Publications by authors named "Kerry L Ivey"

38 Publications

The effects of increasing fruit and vegetable intake in children with asthma: A randomized controlled trial.

Clin Exp Allergy 2021 Sep 14;51(9):1144-1156. Epub 2021 Jul 14.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.

Background: A high fruit and vegetable (F&V) diet reduces asthma exacerbations in adults; this has not been examined in children to date.

Objective: To investigate the effect of a 6-month, high F&V diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial.

Methods: Children (aged 3-11 years) with asthma, history of exacerbations and usual low F&V intake (≤3 serves/day) were randomized to the intervention (high F&V diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression.

Results: 67 children were randomized between September 2015 and July 2018. F&V intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p < 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (X ∆: 0.76 [0.04, 1.48] p = 0.038, X ∆: 0.93 [0.23, 1.64] p = 0.009) and changes in faecal microbiota were observed though there was no difference between groups in systemic inflammation or molecular mechanisms. In the control group, CRP and HDAC enzyme activity increased, while GPR41 expression decreased. No adverse events attributable to the interventions were observed.

Conclusion & Clinical Relevance: A high F&V diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.
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http://dx.doi.org/10.1111/cea.13979DOI Listing
September 2021

Dietary fiber intake, the gut microbiome, and chronic systemic inflammation in a cohort of adult men.

Genome Med 2021 Jun 17;13(1):102. Epub 2021 Jun 17.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: A higher intake of dietary fiber is associated with a decreased risk of chronic inflammatory diseases such as cardiovascular disease and inflammatory bowel disease. This may function in part due to abrogation of chronic systemic inflammation induced by factors such as dysbiotic gut communities. Data regarding the detailed influences of long-term and recent intake of differing dietary fiber sources on the human gut microbiome are lacking.

Methods: In a cohort of 307 generally healthy men, we examined gut microbiomes, profiled by shotgun metagenomic and metatranscriptomic sequencing, and long-term and recent dietary fiber intake in relation to plasma levels of C-reactive protein (CRP), an established biomarker for chronic inflammation. Data were analyzed using multivariate linear mixed models.

Results: We found that inflammation-associated gut microbial configurations corresponded with higher CRP levels. A greater intake of dietary fiber was associated with shifts in gut microbiome composition, particularly Clostridiales, and their potential for carbohydrate utilization via polysaccharide degradation. This was particularly true for fruit fiber sources (i.e., pectin). Most striking, fiber intake was associated with significantly greater CRP reduction in individuals without substantial Prevotella copri carriage in the gut, whereas those with P. copri carriage maintained stable CRP levels regardless of fiber intake.

Conclusions: Our findings offer human evidence supporting a fiber-gut microbiota interaction, as well as a potential specific mechanism by which gut-mediated systemic inflammation may be mitigated.
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http://dx.doi.org/10.1186/s13073-021-00921-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212460PMC
June 2021

Plant-Based Diet Index and Metabolic Risk in Men: Exploring the Role of the Gut Microbiome.

J Nutr 2021 Sep;151(9):2780-2789

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Healthy plant-based diet index (hPDI) is associated with a lower risk of cardiometabolic conditions, but its association as well as interactions with microbiome have not been elucidated.

Objectives: We aimed to investigate the interrelations between hPDI, gut microbiome, and cardiometabolic risk markers.

Methods: hPDI was derived from dietary assessments by a validated FFQ and was examined in relation to metagenomic profiles of 911 fecal samples collected from 303 men aged 71 ± 4 y with an average BMI (in kg/m2) of 25.2 ± 3.6 in the Men's Lifestyle Validation Study. Principal coordinate (PCo) analysis based on Bray-Curtis dissimilarity was conducted, and interactions between hPDI and PCo were examined by using a metabolic risk score composed of blood lipids, BMI, and glycated hemoglobin.

Results: After multivariable adjustment, hPDI was significantly associated with the relative abundance of 7 species and 9 pathways. In particular, higher hPDI was significantly associated with a higher relative abundance of Bacteroides cellulosilyticus and Eubacterium eligens, amino acid biosynthesis pathways (l-isoleucine biosynthesis I and III and l-valine biosynthesis), and the pathway of pyruvate fermentation to isobutanol. A favorable association between hPDI and the metabolic risk score was more pronounced among men with a higher PCo characterized by higher abundance of Bacteroides uniformis and lower abundance of Prevotella copri. At the individual species level, a similar interaction was also observed between hPDI and P. copri, as well as with Clostridium clostridioforme or Blautia hydrogenotrophica (all P-interaction < 0.01).

