New research identifies microbiome metabolites linked to both increased and decreased risk of developing coronary heart disease.
Nine specific gut metabolites have been linked to a higher or lower chance of developing coronary heart disease, according to new research.
Depending on the metabolite, higher levels were linked to either increased risk or a protective effect, with risk estimates ranging from roughly a 40% lower to a 70% higher likelihood of developing coronary heart disease (CHD).
The multi-stage metabolomics analysis used the combining data of more than 240,000 participants across several long-running cohort studies in the US and China.
Across the various cohorts, participants were enrolled between 1987 and 2009, with follow-up for CHD outcomes extending through to 2016–2018.
Participants had no history of CHD, stroke, heart failure, cancer or end-stage renal disease at baseline, and no use of antibiotics or cold and flu medication in the seven days prior to blood collection as these may have influenced gut microbiota. Mean age was between 54 and 63 years, depending on the cohort, and at least half of were women.
Researchers first compared people who developed CHD with matched participants who didn’t, analysing hundreds of metabolites in their blood. The compounds they linked to disease risk were then tested and validated in additional independent cohorts using different analytical methods to confirm the results.
In the initial discovery stage, researchers identified 48 gut microbiome–related metabolites that were significantly associated with coronary heart disease. Most of these remained significant even after adjusting for factors such as age, lifestyle, BMI and existing metabolic conditions.
Further analysis expanded this signal, with a total of 73 metabolites showing associations with heart disease risk across all participants or within specific subgroups. These compounds spanned multiple biological pathways, including amino acids, lipids, nucleotides, carbohydrates, energy metabolism and xenobiotics.
Of these, 61 metabolites were confirmed in independent validation analyses. The strongest and most consistent signals came from amino acid–related pathways, particularly metabolites derived from histidine, glutamate, phenylalanine, tyrosine, tryptophan, and other key metabolic processes.
A more targeted follow-up assay then measured concentrations of the most promising compounds. This included eight metabolites that had passed earlier validation stages, alongside additional compounds already implicated in cardiovascular research. In this final stage, nine metabolites remained significantly associated with CHD after adjusting for demographic and lifestyle factors.
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Several metabolites were associated with a higher risk of coronary heart disease, including 3-hydroxybutyrate (OR 1.27), imidazole-propionate (OR 1.26), TMAO (OR 1.22), 4-hydroxyphenylacetate (OR 1.19), and trans-4-hydroxyproline (OR 1.18). In contrast, indolepropionate was associated with a lower risk of disease (OR 0.89), suggesting a potential protective effect.
Importantly, some of these associations weakened after further adjustment for conditions such as diabetes, hypertension, and dyslipidaemia, suggesting that at least part of the effect of certain metabolites on heart disease risk may be indirect, acting through these underlying metabolic disorders.
The researchers also found that associations varied across population groups. Some metabolites showed stronger links to disease in Black participants compared with White or Asian participants, while others were specific to certain demographic groups or were more strongly associated with cases diagnosed shortly after baseline. However, most associations were consistent across sex, lifestyle factors and baseline metabolic health.
“This is one of the most comprehensive metabolomics studies to date, encompassing discovery, in silico validation, and quantitative validation across individuals from diverse ethnic backgrounds and geographic regions,” the authors wrote.
“Our findings underscore the importance of gut microbial metabolism in cardiovascular disease development and highlight promising molecules that may serve as novel biomarkers or therapeutic targets for future mechanistic and interventional studies.”
