Exploring gut microbiota mechanisms in frailty induced by 5-hydroxymethylfurfural: evidence from mouse models and Mendelian randomization

Frailty in older adults has been linked to gut microbiota, but the underlying mechanisms remain unclear. This study investigates the relationship between gut microbiota and frailty, focusing on the potential mediating roles of serum metabolites, immune cells, and inflammatory proteins. We used a combination of mouse model experiments and Mendelian randomization (MR) analysis to examine how gut microbiota contributes to frailty development. In a mouse model of chronic inflammation-induced frailty, a standardized frailty index was used for assessment. High-throughput 16 S rRNA sequencing revealed significant gut microbiota dysbiosis in frail mice, with a notable elevation in Ruminococcus abundance. Spearman correlation analysis showed a strong positive association between Ruminococcus, frailty scores (⍴ = 0.716, P < 0.001), and inflammatory markers. Metabolomic profiling further identified key metabolites linked to frailty, including S-Methyl-5’-thioadenosine, L-anserine, and indolelactic acid (IAA), with IAA showing a significant correlation with Ruminococcus (P < 0.001). To validate these findings, MR analysis was performed using data from the European Bioinformatics Institute and the MiBioGen consortium. The analysis confirmed a causal relationship between Ruminococcus and frailty (OR = 1.035, 95% CI: 1.011–1.059, P = 0.004). Additionally, HLA-DR expression on CD14 + monocytes was identified as a partial mediator of the effect of Ruminococcus obeum on frailty. Importance. • Chronic-inflammation model establishes frailty in mice, quantified via a validated frailty index. • Gut dysbiosis characteristic of frailty, notably a elevation in Ruminococcus. • Strong link between Ruminococcus and frailty/inflammation, with Spearman’s ⍴ = 0.716. • Serum metabolites (S-MTA, L-anserine, IAA) correlate with frailty—IAA particularly tracks with Ruminococcus levels. • Mendelian randomization confirms causality: genetically higher Ruminococcus increases frailty risk. • CD14⁺ monocyte HLA-DR expression partially mediates the effect of Ruminococcus obeum on frailty.