Dietary Patterns, Circulating Metabolome, and Risk of Type 2 Diabetes

Abstract Circulating metabolites may reflect biological homeostasis and have been linked to dietary intakes and human health, and may hold the promises to facilitate objective assessments of intakes and metabolic response to diets. Here, we integrated metabolomic, genetic, and metagenomic data from five longitudinal cohorts comprising 21,474 participants of diverse ethnic backgrounds, to develop metabolomic signatures for popular dietary patterns (i.e., three guideline-based diets, three plant-based diets, and two mechanism-based diets) and systematically investigated their clinical relevance. Applying machine-learning models in two deeply-phenotyped lifestyle validation studies, we identified eight metabolomic signatures (each included 37 to 66 metabolites) significantly correlated with their respective dietary pattern indices, consistently across multiple independent validation cohorts (r = 0.11–0.38; P < 8.06×10⁻⁹). These signatures included shared metabolites between diets (e.g., up to 67% among guideline-based diets, including hippuric and 3-indolepropionic acid), and metabolites unique to specific diets (e.g., N6,N6,N6-trimethyllysine to proinflammatory diet). In multivariable-adjusted analyses of 5 prospective cohorts (1,832 incident cases during up to 27 years of follow-up), the metabolomic signatures of healthful diets (i.e., Mediterranean and healthful plant-based diets) were associated with lower T2D risk (HR: 0.82–0.90; P < 3×10⁻⁶), while signatures for unhealthy diets (e.g., proinflammatory and hyperinsulinemia diets) were associated with higher T2D risk (HR: 1.23–1.26; P < 2×10⁻¹⁵); these associations were further supported by Mendelian randomization analysis incorporating genetic data. Finally, through genome-wide and taxa-wide associating analyses, we identified 15 genetic loci – including those involved in fatty acid and energy metabolism (e.g., FADS1/2 and CERS4; P < 5×10-8), and 39 gut microbial species – including those relevant to butyric acid metabolism (e.g., E. eligens and F. pranusnitzii; FDR < 0.05), significantly associated with the metabolomic signatures of diets. Genetic variants and gut microbial diversity explained up to 19.1% and 10.6% of the variation in these signatures, respectively, underscoring a potential role of host genetics and gut microbiota in dietary metabolism. In conclusion, our study identified metabolomic signatures reflecting both intakes and individual metabolic response to various diets and are associated with future T2D risk. These signatures may facilitate individualized dietary assessments and risk stratification in future nutritional research. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study is supported by R00DK122128 from the National Institute of Diabetes and Digestive and Kidney Diseases and U2CDK129670. The NHS, NHSII, and HPFS, and their metabolomic studies were supported by National Institutes of Health grants U01 HL145386, UM1 CA186107, R01 CA49449, R01 HL034594, R01 HL088521, U01 CA176726, R01 CA67262, U01 CA167552, R01 HL35464, HL60712, R01 CA50385, P01 CA87969, and R01 AR049880. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I / N01- HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Dr. Kaplan was supported by 2R01HL105756, R01GM145772, 1R01DK134672, and 1R01MD011389 from the National Institutes of Health. The metabolomic and gut microbiome studies from HCHS/SOL were supported by R01DK119268, R01 DK126698, R01HL060712, R01MD011389, R01HL141824, and UM1 HG008898. The WHI is funded by NHLBI through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Harvard T.H. Chan School of Public Health and Brigham and Women's Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.