biostudies-literatureBhave VMAmerican Heart AssociationJackson State UniversityNIBIB NIH HHSNHLBI NIH HHSNIMHD NIH HHSNINDS NIH HHSMississippi State Department of HealthNational Institutes of HealthNIGMS NIH HHS500-510https://www.ebi.ac.uk/biostudies/studies/S-EPMC9974740biostudies-literatureUnknown93(3)<h4>Objective</h4>While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.<h4>Methods</h4>Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.<h4>Results</h4>Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10^-6 ), guanosine (β = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10^-5 ), gluconic acid (β = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10^-3 ), and C7 carnitine (β = -0.16, 95% CI [-0.24, -0.09], p = 4.14 × 10^-5 ). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10^-3 ), gluconic acid (35.7%, p = 2.28 × 10^-3 ), and C7 carnitine (26.2%, p = 1.88 × 10^-2 ) as mediators linking a plant-based diet to reduced stroke risk.<h4>Interpretation</h4>A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500-510.Annals of neurologyPlasma Metabolites Link Dietary Patterns to Stroke Risk.PMC9974740U01 NS041588P20 GM135007U01NS041588HHSN268201800014CR01 EB031114HHSN268201800015IR01 NS099209HHSN268201800012CHHSN268201800011CR21 NS120002HHSN268201800012IHHSN268201800011IHHSN268201800014IHHSN268201800013I17CSA33550004HHSN268201800010IAment ZIrvin MRCushman MBhave VMKijpaisalratana NGerszten RCorrea AKimberly WTPatki AGuarniz AGGao YJudd SChaudhary NSGuo BfalsePlasma Metabolites Link Dietary Patterns to Stroke Risk.<h4>Objective</h4>While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.<h4>Methods</h4>Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.<h4>Results</h4>Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10^-6 ), guanosine (β = -0.13, 95% CI [-0.19, -0.07], p = 6.48 × 10^-5 ), gluconic acid (β = -0.11, 95% CI [-0.18, -0.04], p = 2.06 × 10^-3 ), and C7 carnitine (β = -0.16, 95% CI [-0.24, -0.09], p = 4.14 × 10^-5 ). All of these metabolites were associated with both additional diet patterns and altered stroke risk. Mediation analyses identified guanosine (32.6% mediation, p = 1.51 × 10^-3 ), gluconic acid (35.7%, p = 2.28 × 10^-3 ), and C7 carnitine (26.2%, p = 1.88 × 10^-2 ) as mediators linking a plant-based diet to reduced stroke risk.<h4>Interpretation</h4>A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2023;93:500-510.2023-01-01T00:00:00Z2023 Mar2026-06-04T05:53:38.594Z2025-04-07T04:25:30.561ZS-EPMC99747403637382510.1002/ana.26552