(P19-028-25) Circulating Imidazole Propionate and Coronary Heart Disease Risk: Interplay Between Diet, Gut Microbiome, and Histidine Intake

Objectives: Imidazole propionate (ImP), a microbially derived metabolite of histidine, impairs host glucose tolerance and insulin signaling. This study examines prospective associations of circulating ImP and histidine intake with coronary heart disease (CHD) risk and explores diet-microbiome interactions on ImP concentrations.

Methods: Associations of plasma ImP and histidine intake with CHD risk were evaluated using Cox proportional hazards models in 7432 participants from Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-up Study. Fecal metagenomic and diet records from 296 men in the Men’s Lifestyle Validation Study (MLVS) were analyzed to explore diet, gut microbiome, and ImP interactions, with replication in 205 women from the Mind-Body Study (MBS).

Results: Plasma ImP levels were 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 (HR=0.61; 95%CI=0.33-1.16; p-trend=0.12). In the MLVS, 17 gut microbial species, including Ruminococcus gnavus, Clostridium symbiosum, and Clostridium scindens, were significantly associated with plasma ImP. A microbial score was derived by combining these species abundances and coefficients, showing a strong correlation with plasma ImP (Spearman r=0.31, p< 0.001) and replicated in the MBS (r=0.15, p=0.03). Dietary fiber, particularly pectin, was negatively correlated with plasma ImP. No significant interaction was observed between histidine intake and the microbial score on ImP levels, though elevated ImP was seen with both higher histidine intake and the microbial score under lower pectin intake (p for 3-way interaction=0.01). Similar trends were seen for total fiber, soluble fiber, and insoluble fiber but were not statistically significant.

Conclusions: Elevated plasma ImP concentrations were significantly linked to increased CHD risk, while histidine intake showed no significant association. Specific microbial species may influence ImP production at higher histidine intake under low pectin conditions, though further validation is needed. These findings suggest a novel role of dietary fiber in modulating cardiovascular health.

Funding Sources: This study was supported by grants HL035464, HL060712 (NHLBI), and DK119268, DK126698, DK120870, DK129670 (NIDDK).