Diet, Gut Microbiota, and Histidine Metabolism Toward Imidazole Propionate Production in Relation to Type 2 Diabetes

OBJECTIVE To examine associations of serum imidazole propionate (ImP), histidine, and their ratio with incident type 2 diabetes (T2D) and related dietary and gut microbial factors in U.S. Hispanic/Latino people. RESEARCH DESIGN AND METHODS In the Hispanic Community Health Study/Study of Latinos, we evaluated serum ImP, histidine, and ImP-to-histidine ratio at baseline (2008–2011) and their cross-sectional associations with dietary intake and prospective associations with incident T2D over ∼12 years (n = 4,632). In a subsample with gut microbiota data during a follow-up visit (2016–2018), we examined gut microbial species associated with serum ImP and their potential interactions with dietary intake. RESULTS Serum ImP and ImP-to-histidine ratio were positively associated with incident T2D (hazard ratio [95% CI] 1.17 [1.00–1.36] and 1.33 [1.14–1.55], respectively, comparing highest and lowest tertiles), whereas histidine was inversely associated with incident T2D (hazard ratio 0.75 [95% CI 0.64–0.86]). A higher amount of fiber intake was associated with lower serum ImP level and ImP-to-histidine ratio, whereas histidine intake was not associated with serum ImP level in the overall sample. Fifty-three bacterial species, including 19 putative ImP producers, were associated with serum ImP. Histidine intake was positively associated with serum ImP and ImP-to-histidine ratio only in participants with a high ImP-associated gut microbiota score (P = 0.03 and 0.02, respectively, for interaction). The associations of fiber intake with serum ImP and ImP-to-histidine ratio were partly mediated by ImP-associated gut microbiota (proportion mediated = 31.4% and 19.8%, respectively). CONCLUSIONS This study suggested an unfavorable relationship between histidine metabolism toward ImP production, potentially regulated by dietary intake and gut microbiota, and risk of T2D in U.S. Hispanic/Latino people.