Circulating imidazole propionate and coronary heart disease risk: interplay between histidine intake, fiber, and gut...

Imidazole propionate (ImP), a microbial metabolite of histidine, may impair glucose metabolism, but its relevance to coronary heart disease (CHD) risk and potential diet-microbiota regulations remain unclear. We aimed to examine prospective associations of plasma ImP levels and histidine intake with CHD risk, to identify ImP-predicting gut microbes, and to investigate diet-microbiome interactions influencing ImP levels.

Associations of ImP and histidine with CHD risk were evaluated using Cox models in 7,432 participants from Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-up Study. Microbiome-diet interactions influencing ImP levels were assessed using fecal metagenome and 7-day diet record data in 296 men from the Men's Lifestyle Validation Study, with replication in the Mind-Body Study.

Higher plasma ImP was associated with increased CHD risk (HR comparing extreme quintiles = 1.82; 95%CI = 1.17-2.81; p-trend = 0.002), while histidine intake showed a non-significant inverse association. Although histidine intake was not associated with ImP levels, the intake of fiber, especially pectin, emerged as a key negative predictor. We identified 17 distinct ImP-predicting species, including Clostridium and Blautia species. A parametric ImP-microbial score was constructed based on these species to represent the microbial capacity of producing ImP. Further functional characterization uncovered that the microbial urocanate reductase gene urdA was also associated with cardiovascular risk markers. No significant interaction was observed between histidine intake and the microbial score on ImP levels, but ImP levels increased with higher histidine intake and higher microbial score only under low pectin intake (p for 3-way interaction = 0.01). Similar interactions were seen for total fiber (p = 0.09), soluble fiber (p = 0.09), and insoluble fiber (p = 0.11), without statistical significance.

ImP, but not its dietary precursor histidine, was associated with a higher CHD risk. The gut microbial metabolism of ImP appeared context-dependent, with ImP production from histidine associated with a higher ImP-producing microbial capacity and lower fiber intake. These findings highlight the potential role of dietary fiber and gut microbiome in modulating diet-health associations related to ImP metabolism.