Conclusion: A greater adherence to a healthy plant-based diet by older men was associated with a microbial profile characterized by a higher abundance of multiple species, including B. cellulosilyticus and E. eligens, as well as pathways in amino acid metabolism and pyruvate fermentation. In addition, inverse associations between healthy plant-based diet and human metabolic risk may partially depend on microbial compositions.
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http://dx.doi.org/10.1093/jn/nxab175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417919PMC
September 2021

Dietary yogurt is distinct from other dairy foods in its association with circulating lipid profile: Findings from the Million Veteran Program.

Clin Nutr ESPEN 2021 06 20;43:456-463. Epub 2021 Mar 20.

Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA; Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.

Background & Aims: Dyslipidemia is a major cardiovascular disease risk factor. Research has proposed mechanisms whereby yogurt may improve circulating lipid concentrations. However, at the population level, the association of yogurt, as distinct from other dairy foods, with these important risk factors is poorly understood. This study aimed to determine whether the circulating lipid profile associated with yogurt is different to the circulating lipid profile that is associated with non-yogurt dairy products, specifically milk and cheese.

Methods: The current study included the 192,564 US Veterans enrolled in the Million Veteran Program who reported frequency of yogurt consumption (assessed via food frequency questionnaire) and had lipid concentrations assessed. Trends were evaluated with linear regression. Mean age was 65 (SD = 11) years [20, 100 years].

Results: A one serve/day higher yogurt consumption was positively associated (coefficient ± SE) with the concentration of high-density lipoprotein cholesterol (HDLC) in individuals who were not (0.26 ± 0.12 mg/dL, P value = 0.025), and who were (0.25 ± 0.09, P value = 0.004), using antilipemic agents. Furthermore, higher yogurt consumption was inversely associated with the concentration of triglycerides, but only in individuals who were not using antilipemic agents (-1.46 ± 0.58, P value = 0.012).

Conclusion: These apparent beneficial associations of yogurt with HDLC and triglycerides were independent of consumption of non-yogurt dairy foods and were not observed for consumption of either milk or cheese. In this prospective cohort study of U.S. Veterans, we found a beneficial relationship between higher frequency of yogurt consumption with circulating HDLC and triglyceride concentrations that was distinct from non-yogurt dairy foods.
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http://dx.doi.org/10.1016/j.clnesp.2021.02.022DOI Listing
June 2021

Interplay between diet and gut microbiome, and circulating concentrations of trimethylamine N-oxide: findings from a longitudinal cohort of US men.

Gut 2021 Apr 29. Epub 2021 Apr 29.

Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA

Objectives: Gut-produced trimethylamine N-oxide (TMAO) is postulated as a possible link between red meat intake and poor cardiometabolic health. We investigated whether gut microbiome could modify associations of dietary precursors with TMAO concentrations and cardiometabolic risk markers among free-living individuals.

Design: We collected up to two pairs of faecal samples (n=925) and two blood samples (n=473), 6 months apart, from 307 healthy men in the Men's Lifestyle Validation Study. Diet was assessed repeatedly using food-frequency questionnaires and diet records. We profiled faecal metagenome and metatranscriptome using shotgun sequencing and identified microbial taxonomic and functional features.

Results: TMAO concentrations were associated with the overall microbial compositions (permutational analysis of variance (PERMANOVA) test p=0.001). Multivariable taxa-wide association analysis identified 10 bacterial species whose abundance was significantly associated with plasma TMAO concentrations (false discovery rate <0.05). Higher habitual intake of red meat and choline was significantly associated with higher TMAO concentrations among participants who were microbial TMAO-producers (p<0.05), as characterised based on four abundant TMAO-predicting species, but not among other participants (for red meat=0.003; for choline, =0.03). Among abundant TMAO-predicting species, significantly strengthened the positive association between red meat intake and HbA1c levels (=0.01). Secondary analyses revealed that some functional features, including choline trimethylamine-lyase activating enzymes, were associated with TMAO concentrations.

Conclusion: We identified microbial taxa that were associated with TMAO concentrations and modified the associations of red meat intake with TMAO concentrations and cardiometabolic risk markers. Our data underscore the interplay between diet and gut microbiome in producing potentially bioactive metabolites that may modulate cardiometabolic health.
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http://dx.doi.org/10.1136/gutjnl-2020-322473DOI Listing
April 2021

The Structure of Relationships between the Human Exposome and Cardiometabolic Health: The Million Veteran Program.

Nutrients 2021 Apr 19;13(4). Epub 2021 Apr 19.

Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA 02130, USA.

