Dietary nitrate intake and net nitrite-generating capacity of the oral microbiome interact to enhance cardiometabolic health: Results from the Oral Infections Glucose Intolerance and Insulin Resistance Study (ORIGINS)

BackgroundWe investigated the association between dietary nitrate intake and early clinical cardiometabolic risk biomarkers, and explored whether the oral microbiome modifies the association between dietary nitrate intake and cardiometabolic biomarkers. MethodsCross-sectional data from 668 (mean [SD] age 31 [9] years, 73% women) participants was analyzed. Dietary nitrate intakes and alternative healthy eating index (AHEI) scores were calculated from food frequency questionnaire responses and a validated US food database. Subgingival 16S rRNA microbial genes (Illumina, MiSeq) were sequenced, and PICRUSt2 estimated metagenomic content. The Microbiome Induced Nitric oxide Enrichment Score (MINES) was calculated as a microbial gene abundance ratio representing enhanced net capacity for NO generation. Cardiometabolic risk biomarkers included systolic and diastolic blood pressure, HbA1c, glucose, insulin, and insulin resistance (HOMA-IR), and were regressed on nitrate intake tertiles in adjusted multivariable linear models. ResultsMean nitrate intake was 190[171] mg/day. Higher nitrate intake was associated with lower insulin, and HOMA-IR but particularly among participants with low abundance of oral nitrite enriching bacteria. For example, among participants with a low MINES, mean insulin[95%CI] levels in high vs. low dietary nitrate consumers were 5.8[5.3,6.5] vs. 6.8[6.2,7.5] (p=0.004) while respective insulin levels were 6.0[5.4,6.6] vs. 5.9[5.3,6.5] (p=0.76) among partcipants with high MINES (interaction p=0.02). ConclusionHigher dietary nitrate intake was only associated with lower insulin and insulin resistance among individuals with reduced capacity for oral microbe-induced nitrite enrichment. These findings have implications for future precision medicine-oriented approaches that might consider assessing the oral microbiome prior to enrollment into dietary interventions or making dietary recommendations. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIn this population-based study we identified an interaction between dietary nitrate intake and oral nitrite enriching bacteria on cardiometabolic outcomes. C_LIO_LIHigher dietary nitrate intake was associated with lower insulin and insulin resistance only among participants with low abundance of oral nitrite enriching bacteria. C_LIO_LIThis study suggests that cardiometabolic benefits of nitrate consumption might depend on the host microbiomes capacity to metabolize nitrates. C_LI What are the clinical implications?O_LIAmong people with low microbiome capacity for nitrate metabolism, higher levels of nitrate might be necessary to realize cardiometabolic benefits. C_LIO_LILack of microbiome assessments in prior studies could partially explain inconsistent findings from previous nitrate supplementation trials and observational studies. C_LIO_LIFuture precision-medicine oriented trials studying the effects of dietary nitrate recommendations on cardiometabolic health, should consider assessing the oral microbiome. C_LI