DB06 Gut Microbiota Alterations and Microbiota-Derived Indole-3-Carboxaldehyde Are Associated with MASLD

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>MASLD is associated with alterations in gut microbiota composition and function; however, the contribution of microbiota-derived metabolites to disease pathogenesis remains incompletely understood.</jats:p> </jats:sec> <jats:sec> <jats:title>Purpose</jats:title> <jats:p>This study aimed to characterize gut microbiota composition, microbiota-derived metabolites and their interrelationships in overweight and obese individuals with and without MASLD.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We included 120 overweight/obese participants: 71 with ultrasound-confirmed MASLD and 49 non-MASLD controls. Fecal microbiota composition was assessed by 16S rRNA gene sequencing, while plasma short-chain fatty acids, TCA-cycle intermediates, and tryptophan-derived metabolites were quantified using targeted UHPLC-qTOF-MS metabolomics. Statistical analyses were adjusted for age, sex, BMI and diabetes status.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>MASLD was associated with reduced gut microbial diversity, including lower observed richness, Shannon diversity and Faith’s phylogenetic diversity. Beta diversity analysis showed significant differences in microbial community composition, mainly driven by community membership. Differential abundance analysis identified several taxa enriched in non-MASLD participants, including Methanobrevibacter, Paraprevotella, Desulfovibrio, Peptococcus and Candidatus Soleaferrea, while functional prediction suggested enrichment of archaeal and methanogenesis-related pathways in non-MASLD individuals. Regarding microbiota-derived metabolites, indole-3-carboxaldehyde (I3A), a microbial tryptophan-related metabolite, was enriched in non-MASLD participants and independently associated with lower odds of MASLD (OR = 0.56, 95% CI 0.35–0.85, p = 0.010). Microbiome–metabolome integration revealed a positive association between Peptococcus abundance and circulating I3A levels.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These findings suggest that MASLD is associated with specific alterations in gut microbiota composition and microbial metabolism, and identify I3A as a potentially protective metabolite of interest for future mechanistic studies.</jats:p> </jats:sec>