Abstract Background Hyperhomocysteinemia is associated with increased cardiovascular and cerebrovascular risk and has been identified as one of the factors indicating poor prognosis in patients with acute coronary syndrome (ACS). Numerous studies have demonstrated the significant influence of gut microbiota on host metabolism. However, the relationship between gut microbiota and blood homocysteine (Hcy) levels remains poorly understand. Purpose This study aimed to investigate the correlation between gut microbiota composition, fecal metabolites, and blood Hcy levels in ACS patients. Methods Fecal samples of 37 hospitalized patients diagnosed with ACS were collected for 16S rRNA sequencing and non-targeted metabolomics analysis. Among them, 19 patients underwent blood Hcy testing during the same hospitalization. Spearman correlation analysis was used to assess relationships between gut microbiota, fecal metabolites, and blood Hcy levels. Group comparisons were made based on Hcy levels using non-parametric Mann-Whitney test. Results At the family level, among the primary constituent bacteria of the fecal microbiome, the relative abundance of intestinal Bifidobacteriaceae was found to be significantly negatively correlated with blood Hcy levels (Spearman r = -0.67, P = 0.002) (Figure 1B). This correlation was further confirmed at the genus level (Bifidobacterium; Spearman r = -0.67, P = 0.002). At the species level, the relative abundance of Bifidobacterium longum showed the most significant correlation with blood Hcy levels (Spearman r = -0.60, P = 0.008). When blood Hcy level was used as a grouping variable (cut-off: 13 mmol/L), a significant difference in the intensity of intestinal Bifidobacteriaceae was observed between the high Hcy and low Hcy groups (P 0.01) (Figure 1C). A total of 1,037 metabolites were detected in the fecal metabolomics analysis. Among them, inosine and some other metabolites were found to have significant association with the intensity of gut Bifidobacteriaceae (Figure 1D). We further tested the relationship between stool metabolites and serum Hcy levels and found that fecal metabolites including inosine positively correlated with serum Hcy levels (Figure 1E). Conclusions This preliminary multi-omics investigation demonstrates a significant inverse correlation between the abundance of gut Bifidobacteriaceae and blood Hcy levels in patients with ACS. Notably, some fecal metabolites, including inosine, were identified to exhibit significant associations with both intestinal Bifidobacteriaceae and circulating Hcy levels. Given that Bifidobacteriaceae have long been recognized as probiotic bacteria and inosine is increasingly acknowledged as a metabolic modulator, our findings suggest the existence of a potential microbiota-metabolite-Hcy axis. Further research involving larger cohorts and mechanistic studies is warranted.
Zhou et al. (2025) studied this question.