The represents the array of dietary, lifestyle, and demographic factors to which an individual is exposed. Individual components of the exposome, or groups of components, are recognized as influencing many aspects of human physiology, including cardiometabolic health. However, the influence of the whole exposome on health outcomes is poorly understood and may differ substantially from the sum of its individual components. As such, studies of the complete exposome are more biologically representative than fragmented models based on subsets of factors. This study aimed to model the system of relationships underlying the way in which the diet, lifestyle, and demographic components of the overall exposome shapes the cardiometabolic risk profile. The current study included 36,496 US Veterans enrolled in the VA Million Veteran Program (MVP) who had complete assessments of their diet, lifestyle, demography, and markers of cardiometabolic health, including serum lipids, blood pressure, and glycemic control. The cohort was randomly divided into training and validation datasets. In the training dataset, we conducted two separate exploratory factor analyses (EFA) to identify common factors among exposures (diet, demographics, and physical activity) and laboratory measures (lipids, blood pressure, and glycemic control), respectively. In the validation dataset, we used multiple normal regression to examine the combined effects of exposure factors on the clinical factors representing cardiometabolic health. The mean ± SD age of participants was 62.4 ± 13.4 years for both the training and validation datasets. The EFA revealed 19 Exposure Common Factors and 5 Physiology Common Factors that explained the observed (measured) data. Multivariate regression in the validation dataset revealed the structure of associations between the Exposure Common Factors and the Physiology Common Factors. For example, we found that the factor for fruit consumption was inversely associated with the factor summarizing total cholesterol and low-density lipoprotein cholesterol (LDLC, = 0.008), and the latent construct describing light levels of physical activity was inversely associated with the blood pressure latent construct ( < 0.0001). We also found that a factor summarizing that participants who frequently consume whole milk are less likely to frequently consume skim milk, was positively associated with the latent constructs representing total cholesterol and LDLC as well as systolic and diastolic blood pressure ( = 0.0006 and <0.0001, respectively). Multiple multivariable-adjusted regression analyses of exposome factors allowed us to model the influence of the exposome as a whole. In this metadata-rich, prospective cohort of US Veterans, there was evidence of structural relationships between diet, lifestyle, and demographic exposures and subsequent markers of cardiometabolic health. This methodology could be applied to answer a variety of research questions about human health exposures that utilize electronic health record data and can accommodate continuous, ordinal, and binary data derived from questionnaires. Further work to explore the potential utility of including genetic risk scores and time-varying covariates is warranted.
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http://dx.doi.org/10.3390/nu13041364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073795PMC
April 2021

Dietary Gluten Intake Is Not Associated With Risk of Inflammatory Bowel Disease in US Adults Without Celiac Disease.

Clin Gastroenterol Hepatol 2021 Mar 26. Epub 2021 Mar 26.

Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Clinical and Translation Epidemiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts. Electronic address:

Background & Aims: Diet is thought to play a role in the development of inflammatory bowel disease (IBD), although the relationship between gluten intake and risk of IBD has not been explored. The aim of this study was to determine the relationship between gluten intake and risk of incident Crohn's disease (CD) and ulcerative colitis (UC).

Methods: We performed a prospective cohort study of 208,280 US participants from the Nurses' Health Study (1986-2016), Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016) who did not have IBD at baseline or celiac disease, and who completed semiquantitative food frequency questionnaires. We used Cox proportional hazards modeling to estimate the risk of IBD according to quintiles of cumulative average energy-adjusted dietary gluten intake over the follow-up period.

Results: We documented 337 CD cases and 447 UC cases over 5,115,265 person-years of follow-up evaluation. Dietary gluten intake was not associated with risk of IBD. Compared with participants in the lowest quintile of gluten intake, the adjusted hazard ratios and 95% CIs for participants in the highest quintile of gluten intake were 1.16 (95% CI, 0.82-1.64; P = .41) for CD and 1.04 (95% CI, 0.75-1.44; P = .64) for UC. Adjusting for primary sources of gluten intake did not materially change our estimates.

Conclusions: In 3 large adult US prospective cohorts, gluten intake was not associated with risk of CD or UC. Our findings are reassuring at a time when consumption of gluten has been increasingly perceived as a trigger for chronic gastrointestinal diseases.
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http://dx.doi.org/10.1016/j.cgh.2021.03.029DOI Listing
March 2021

The gut microbiome modulates the protective association between a Mediterranean diet and cardiometabolic disease risk.

