Efavirenz Mitigates Dyslipidemia and Attenuates Ulcerative Colitis through Gut Microbiota Modulation

Antiretroviral therapy (ART) is central to controlling human immunodeficiency virus (HIV) infection, yet it is frequently associated with dyslipidemia, a condition linked to the exacerbation of ulcerative colitis (UC) in people living with HIV (PLWH). The underlying mechanisms of ART-induced dyslipidemia and its contribution to UC progression remain incompletely understood. Here, we demonstrate that efavirenz (EFV), a widely used non-nucleoside reverse transcriptase inhibitor, mitigates ART-induced dyslipidemia and ameliorates UC symptoms. Our in vitro investigations reveal that palmitic acid (PA)-induced inflammation in human normal colorectal mucosal cells (FHCs) is mediated by the activation of the Akt phosphorylation pathway, triggered by the accumulation of 7-dehydrocholesterol (7-DHC), a substrate of 7-dehydrocholesterol reductase (DHCR7). While EFV did not directly modulate this inflammatory cascade in FHCs, in vivo studies using a high-fat diet (HFD)-induced dyslipidemia rat model demonstrated that EFV significantly attenuated elevated lipid levels and improved DHCR7 expression in dextran sulfate sodium (DSS)-induced UC tissues. Notably, fecal microbiota transplantation (FMT) from EFV-treated rats to HFD-fed recipients reduced dyslipidemia and restored DHCR7 expression, thereby suppressing 7-DHC-driven Akt phosphorylation and inflammatory responses in UC tissues. Our findings suggest a mechanism by which EFV mitigates dyslipidemia and UC progression, mediated through the regulation of lipid metabolism and gut microbiota. These findings provide compelling evidence for the potential of EFV to regulate dyslipidemia and associated comorbidities in HIV-infected individuals.