Histidine Intake, Human Gut Microbiome, Plasma Levels of Imidazole Propionate, and Coronary Heart Disease Risk in US Adults

Imidazole propionate (ImP), a microbiota metabolite from histidine, has been linked to cardiometabolic conditions in humans. The current study aimed to elucidate inter-relationships between histidine intake, gut microbial composition and functional potentials, circulating ImP levels, and the risk of coronary heart disease (CHD) in U.S. adults. A total of 896 fecal samples and 462 blood samples were collected from 298 healthy men in the Men's Lifestyle Validation Study. Multivariate Association with Linear Models 2 was used to analyze the associations between microbial features and plasma ImP levels. Associations between plasma ImP and CHD risk was examined using Cox proportional hazards regression models among 7,793 participants pooled from the Health Professionals Follow-up Study, Nurses’ Health Study (NHS), and NHSII with existing ImP measurements. The overall microbial composition was associated with plasma ImP levels (PERMANOVA p = 0.001). Multivariable taxa-wide association analysis identified 14 bacterial species, such as Ruminococcus Obeum, Clostridium clostridioforme, C. nexile, C. symbiosum and Gordonibacter pamelaeae, that were significantly (FDR P < 0.05) associated with plasma ImP levels. A non-parametric score was derived to summarize the abundance of the 14 species. Higher intake of red meat and histidine was significantly associated with higher ImP levels among participants with a higher ImP-Species Score (for red meat, P-inter = 0.04; for histidine, P-inter = 0.01), but not among others (P > 0.05). In the pooled cohort, compared with participants in the lowest ImP tertile, the relative risk (95% CI) of CHD was 2.06 (1.96, 2.43) among those in the highest ImP tertile (P- trend = 0.0001). Histidine consumption was not associated with CHD risk in the same study population. We identified multiple microbiota species that were associated with plasma ImP concentrations and collectively predicted stronger associations of histidine or red meat intake with ImP concentrations. Plasma ImP concentrations were significantly associated with an increased risk of developing CHD. These data emphasize the role of human gut microbiota in modulating the production of ImP through histidine intake. The National Institutes of Health Boston Nutrition Obesity Research Centre.