Sex-Dependent Gut Microbiota Features and Functional Signatures in Metabolic Disfunction-Associated Steatotic Liver Disease

Abstract

Background/Objectives: This study investigates the gut microbiota’s role in metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on microbial and functional signatures and sex-based differences. Methods: Using baseline data from 98 MASLD patients and 45 controls from the Fatty Liver in Obesity (FLiO) study, the gut microbiota was profiled with 16S gene sequencing, followed by statistical and machine learning analyses to identify disease-associated microbial signatures. Results: Notable alpha and beta diversity differences were observed between MASLD patients and the controls, varying by sex. Machine learning models highlighted specific microbial signatures for each sex, achieving high accuracy (area under the receiver operating characteristic curves of 0.91 for women and 0.72 for men). The key microbial taxa linked to MASLD included Christensenella and Limosilactobacillus in women and Beduinibacterium and Anaerotruncus in men. Functional profiling showed that MASLD patients had increased pathways for amine biosynthesis and amino acid degradation, while the controls exhibited enhanced fermentation pathways. These microbial features were associated with systemic inflammation, insulin resistance, and metabolite production linked to gut dysbiosis. Conclusions: The findings support the potential of gut microbiota signatures to be used as non-invasive indicators of MASLD and highlight sex-specific variations that could inform personalized diagnostic and therapeutic approaches.