Gut microbiome and metabolite signatures in critical limb threatening ischemia

Summary: Background: Atherosclerotic disease entails with distinct clinical phenotypes, of which chronic coronary syndrome (CCS) and critical limb-threatening ischemia (CLTI) are key manifestations. While plaque morphology and clinical course differ in vascular territory, the underlying pathophysiology leading to distinct diseases remain unexplored. The gut-microbiome axis with derived mediators trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) has emerged as proatherogenic or protective in vascular diseases, however the differential abundance, composition and metabolites have not been investigated in CCS or CLTI. Patients and methods: In this cross-sectional clinical trial, we included patients with CCS and CLTI within 24 h of clinical presentation. Analyses of the gut microbiome and downstream metabolites were assessed. Microbiome-derived metabolites were analyzed from peripheral blood samples. Gut microbiome samples were characterized by 16S rRNA gene analysis. Results: We enrolled 40 patients with 20 patients each presenting with CCS and CLTI, respectively. While alpha and beta diversity were similar, CCS patients exhibited distinct microbial signatures, including higher abundance of Dialister, Monoglobus, Lachnospira, Barnesiella, Fusicatenibacter, Collinsella, and Roseburia. Subsequent analysis of microbiome-derived metabolites revealed significantly lower serum concentrations of isovaleric acid and a non-significant trend toward TMAO elevation in the CLTI group compared to the CCS group. Conclusions: In this pilot trial we demonstrate that distinct differences in gut bacteria and microbiome-derived metabolites exist between patients with CCS and CLTI. These findings may highlight microbiome-metabolite interactions in chronic atherosclerotic disease and support larger studies to elucidate causal mechanisms.