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

Low serum sRAGE levels were prospectively associated with greater odds of new-onset or persistent MASLD.

• Among 289 subjects, 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).
• Mean follow-up was 6.67 ± 0.73 years; mean age was 58.54 ± 6.54 years; 57.8% were men.
• MASLD was evaluated by ultrasonography or controlled attenuation parameter at two time points.
• A dose-response association was observed across sRAGE tertiles.

Significant alpha- and beta-diversity differences in gut microbiota were found between MASLD and non-MASLD groups.

• Cross-sectional analysis was performed on a subsample of 136 subjects with gut microbiota measurements.
• Gut microbiota was assessed using 16S rRNA sequencing (V3–V4 region, Illumina MiSeq).
• Both alpha-diversity and beta-diversity differed significantly between MASLD and non-MASLD groups.
• Beta-diversity variation across sRAGE groups resembled that observed between the MASLD groups.

Low sRAGE levels and MASLD shared enrichment in specific gut microbial taxa.

• Shared taxa linked to both low sRAGE levels and MASLD included Streptococcaceae, Enterobacteriaceae, Streptococcus, Dorea, and Klebsiella.
• These taxa were identified in the cross-sectional subsample of 136 subjects.
• The overlap in microbial signatures between low sRAGE and MASLD groups suggests a potential shared biological pathway.

Non-MASLD status and high sRAGE levels were associated with enrichment in potentially protective gut microbial taxa.

• Christensenellaceae, Akkermansiaceae, Christensenellaceae R-7 group, and Akkermansia were associated with both non-MASLD and high sRAGE levels.
• These taxa are generally considered health-associated or potentially protective in the metabolic disease literature.
• Findings were from the cross-sectional subsample of 136 subjects using 16S rRNA sequencing.

The study design combined a prospective cohort analysis with a cross-sectional gut microbiota sub-analysis.

• The prospective component included 289 subjects assessed at two time points for sRAGE and MASLD.
• The cross-sectional gut microbiota analysis was performed on a subsample of 136 subjects.
• Gut microbiota was measured using 16S rRNA sequencing targeting the V3–V4 region on Illumina MiSeq.
• MASLD was assessed by ultrasonography or controlled attenuation parameter.