Gut microbial tyramine facilitates intestinal damage and metabolic dysfunction-associated steatotic liver disease development.

BACKGROUND: Emerging evidence indicates that gut microbiota and intestinal injury are crucial in pediatric metabolic dysfunction-associated steatotic liver disease (MASLD), yet the role of key gut microbial metabolites such as tyramine in pediatric MASLD remains largely unknown. In this study, we aimed to explore the role of gut microbial tyramine in intestinal damage and MASLD development in children. METHODS: We investigated the functions and mechanisms of previously isolated Enterococcus faecium B6 (E. faecium B6) and its derived tyramine in a mice model of intestinal injury and MASLD development. An integrative analysis of transcriptomics and proteomics was performed on mouse liver to explore the molecular mechanisms of tyramine in MASLD progression. Targeted metabolomics was performed using fecal samples from a hospital-based population (27 MASLD cases and 27 matched controls) to measure tyramine levels. The association of serum tyramine and MASLD risk was then validated in a school-based population, using serum samples of 294 children in the MASLD group and 235 controls. RESULTS: E. faecium B6 and its metabolite tyramine significantly disrupted the intestinal barrier and increased intestinal permeability in mice. Tyramine supplementation promoted MASLD-related metabolic phenotype in mice. Multi-omics analysis indicated that the PPAR signaling pathway played an important role in the molecular mechanisms. Tyramine contributed to lipid accumulation mainly by increasing lipid synthesis and lipid uptake but reducing the β-oxidation processes in the mouse liver, as shown by real-time quantitative polymerase chain reaction and western blot. Furthermore, we demonstrated from the hospital-based cohort that tyramine concentration was significantly higher in the MASLD group than in the control group. Consistently, the school-based cohort demonstrated a higher risk of MASLD in the high-tyramine group compared to the low-tyramine group, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of 3.65 (95% CI: 2.66-4.32). CONCLUSIONS: These results demonstrated that gut microbial tyramine effectively induced intestinal damage and facilitated MASLD development in mice. Tyramine was positively associated with the risk of MASLD in children. This study offered mechanistic insights into the pathogenesis of MASLD and opened therapeutic opportunities for such metabolic diseases.