Nat Med 2021 02 11;27(2):333-343. Epub 2021 Feb 11.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

To address how the microbiome might modify the interaction between diet and cardiometabolic health, we analyzed longitudinal microbiome data from 307 male participants in the Health Professionals Follow-Up Study, together with long-term dietary information and measurements of biomarkers of glucose homeostasis, lipid metabolism and inflammation from blood samples. Here, we demonstrate that a healthy Mediterranean-style dietary pattern is associated with specific functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings advance the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.
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http://dx.doi.org/10.1038/s41591-020-01223-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186452PMC
February 2021

Reproducibility and Validity of a Semiquantitative Food Frequency Questionnaire in Men Assessed by Multiple Methods.

Am J Epidemiol 2021 06;190(6):1122-1132

Among 626 participants of the Men's Lifestyle Validation Study (2011-2013), we evaluated the validity and reproducibility of a self-administered 152-item semiquantitative food frequency questionnaire (SFFQ) using two 7-day dietary records (7DDRs), 4 Automated Self-Administered 24-hour dietary recalls (ASA24s), four 24-hour urine samples, 1 doubly labeled water measurement (repeated in 104 participants), and 2 fasting blood samples, collected over 15 months. Compared with 7DDRs, SFFQs underestimated energy intake, macronutrients, and sodium intake but overestimated some micronutrients. The mean of the Spearman correlation coefficients was 0.66 (range, 0.38-0.88) between 46 energy-adjusted nutrients estimated from 7DDRs and the final SFFQ, deattenuated for within-person variation in the 7DDRs. These deattenuated correlations were similar using ASA24s as the comparison. Relative to biomarkers, SFFQs underestimated energy, sodium, and protein intakes, as well as the sodium:potassium ratio. The energy-adjusted correlations between the final SFFQ and the biomarkers were slightly lower than the correlations between the SFFQ and 7DDRs. Using the method of triads to calculate validity coefficients, the median validity coefficient between SFFQ and true intake was 0.65 and 0.69 using 7DDRs and ASA24s, respectively, as the third method. These data indicate that this SFFQ provided reasonably valid estimates for a wide range of nutrients when evaluated by multiple comparison methods.
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http://dx.doi.org/10.1093/aje/kwaa280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168140PMC
June 2021

Prospective Study of Skipping Meals to Lose Weight as a Predictor of Incident Type 2 Diabetes With Potential Modification by Cardiometabolic Risk Factors: The Canadian 1995 Nova Scotia Health Survey.

Can J Diabetes 2021 Jun 17;45(4):306-312. Epub 2020 Sep 17.

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; QEII Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada; Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada. Electronic address:

Background: Skipping meals is an increasingly common practice to lose weight among North American adults. However, the long-term effect of this practice on incident type 2 diabetes mellitus (T2DM) remains unknown. We assessed whether skipping meals to lose weight is associated with T2DM risk and whether this association is modified by cardiometabolic risk factors.

Methods: Skipping meals to lose weight was assessed by questionnaire in 2,288 adults from the 1995 Nova Scotia Health Survey and was linked to administrative health databases to determine T2DM incidence in the following 23 years. Multivariable-adjusted Cox proportional hazards models estimated hazard ratios (aHRs) and 95% confidence intervals (CIs) for T2DM.

Results: During follow up, 378 T2DM cases were diagnosed. Compared with participants who did not skip meals to lose weight, those who did (2.2%) had a 125% higher risk of T2DM (aHR, 2.25; 95% CI, 1.31 to 3.86). This association was no longer present after further adjustment for baseline body mass index (BMI) (aHR, 1.66; 95% CI, 0.96 to 2.85). Skipping meals to lose weight was associated with T2DM among participants who were men (n=1,135; aHR, 2.09; 95% CI, 1.09 to 4.02) or had a BMI <30 kg/m (n=1,676; aHR, 2.64, 95% CI, 1.15 to 6.06), elevated cholesterol (n=1,146; aHR, 2.11; 95% CI, 1.06 to 4.22), high blood pressure (n=1,133; aHR, 2.10; 95% CI, 1.10 to 4.01) and restless sleep (n=1,186; aHR, 2.19; 95% CI, 1.13 to 4.25), but not among women, those with a BMI of ≥30 kg/m and those without elevated cholesterol, high blood pressure or restless sleep.

Conclusions: Skipping meals to lose weight may be a predictive modifiable risk factor for developing T2DM over time, potentially working in connection with other T2DM risk factors.
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http://dx.doi.org/10.1016/j.jcjd.2020.09.009DOI Listing
June 2021

Intestinal microbiology shapes population health impacts of diet and lifestyle risk exposures in Torres Strait Islander communities.

Elife 2020 10 19;9. Epub 2020 Oct 19.

Microbiome and Host Health Programme, South Australian Health and Medical Research Institute, Adelaide, Australia.

