Background
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent comorbidity in people with HIV (PWH). Gut microbiota profiles such as lower diversity and/or alterations in microbiota community structure, have been variably associated with MASLD in people with and without HIV. Recent murine models of metabolic diseases, including MASLD, demonstrated beneficial effects of semaglutide on gut microbiota profiles and improved disease outcomes, though the effects on human gut microbiota are unknown. We previously demonstrated that semaglutide was highly effective in improving MASLD for PWH. Here we investigated the effects of semaglutide on the gut microbiome within that cohort.
Methods
SLIM LIVER, a single-arm, pilot study enrolled PWH ≥18 years old on suppressive antiretroviral therapy (ART) with MASLD. Participants received semaglutide 1 mg/week subcutaneously for 24 weeks. 16S rRNA and shotgun metagenomic sequencing was performed on stool collected at Weeks (W) 0 and 24. The treatment effects on microbiota were analyzed using generalized linear mixed modeling accounting for age, race/ethnicity, and gender identity (other demographic/clinical variables were not associated with microbiota at W0).
Results
51 people were enrolled; paired W0 and 24 stool samples were available from 42 participants (mean age 49 years, [SD 11]; BMI 35.4 [5.9] kg/m2; 35% cis and 7% trans female; 31% Black; 38% Hispanic/Latino; 79% on INSTI-based ART). Overall microbiota composition (β-diversity; GLMM-MiRKAT) differed between W0 and 24 at genus (P=0.002) and species levels (P=0.011). α-diversity increased (Shannon H, P=0.0075) over 24 weeks. Relative abundances of bacterial genera Clostridium and Enterococcus increased significantly (FDR<0.05). Anaerostipes, Ruminococcus-torques-group, and Lachnoclostridium significantly decreased. Metagenomic analysis identified an increase in Methanobrevibacter sp. (domain Archaea) over time (nominal p<0.05).
Conclusions
We provide first-in-human evidence that use of semaglutide alters gut microbiota profiles in PWH with MASLD. Potentially beneficial effects included increasing diversity and abundance of genera (e.g. Methanobrevibacter) where low abundance was associated with MASLD pathogenesis in people without HIV. However, we observed decreases in some bacteria (e.g. Lachnoclostridium) where low abundance was previously associated with MASLD in other populations. Thus, semaglutide treatment in PWH with MASLD had a range of impact on microbiota abundance.
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