Plasma imidazole propionate (ImP)—a microbial metabolite of histidine produced via the urocanate reductase pathway—was associated with an 82% higher coronary heart disease risk comparing extreme quintiles (HR 1.82; 95% CI 1.17–2.81) in 7,432 participants from three large prospective cohorts (NHS, NHSII, HPFS). Critically, dietary histidine intake itself showed no significant CHD association, and histidine intake did not predict plasma ImP levels. Instead, pectin intake emerged as the strongest negative predictor of ImP, with a three-way interaction revealing that ImP accumulates only when both microbial ImP-producing capacity (indexed by 17 species including Clostridium and Blautia) and histidine intake are high under low-pectin conditions.
This finding meaningfully reframes how we think about amino acid metabolism and cardiovascular risk. The histidine-CHD relationship has been ambiguous in prior literature partly because studies rarely accounted for gut microbial context. The identification of urdA—the microbial urocanate reductase gene—as independently associated with cardiovascular risk markers adds mechanistic specificity that moves this beyond correlational epidemiology. Practically, the data suggest that optimizing fiber intake, particularly pectin-rich foods like apples and citrus, may suppress a harmful metabolic pathway regardless of protein intake patterns. Limitations are notable: microbiome data came from only 296 men, plasma ImP was measured at single timepoints, and causality cannot be established from observational design. Still, for a research landscape crowded with generic fiber-health associations, this mechanistic triangulation is genuinely incremental and actionable.
