GUEST AUTHOR: Ragon core member Douglas Kwon, MD, PhD, (left) and Broad Institute core member Ramnik Xavier, MD, (right) collaborated on the paper published in Nature Microbiology.

A large international study, published in Nature Microbiology and led by the Kwon Lab at the Ragon Institute and the Xavier Lab at the Broad Institute, shows that HIV infection and common antiretroviral drugs change the gut microbiome in distinct, geography-dependent ways. These changes notably may help explain ongoing inflammation and heart-disease risk in people living with HIV. The team analyzed whole-metagenome data from 327 people with HIV and 260 controls in Uganda, Botswana, and the United States.

The researchers found that gut bacteria vary by geography in people with HIV, but what the microbiome is doing (its functions and pathways) shifts in similar ways across all three regions. These functional changes are additionally worse in people with very low immune cell counts. This suggests a common pattern of microbiome disruption tied to HIV-related immune damage, beyond local diets or lifestyles.

The study also highlights the role of HIV treatment itself. In Uganda and Botswana, people taking the antiretroviral efavirenz had lower levels of fiber-consuming Prevotella species and signs of a disrupted network of bacteria that normally cooperate to break down plant fibers—paired with higher markers of inflammation and thicker carotid artery walls, a sign linked to atherosclerosis. These efavirenz-linked patterns were not seen in the U.S. cohort, underscoring that drug effects can differ by regional microbiomes.

Considering how this may occur, the team proposes a microbiological factor. Efavirenz may cross-inhibit bacterial reverse transcriptases that some gut bacteria use as part of their defenses against phages (bacterial viruses). Computational and lab tests support this mechanism and connect it to the observed drop in Prevotella in certain regions.

By linking HIV, specific drugs, and geography to shared microbiome functions—and to clinical signals like inflammation and atherosclerosis—this work points to microbiome-aware, region-sensitive care. The findings suggest that treatment choices, and future microbiome-guided strategies, may need to consider local gut ecosystems to reduce long-term health risks.