Low Serum sRAGE and MASLD Are Associated and Share a Similar Gut Microbiota Profile: A Prospective and Cross-Sectional Analysis

Background/Aims: The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is multifactorial, with evidence suggesting a protective role for the soluble receptor for advanced glycation end-products (sRAGE). While gut microbiota dysbiosis and MASLD have been linked, evidence of their association with sRAGE remains limited. We aimed to test the prospective association between serum sRAGE levels and MASLD and to explore associated patterns of gut microbiota composition. Methods: A prospective cohort study assessed serum sRAGE levels and MASLD at two time points, with new-onset or persistence of MASLD evaluated by ultrasonography or controlled attenuation parameter. A cross-sectional analysis was performed on a sub-sample with gut microbiota measurements using 16S rRNA sequencing (V3-V4, Illumina MiSeq). Results: Among 289 subjects in the prospective analysis (mean follow-up: 6.67 ± 0.73 years, mean age: 58.54 ± 6.54 years, 57.8% men), low sRAGE levels were associated with 2.22-fold greater odds of new-onset/persistent MASLD (95% CI 1.15–4.26, p = 0.017), with a dose–response association across sRAGE tertiles. The cross-sectional analysis with a subsample of 136 subjects showed significant α- and β-diversity differences between MASLD and non-MASLD groups. Moreover, β-diversity variation across sRAGE groups resembled that observed between the MASLD groups. Shared taxa linked to low sRAGE levels and MASLD included Streptococcaceae, Enterobacteriaceae, Streptococcus, Dorea, and Klebsiella. Non-MASLD and high sRAGE levels were associated with Christensenellaceae, Akkermansiaceae, Christensenellaceae R-7 group and Akkermansia. Conclusions: Low sRAGE levels are associated with higher odds of MASLD. MASLD and low sRAGE levels share a similar gut microbiota signature, suggesting a potential biological link that warrants further investigation.