A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases.

Cardiometabolic diseases (CMD) are on the rise globally with one billion people expected to suffer from obesity and 643 million from type 2 diabetes by 2030, of which one-third will likely develop chronic kidney disease and two-thirds will die from cardiovascular disease (CVD). However, the mechanistic and molecular drivers of the transition from health to disease remain elusive. Here, in 275 metabolically healthy individuals recruited to the MetaCardis study, we identify a gut microbiome-kidney-heart axis that is predictive of future cardiovascular events. This axis, as evidenced by the associations between gut microbial metabolism of phenylalanine and tyrosine with variations in both kidney functon(as measured by estimated glomerular filtration rate) and circulating pro-atrial natriuretic peptide concentration, shows a depletion pattern in metabolically unhealthy participants of the MetaCardis study (n = 1,602) indicating a loss of health-sustaining microbiome features with CMD progression. We then validate that microbial compounds from the phenylalanine and tyrosine pathways and their host co-metabolites act as mediators of the gut microbiome-kidney associations. Moreover, Mendelian Randomization analysis adds genetic evidence to suggest that the microbial mediator metabolites regulate host kidney function and vice versa. Finally, we demonstrate that plasma metabolites derived from the microbial metabolism of phenylalanine and tyrosine associate with incident CVD in the Canadian Longitudinal Study on Aging (n = 8,669). Collectively, our results depict the presence of a gut microbiome-kidney-heart axis in metabolically healthy individuals. Major aberrations of the gut microbiome as part of this axis throughout life may increase risk of CVD.