gut injury became even more severe—showing that T-cell metabolism directly shapes epithelial health and that this effect is not confined to HIV infection.

These findings reframe a long-standing problem in HIV—from an epithelial-only issue to one driven in part by immune cell metabolism—and point to a treatable pathway already familiar in other diseases. If confirmed in clinical studies, therapies that restore this fuel program in gut T cells could help reduce microbial leakage and chronic inflammation, lowering the risk of inflammatory non-AIDS conditions in people living with HIV.