Distinct Gut Microbiota Signatures Are Associated with Severity of Metabolic Dysfunction-Associated Steatotic Liver Disease in People with HIV

The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to severe forms, including metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, involves metabolic dysfunction, genetics, and gut dysbiosis. People with HIV (PWH) represent a high-risk group for MASLD, but the role of gut microbiota alterations in disease severity within this population remains poorly understood. We prospectively recruited PWH with MASLD, defined as the controlled attenuation parameter (CAP) ≥ 238 dB/m, and excluded those with viral hepatitis coinfection or alcohol abuse. Severe MASLD was defined as the presence of MASH (cytokeratin-18 ≥ 130.5 U/L) and/or significant liver fibrosis (liver stiffness ≥ 7.1 kPa). Stool samples were collected for 16S rRNA gene sequencing to characterize gut microbiota composition. Functional predictions were generated using PICRUSt. The differential abundance of bacterial taxa and predicted functions were analyzed using a generalized linear model with a negative binomial distribution. Among 34 PWH with MASLD, 18 (53%) met the criteria for severe MASLD. Microbiota profiling revealed significant differences in bacterial genera between the PWH with and without severe MASLD. Enrichment was observed in the <i>Ruminococcus gnavus</i> group, <i>Negativibacillus</i>, <i>Holdemanella</i>, <i>Subdoligranulum</i>, the <i>Eubacterium hallii</i> group, and <i>Butyricicoccus</i>, while depletion was seen in <i>Prevotella</i>, <i>Alloprevotella</i>, <i>Dialister</i>, <i>Catenibacterium</i>, the <i>Christensenellaceae R 7</i> group, <i>Clostridium sensu stricto</i>, <i>Olsenella</i>, <i>Oscillospiraceae UCG-005</i>, <i>Libanicoccus</i>, and the <i>Eubacterium siraeum</i> group. Predicted functional pathways related to fatty acid degradation, folate biosynthesis, and amino acids metabolism did not differ between groups. MASLD severity in PWH is associated with a distinct gut microbiota signature, though not with functional pathway alterations. Microbial profiling may complement existing non-invasive biomarkers for risk stratification in this high-risk population.