Poor diet and lifestyle exposures are implicated in substantial global increases in non-communicable disease burden in low-income, remote, and Indigenous communities. This observational study investigated the contribution of the fecal microbiome to influence host physiology in two Indigenous communities in the Torres Strait Islands: Mer, a remote island where a traditional diet predominates, and Waiben a more accessible island with greater access to takeaway food and alcohol. Counterintuitively, disease markers were more pronounced in Mer residents. However, island-specific differences in disease risk were explained, in part, by microbiome traits. The absence of , for example, significantly (p=0.014) moderated island-specific patterns of systolic blood pressure in multivariate-adjusted models. We also report mediatory relationships between traits of the fecal metagenome, disease markers, and risk exposures. Understanding how intestinal microbiome traits influence response to disease risk exposures is critical for the development of strategies that mitigate the growing burden of cardiometabolic disease in these communities.
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http://dx.doi.org/10.7554/eLife.58407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572126PMC
October 2020

A lipid-related metabolomic pattern of diet quality.

Am J Clin Nutr 2020 12;112(6):1613-1630

Channing Division of Network Medicine Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Background: Adherence to a healthy diet has been associated with reduced risk of chronic diseases. Identifying nutritional biomarkers of diet quality may be complementary to traditional questionnaire-based methods and may provide insights concerning disease mechanisms and prevention.

Objective: To identify metabolites associated with diet quality assessed via the Alternate Healthy Eating Index (AHEI) and its components.

Methods: This cross-sectional study used FFQ data and plasma metabolomic profiles, mostly lipid related, from the Nurses' Health Study (NHS, n = 1460) and Health Professionals Follow-up Study (HPFS, n = 1051). Linear regression models assessed associations of the AHEI and its components with individual metabolites. Canonical correspondence analyses (CCAs) investigated overlapping patterns between AHEI components and metabolites. Principal component analysis (PCA) and explanatory factor analysis were used to consolidate correlated metabolites into uncorrelated factors. We used stepwise multivariable regression to create a metabolomic score that is an indicator of diet quality.

Results: The AHEI was associated with 83 metabolites in the NHS and 96 metabolites in the HPFS after false discovery rate adjustment. Sixty-three of these significant metabolites overlapped between the 2 cohorts. CCA identified "healthy" AHEI components (e.g., nuts, whole grains) and metabolites (n = 27 in the NHS and 33 in the HPFS) and "unhealthy" AHEI components (e.g., red meat, trans fat) and metabolites (n = 56 in the NHS and 63 in the HPFS). PCA-derived factors composed of highly saturated triglycerides, plasmalogens, and acylcarnitines were associated with unhealthy AHEI components while factors composed of highly unsaturated triglycerides were linked to healthy AHEI components. The stepwise regression analysis contributed to a metabolomics score as a predictor of diet quality.

Conclusion: We identified metabolites associated with healthy and unhealthy eating behaviors. The observed associations were largely similar between men and women, suggesting that metabolomics can be a complementary approach to self-reported diet in studies of diet and chronic disease.
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http://dx.doi.org/10.1093/ajcn/nqaa242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727474PMC
December 2020

Association of diet with circulating trimethylamine-N-oxide concentration.

Am J Clin Nutr 2020 12;112(6):1448-1455

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Trimethylamine-N-oxide (TMAO) is a compound that is present in seafood and produced through human gut microbial metabolism of its precursors. Previous studies have suggested that elevated TMAO concentrations are associated with an increased risk of cardiovascular events. However, the association between diet and TMAO concentrations in free-living adult populations has not been adequately described.

Objectives: The objective of this study was to identify dietary predictors of plasma TMAO concentrations.

Methods: TMAO concentrations were assessed in 2 fasting plasma samples collected 6 mo apart among 620 healthy men. Short-term and long-term dietary intakes were assessed during the same time-frame of blood collections via repeated 7-d dietary records (7DDRs) and a semiquantitative food-frequency questionnaire (SFFQ), respectively. We grouped individual food items into 21 groups and regressed against averaged TMAO concentrations. We also assessed the association between dietary scores and TMAO concentrations.

Results: In models adjusted for demographic characteristics and mutually adjusted for food groups, SFFQ-assessments of fish and egg intakes were significantly associated with increased TMAO concentration (β = 0.082; 95% CI: 0.021, 0.14; P = 0.009 for fish; β = 0.065; 95% CI: 0.004, 0.13; P = 0.039 for egg). The positive association between fish consumption and TMAO concentration was replicated in the 7DDR-assessments (β = 0.12; 95% CI: 0.060, 0.18; P < 0.001). There was no association between red meat intake and TMAO concentrations. The unhealthful plant-based diet index (uPDI) was inversely associated (β = -0.013; 95% CI: -0.021, -0.005; P = 0.001) and healthy dietary scores were positively correlated with TMAO concentration.

