Rural–urban environmental differences shape gut microbiome and metabolome signatures linked to cardiovascular disease risk in sub-Saharan Africa

Background Environmental transitions such as rural-to-urban migration have been linked to rising cardiovascular disease (CVD) burden in sub-Saharan Africa, yet the underlying biological mechanisms remain poorly understood. We have recently reported that individuals living in a rural setting had lower blood pressure compared to those living in an urban setting. Emerging evidence implicates the gut microbiome in cardiometabolic risk regulation, but few studies have explored its role in African populations across proximate but contrasting environments. Methods We profiled the gut microbiome (16s rRNA sequencing) and faecal metabolome (untargeted Liquid Chromatography Mass Spectrometry) of 216 individuals living in rural and urban Uganda. We assessed diversity metrics, differential abundance, metabolome and microbial associations with CVD risk factors. Mediation models were used to test whether gut microbiota mediated environmental effects on CVD risk. We integrated multi-omics data to identify microbiome–metabolome–CVD networks. Results Rural individuals had significantly higher gut microbial alpha diversity and distinct beta diversity compared to urban residents (Shannon index p = 9.17 × 10⁻¹²; principal coordinates analysis of Bray–Curtis dissimilarity with PERMANOVA p < 0.001). A total of 250 out of 1008 microbial taxa differed in abundance between settings, including Succinivibrio and Desulfovibrio (urban-enriched) and Agathobacter and Faecalibacterium (rural-enriched). Several taxa, such as Succinivibrio and Erysipelatoclostridiaceae, mediated the association between urban living and elevated blood pressure. Metabolomic profiling revealed distinct setting-specific signatures: prenol lipids, fatty acyls, and carboxylic acids were predominant among differentially abundant metabolites. Partial least square discriminant analysis showed clear separation of metabolome profiles of individuals living in rural setting from those living in urban setting. Pathway enrichment analysis highlighted vitamin K metabolism as major biological pathway enriched by the differentially abundant metabolites. Integrated microbiome–metabolome analyses revealed co-regulated modules linked to blood pressure, and tripartite networks uncovered microbe–metabolite–CVD paths, including rural-enriched Jeotgalibaca negatively correlated with blood pressure–associated metabolites. Conclusions Our findings highlight distinct gut microbial and metabolic signatures linked to cardiovascular disease risk that differ in rural and urban African environments. These results underscore the importance of environmental context in microbiome–host interactions and support the inclusion of microbiome profiling in strategies to predict and reduce CVD risk in transitioning populations. Moreover, understanding the drivers of these urban–rural differences in microbiota may enable the identification and intentional harnessing of protective features of rural living for the benefit of urban population.