Cardiovascular diseases (CVD) remain a major global health challenge. Early markers of disease initiation and progression are urgently needed. We, and others, have previously shown changes in the gut microbiome in association with metabolic and CVD. Here, we demonstrate that gut microbiome-related changes can be detected in association with subclinical variations in heart and kidney function. Markers related to gut microbial metabolism of aromatic amino acids, phenylalanine and tyrosine, associate with circulating pro-atrial natriuretic peptide and estimated glomerular filtration rate in a metabolically healthy European population. Observational and genetic evidence further identify microbiome-related metabolites as mediators of this gut microbiome-kidney axis, with their baseline levels associating with incident CVD in an external Canadian population. Altogether, our work suggests that the gut microbiome interacts with the cardiorenal axis and participates in an interorgan crosstalk affecting host physiology and risk of CVD.

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.