Conclusions: TMAO concentration was significantly associated with fish intake, but not with red meat consumption. uPDI, an unhealthy dietary pattern, was inversely related to TMAO concentration. As such, this study suggests that in free-living populations, higher circulating concentrations of TMAO cannot simply be interpreted as a marker of unhealthy food intake or an unhealthy dietary pattern.
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http://dx.doi.org/10.1093/ajcn/nqaa225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727477PMC
December 2020

Dietary flavonoids and flavonoid-rich foods: validity and reproducibility of FFQ-derived intake estimates.

Public Health Nutr 2020 12 23;23(18):3295-3303. Epub 2020 Jul 23.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Objective: To evaluate the validity and reproducibility of a 152-item semi-quantitative FFQ (SFFQ) for estimating flavonoid intakes.

Design: Over a 1-year period, participants completed two SFFQ and two weighed 7-d dietary records (7DDR). Flavonoid intakes from the SFFQ were estimated separately using Harvard (SFFQHarvard) and Phenol-Explorer (SFFQPE) food composition databases. 7DDR flavonoid intakes were derived using the Phenol-Explorer database (7DDRPE). Validity was assessed using Spearman's rank correlation coefficients deattenuated for random measurement error (rs), and reproducibility was assessed using rank intraclass correlation coefficients.

Setting: This validation study included primarily participants from two large observational cohort studies.

Participants: Six hundred forty-one men and 724 women.

Results: When compared with two 7DDRPE, the validity of total flavonoid intake assessed by SFFQPE was high for both men and women (rs = 0·77 and rs = 0·74, respectively). The rs for flavonoid subclasses ranged from 0·47 for flavones to 0·78 for anthocyanins in men and from 0·46 for flavonols to 0·77 for anthocyanins in women. We observed similarly moderate (0·4-0·7) to high (≥0·7) validity when using SFFQHarvard estimates, except for flavonesHarvard (rs = 0·25 for men and rs = 0·19 for women). The SFFQ demonstrated high reproducibility for total flavonoid and flavonoid subclass intake estimates when using either food composition database. The intraclass correlation coefficients ranged from 0·69 (flavonolsPE) to 0·80 (proanthocyanidinsPE) in men and from 0·67 (flavonolsPE) to 0·77 (flavan-3-ol monomersHarvard) in women.

Conclusions: SFFQ-derived intakes of total flavonoids and flavonoid subclasses (except for flavones) are valid and reproducible for both men and women.
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http://dx.doi.org/10.1017/S1368980020001627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736217PMC
December 2020

Association between yogurt consumption and plasma soluble CD14 in two prospective cohorts of US adults.

Eur J Nutr 2021 Mar 16;60(2):929-938. Epub 2020 Jun 16.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: Although evidence suggests an inverse association between yogurt consumption and the risk of disorders, such as type 2 diabetes and certain cancers, the mechanisms remain poorly understood. We aimed to examine the association between yogurt consumption and concentrations of plasma soluble CD14, a marker of gut barrier dysfunction.

Methods: We analyzed cross-sectional data from 632 women in the Nurses' Health Study (1989-1990) and 444 men in the Health Professionals Follow-up Study (1993-1994) with soluble CD14 concentrations. We estimated yogurt consumption from food frequency questionnaires. We used multivariable-adjusted linear regression models to estimate the percentage difference (95% CI) of soluble CD14 concentrations by yogurt consumption.

Results: Among men, higher consumption was associated with a lower soluble CD14 concentration (at least 2 cups/week vs. non-consumers; unadjusted % difference: - 7.6%; 95% CI - 13.0%, - 2.1%; P = 0.003). The inverse association was slightly attenuated following multivariable adjustment (% difference: - 5.8%; 95% CI - 11.0%, - 0.1%; P = 0.01). For the same comparison, yogurt consumption was inverse, but not statistically significant associated with soluble CD14 concentration in women (% difference: - 1.2%; 95% CI - 5.6%, 3.5%; P = 0.64). In stratified analyses, the inverse association between yogurt consumption and the concentrations of soluble CD14 was slightly stronger in men who consumed alcohol at least 20 g/day.

