Association of Gut Microbiota-Related Metabolites and Type 2 Diabetes in Two Puerto Rican Cohorts.

(1) Aims: Gut microbiota metabolites may play integral roles in human metabolism and disease progression. However, evidence for associations between metabolites and cardiometabolic risk factors is sparse, especially in high-risk Hispanic populations. We aimed to evaluate the cross-sectional and longitudinal relationships between gut microbiota related metabolites and measures of glycemia, dyslipidemia, adiposity, and incident type 2 diabetes in two Hispanic observational cohorts. (2) Methods: We included data from 670 participants of the Boston Puerto Rican Health Study (BPRHS) and 999 participants of the San Juan Overweight Adult Longitudinal Study (SOALS). Questionnaires and clinical examinations were conducted over 3 years of follow-up for SOALS and 6 years of follow-up for BPRHS. Plasma metabolites, including L-carnitine, betaine, choline, and trimethylamine N-oxide (TMAO), were measured at baseline in both studies. We used multivariable linear models to evaluate the associations between metabolites and cardiometabolic risk factors and multivariable logistic and Poisson regressions to assess associations with prevalent and incident type 2 diabetes, adjusted for potential confounding factors. Cohort-specific analyses were combined using a fixed-effects meta-analysis. (3) Results: Higher plasma betaine was prospectively associated with lower fasting glucose [-0.97 mg/dL (95% CI: -1.59, -0.34), p = 0.002], lower HbA1c [-0.02% (95% CI: -0.04, -0.01), p = 0.01], lower HOMA-IR [-0.14 (95% CI: -0.23, -0.05), p = 0.003], and lower fasting insulin [-0.27 mcU/mL (95% CI: -0.51, -0.03), p = 0.02]. Betaine was also associated with a 22% lower incidence of type 2 diabetes (IRR: 0.78, 95% CI: 0.65, 0.95). L-carnitine was associated with lower fasting glucose [-0.68 mg/dL (95% CI: -1.29, -0.07), p = 0.03] and lower HbA1c at follow-up [-0.03% (95% CI: -0.05, -0.01), p < 0.001], while TMAO was associated with higher fasting glucose [0.83 mg/dL (95% CI: 0.22, 1.44), p = 0.01] and higher triglycerides [3.52 mg/dL (95% CI: 1.83, 5.20), p < 0.0001]. Neither choline nor TMAO were associated with incident type 2 diabetes. (4) Conclusions: Higher plasma betaine showed consistent associations with a lower risk of glycemia, insulinemia, and type 2 diabetes. However, TMAO, a metabolite of betaine, was associated with higher glucose and lipid concentrations. These observations demonstrate the importance of gut microbiota metabolites for human cardiometabolic health.

Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies.

BACKGROUND: A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity. METHODS: In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity. FINDINGS: The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity. CONCLUSIONS: This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity. FUNDING: This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

Sugar-sweetened or artificially-sweetened beverage consumption, physical activity, and risk of cardiovascular disease in adults: a prospective cohort study.

BACKGROUND: Whether physical activity could mitigate the adverse impacts of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) on incident cardiovascular disease (CVD) remains uncertain. OBJECTIVES: This study aimed to examine the independent and joint associations between SSB or ASB consumption and physical activity and risk of CVD, defined as fatal and nonfatal coronary artery disease and stroke, in adults from 2 United States-based prospective cohort studies. METHODS: Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs between SSB or ASB intake and physical activity with incident CVD among 65,730 females in the Nurses' Health Study (1980-2016) and 39,418 males in the Health Professional's Follow-up Study (1986-2016), who were free from chronic diseases at baseline. SSBs and ASBs were assessed every 4-y and physical activity biannually. RESULTS: A total of 13,269 CVD events were ascertained during 3,001,213 person-years of follow-up. Compared with those who never/rarely consumed SSBs or ASBs, the HR for CVD for participants consuming ≥2 servings/d was 1.21 (95% CI: 1.12, 1.32; P-trend < 0.001) for SSBs and 1.03 (95% CI: 0.97, 1.09; P-trend = 0.06) for those consuming ≥2 servings/d of ASBs. The HR for CVD per 1 serving increment of SSB per day was 1.18 (95% CI: 1.10, 1.26) and 1.12 (95% CI: 1.04, 1.20) for participants meeting and not meeting physical activity guidelines (≥7.5 compared with <7.5 MET h/wk), respectively. Compared with participants who met physical activity guidelines and never/rarely consumed SSBs, the HR for CVD was 1.47 (95% CI: 1.37, 1.57) for participants not meeting physical activity guidelines and consuming ≥2 servings/wk of SSBs. No significant associations were observed for ASB when stratified by physical activity. CONCLUSIONS: Higher SSB intake was associated with CVD risk regardless of physical activity levels. These results support current recommendations to limit the intake of SSBs even for physically active individuals.

Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry.

BACKGROUND: The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH). METHODS: Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n = 4,557) or post-diagnosis (n = 1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted HR and 95% confidence intervals (CI). RESULTS: Women in the highest versus lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74-1.04; Ptrend = 0.12) for HEI-2015; 0.82 (0.69-0.97; Ptrend = 0.02) for AHEI; 0.73 (0.59-0.92; Ptrend = 0.02) for aMED; and 0.78 (0.65-0.94; Ptrend = 0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index <25 kg/m2 and women with hormone receptor positive tumors. CONCLUSIONS: Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer. IMPACT: Adherence to a healthy diet may improve survival of women with breast cancer.

Changes in metabolomics profiles over ten years and subsequent risk of developing type 2 diabetes: Results from the Nurses' Health Study.

BACKGROUND: Metabolomics profiles were consistently associated with type 2 diabetes (T2D) risk, but evidence on long-term metabolite changes and T2D incidence is lacking. We examined the associations of 10-year plasma metabolite changes with subsequent T2D risk. METHODS: We conducted a nested T2D case-control study (n=244 cases, n=244 matched controls) within the Nurses' Health Study. Repeated metabolomics profiling (170 targeted metabolites) was conducted in participant blood specimens from 1989/1990 and 2000/2001, and T2D occurred between 2002 and 2008. We related 10-year metabolite changes (Δ-values) to subsequent T2D risk using conditional logistic models, adjusting for baseline metabolite levels and baseline levels and concurrent changes of BMI, diet quality, physical activity, and smoking status. FINDINGS: The 10-year changes of thirty-one metabolites were associated with subsequent T2D risk (false discovery rate-adjusted p-values [FDR]<0.05). The top three high T2D risk-associated 10-year changes were (odds ratio [OR] per standard deviation [SD], 95%CI): Δisoleucine (2.72, 1.97-3.79), Δleucine (2.53, 1.86-3.47), and Δvaline (1.93, 1.52-2.44); other high-risk-associated metabolite changes included alanine, tri-/diacylglycerol-fragments, short-chain acylcarnitines, phosphatidylethanolamines, some vitamins, and bile acids (ORs per SD between 1.31and 1.82). The top three low T2D risk-associated 10-year metabolite changes were (OR per SD, 95% CI): ΔN-acetylaspartic acid (0.54, 0.42-0.70), ΔC20:0 lysophosphatidylethanolamine (0.68, 0.56-0.82), and ΔC16:1 sphingomyelin (0.68, 0.56-0.83); 10-year changes of other sphingomyelins, plasmalogens, glutamine, and glycine were also associated with lower subsequent T2D risk (ORs per SD between 0.66 and 0.78). INTERPRETATION: Repeated metabolomics profiles reflecting the long-term deterioration of amino acid and lipid metabolism are associated with subsequent risk of T2D.

Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry.

BACKGROUND: Soy foods possess both antiestrogenic and estrogen-like properties. It remains controversial whether women diagnosed with breast cancer should be advised to eat more or less soy foods, especially for those who receive hormone therapies as part of cancer treatment. METHODS: The association of dietary intake of isoflavone, the major phytoestrogen in soy, with all-cause mortality was examined in 6235 women with breast cancer enrolled in the Breast Cancer Family Registry. Dietary intake was assessed using a Food Frequency Questionnaire developed for the Hawaii-Los Angeles Multiethnic Cohort among 5178 women who reported prediagnosis diet and 1664 women who reported postdiagnosis diet. Cox proportional-hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a median follow-up of 113 months (approximately 9.4 years), 1224 deaths were documented. A 21% decrease was observed in all-cause mortality for women who had the highest versus lowest quartile of dietary isoflavone intake (≥1.5 vs < 0.3 mg daily: HR, 0.79; 95% confidence interval CI, 0.64-0.97; Ptrend = .01). Lower mortality associated with higher intake was limited to women who had tumors that were negative for hormone receptors (HR, 0.49; 95% CI, 0.29-0.83; Ptrend = .005) and those who did not receive hormone therapy for their breast cancer (HR, 0.68; 95% CI, 0.51-0.91; Ptrend = .02). Interactions, however, did not reach statistical significance. CONCLUSIONS: In this large, ethnically diverse cohort of women with breast cancer living in North America, a higher dietary intake of isoflavone was associated with reduced all-cause mortality. Cancer 2017;123:2070-2079. © 2017 American Cancer Society.