A potential gut microbiome–kidney–heart axis linked to early cardiorenal dysfunction and future cardiovascular disease (CVD) risk has been identified through multiomics analysis, highlighting the impact of gut microbiome changes on cardiac health and opportunities for earlier risk stratification and precision prevention.

The external longitudinal cohort study, led by investigators from Imperial College London, aimed to determine whether gut microbiome-related metabolic changes could be detected before the onset of overt cardiometabolic disease. The results were published in the journal Nature Communications.

Using plasma and faecal samples from the MetaCardis cohort, the researchers combined plasma metabolomics with quantitative gut microbiome profiling to examine associations among microbial metabolites, kidney function and cardiac biomarkers.

The analysis included 275 metabolically healthy adults aged 20–76 years (62% female), recruited from France, Germany and Denmark. Participants had a body mass index ≤25 kg/m² and no metabolic syndrome, type 2 diabetes or ischaemic heart disease.

These findings were compared with 1,602 individuals with cardiometabolic disease, including obesity, metabolic syndrome, type 2 diabetes and ischaemic heart disease. External validation was undertaken in 8,669 participants from the Canadian Longitudinal Study on Aging (CLSA).

Gut microbial metabolites and CVD

The investigators focused on associations between gut microbial metabolites and the estimated glomerular filtration rate (eGFR), as well as circulating pro-atrial natriuretic peptide (proANP) – a marker of cardiac stress and haemodynamic regulation.

Microbial pathways involved in phenylalanine and tyrosine metabolism were strongly associated with kidney and cardiac function. Several microbiome-derived metabolites, including vanillactate, phenylacetylglutamine and 3-(4-hydroxyphenyl)lactate, were associated with lower eGFR and higher circulating proANP levels.

The study also identified several microbial features associated with more favourable kidney and cardiovascular physiology among metabolically healthy individuals.

Higher levels of short-chain fatty acid-producing bacteria, including Faecalibacterium prausnitzii, Roseburia faecis and Roseburia inulinivorans, were associated with lower circulating levels of potentially harmful microbial metabolites.

These included phenylacetylglutamine, phenylacetylcarnitine, 4-cresyl sulphate and 4-cresyl glucuronide, which were associated with a higher incidence of myocardial infarction over three years of follow-up in the CLSA cohort.

The beneficial microbial signals were strongest in metabolically healthy individuals. As participants became overweight or developed early metabolic dysfunction, many of these apparently protective patterns weakened or disappeared.

‘Precision medicine in action’

Commenting on the findings, first author Dr Kanta Chechi, research fellow at Imperial, said: ‘The most thrilling aspect of this work is that we find these microbiome-related signatures in a clinically healthy population.

‘This suggests disturbances in our gut microbiome may initiate metabolic and heart disease. Detecting these signatures early means we could target gut microbes to prevent disease in at-risk individuals.’

However, the healthy cohort was relatively modest in size, and metabolomic signatures may have been influenced by diet, medication use and other lifestyle factors despite extensive confounder adjustment, the authors noted. The cohort was primarily of European ancestry, so evaluation in more diverse populations is also needed.

Additional mechanistic and interventional studies will determine whether modifying microbiome-derived metabolites can alter CVD outcomes, the authors said.

Nevertheless, the findings add to growing evidence linking gut microbial metabolism with cardiovascular and renal physiology, that support the concept of a gut microbiome–kidney–heart axis.

Senior author, Professor Marc-Emmanuel Dumas, chair in systems medicine at Imperial, added: ‘We’ve uncovered the hidden biological hotline connecting the gut microbiome, kidneys and heart, which can flag cardiovascular risk years before disease strikes.

‘Gut microbes and their metabolites are like an early warning system, and we’ve finally learned to listen.

‘This is precision medicine in action and could transform cardiovascular disease prevention.’

Reference
Chechi K et al. A gut microbiome-kidney-heart axis predictive of future cardiovascular diseases. Nat Commun 2026;17:3477.