Conclusions: Higher yogurt consumption was associated with lower soluble CD14 concentrations, especially in men. Our findings suggest the strengthening of gut barrier function as a plausible mechanism for the observed inverse associations of yogurt consumption with gastrointestinal diseases and disorders involving other systems.
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http://dx.doi.org/10.1007/s00394-020-02303-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738354PMC
March 2021

Airway abundance of predicts response to azithromycin in adults with persistent uncontrolled asthma.

Eur Respir J 2020 10 1;56(4). Epub 2020 Oct 1.

SAHMRI Microbiome Research Laboratory, Flinders University College of Medicine and Public Health, Adelaide, Australia.

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http://dx.doi.org/10.1183/13993003.00194-2020DOI Listing
October 2020

Total bacterial load, inflammation, and structural lung disease in paediatric cystic fibrosis.

J Cyst Fibros 2020 11 19;19(6):923-930. Epub 2020 Mar 19.

SAHMRI Microbiome Research Laboratory, Flinders University College of Medicine and Public Health, Adelaide, SA, Australia; Microbiome and Host Health, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA, Australia.

Background: Cystic fibrosis (CF) is characterised by reduced airway clearance, microbial accumulation, inflammation, and lung function decline. Certain bacterial species may contribute disproportionately to worsening lung disease. However, the relative importance of these microorganisms compared to the absolute abundance of all bacteria is uncertain. We aimed to identify the characteristics of lower airway microbiology that best reflect CF airway inflammation and disease in children.

Methods: Analysis was performed on bronchoalveolar lavage (BAL) fluid from 78 participants of the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial, aged 4.5-5.5 years. Universal bacterial quantitative PCR (qPCR), species-specific qPCR, and 16S rRNA gene sequencing were performed on DNA extracts to determine total bacterial load, species-specific load and taxa relative abundance. Quantification of pre-specified pathogens was performed by culture-based methods. Bacteriological data were related to neutrophil counts, interleukin-8, lung function, and two computed-tomography based measures, CF-CT (as the primary measure) and PRAGMA.

Results: Of all bacteriological measures assessed, total bacterial load determined by qPCR correlated most strongly with structural disease (CF-CT total score, r=0.30, P=0.0095). Specifically, total bacterial load correlated with bronchiectasis, airway wall thickening, mucus plugging and parenchymal disease sub-scores. In contrast, culture-based quantification, microbiota-derived measures, and pathogen-specific qPCR-based quantification were weakly associated with total CF-CT. Regression analyses supported correlation findings, with total bacterial load explaining the greatest variance in total CF-CT (R=0.097, P=0.0061). Correlations with PRAGMA score were comparable to CF-CT total score.

Conclusions: Within the ACFBAL trial, culture-independent quantification of total bacteria provided the most clinically-informative bacteriological measure in 5-year-old CF patients.
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http://dx.doi.org/10.1016/j.jcf.2020.03.008DOI Listing
November 2020

Association Between Sulfur-Metabolizing Bacterial Communities in Stool and Risk of Distal Colorectal Cancer in Men.

Gastroenterology 2020 04 20;158(5):1313-1325. Epub 2020 Jan 20.

Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Electronic address:

Background & Aims: Sulfur-metabolizing microbes, which convert dietary sources of sulfur into genotoxic hydrogen sulfide (HS), have been associated with development of colorectal cancer (CRC). We identified a dietary pattern associated with sulfur-metabolizing bacteria in stool and then investigated its association with risk of incident CRC using data from a large prospective study of men.

Methods: We collected data from 51,529 men enrolled in the Health Professionals Follow-up Study since 1986 to determine the association between sulfur-metabolizing bacteria in stool and risk of CRC over 26 years of follow-up. First, in a subcohort of 307 healthy men, we profiled serial stool metagenomes and metatranscriptomes and assessed diet using semiquantitative food frequency questionnaires to identify food groups associated with 43 bacterial species involved in sulfur metabolism. We used these data to develop a sulfur microbial dietary score. We then used Cox proportional hazards modeling to evaluate adherence to this pattern among eligible individuals (n = 48,246) from 1986 through 2012 with risk for incident CRC.

Results: Foods associated with higher sulfur microbial diet scores included increased consumption of processed meats and low-calorie drinks and lower consumption of vegetables and legumes. Increased sulfur microbial diet scores were associated with risk of distal colon and rectal cancers, after adjusting for other risk factors (multivariable relative risk, highest vs lowest quartile, 1.43; 95% confidence interval 1.14-1.81; P-trend = .002). In contrast, sulfur microbial diet scores were not associated with risk of proximal colon cancer (multivariable relative risk 0.86; 95% CI 0.65-1.14; P-trend = .31).

Conclusions: In an analysis of participants in the Health Professionals Follow-up Study, we found that long-term adherence to a dietary pattern associated with sulfur-metabolizing bacteria in stool was associated with an increased risk of distal CRC. Further studies are needed to determine how sulfur-metabolizing bacteria might contribute to CRC pathogenesis.
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http://dx.doi.org/10.1053/j.gastro.2019.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384232PMC
April 2020

DNA extraction approaches substantially influence the assessment of the human breast milk microbiome.

Sci Rep 2020 01 10;10(1):123. Epub 2020 Jan 10.

South Australian Health and Medical Research Institute, Microbiome & Host Health Programme, Adelaide, South Australia, Australia.

In addition to providing nutritional and bioactive factors necessary for infant development, human breast milk contains bacteria that contribute to the establishment of commensal microbiota in the infant. However, the composition of this bacterial community differs considerably between studies. We hypothesised that bacterial DNA extraction methodology from breast milk samples are a substantial contributor to these inter-study differences. We tested this hypothesis by applying five widely employed methodologies to a mock breast milk sample and four individual human breast milk samples. Significant differences in DNA yield and purity were observed between methods (P < 0.05). Microbiota composition, assessed by 16S rRNA gene amplicon sequencing, also differed significantly with extraction methodology (P < 0.05), including in the contribution of contaminant signal. Concerningly, many of the bacterial taxa identified here as contaminants have been reported as components of the breast milk microbiome in other studies. These findings highlight the importance of using stringent, well-validated, DNA extraction methodologies for analysis of the breast milk microbiome, and exercising caution interpreting microbiota data from low-biomass contexts.
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http://dx.doi.org/10.1038/s41598-019-55568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954186PMC
January 2020

Role of Dietary Flavonoid Compounds in Driving Patterns of Microbial Community Assembly.

mBio 2019 09 24;10(5). Epub 2019 Sep 24.

Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.

Flavonoids are a group of polyphenolic dietary compounds found in many different plant-based foods. There is increasing evidence that higher flavonoid intake may be causally linked to a reduced risk of cardiovascular disease and other chronic diseases. The bioactivity and bioavailability of many dietary flavonoids can be influenced by gastrointestinal microbiome metabolism. However, the role that habitual flavonoid intake plays in shaping the human gut microbiome is poorly understood. We describe an application of an ecosystem-based analytic approach to nutritional, microbiome, and questionnaire data from a cohort of more than 240 generally healthy adult males to assess the role of dietary flavonoid compounds in driving patterns of microbial community assembly. We identified six subclass-specific microbial communities (SMCs) uniquely and independently associated with intakes of the six flavonoid subclasses. was positively associated with intakes of flavonol and flavanone, and was positively associated with intakes of flavonols and flavanol monomers. In contrast, for nearly all flavonoid subclasses, was inversely associated with subclass consumption. Consuming tea at least once per week explained 10.4% of the total variance in assembly of the 20 species comprising the flavanol monomer SMC. The novel methodology employed, necessitated by multidimensional microbiome data that consist of nonindependent features that exhibit a wide range of distributions and mean values, addresses a major challenge in our ability to understand associations of the microbiome in a wide range of clinical and epidemiologic settings. Dietary flavonoids, which have been implicated in lowering chronic disease risk and improving blood pressure, represent a diverse group of polyphenolic compounds found in many commonly consumed foods such as tea, red wine, apples, and berries. The bioactivity and bioavailability of more dietary flavonoids can be influenced by gastrointestinal microbiome metabolism. With demonstrated prebiotic and antimicrobial effects in and in animal models, it is surprising that there are not many human studies investigating the role dietary flavonoids play in shaping the gastrointestinal microbiome. Our analysis revealed patterns of community assembly that uniquely and independently characterize an individual's exposure to various flavonoid compounds. Furthermore, this study confirmed, independent from effects of other dietary and lifestyle factors included in the multivariate-adjusted model, that flavonoid intake is associated with microbial community assembly.
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http://dx.doi.org/10.1128/mBio.01205-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759757PMC
September 2019

Examining the Evidence for an Adult Healthy Middle Ear Microbiome.

mSphere 2019 09 4;4(5). Epub 2019 Sep 4.

Infection and Immunity Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Otitis media (OM) is a cluster of diseases of the middle ear that commonly result from bacterial infection. OM subtypes in which the tympanic membrane is intact (acute otitis media and otitis media with effusion) are presumed to result from pathogen translocation through the eustachian tube. Recent molecular-based studies have suggested that a diverse middle ear microbiome exists in the absence of disease. These have been largely unsupported by culture and feature species that commonly contaminate low-biomass sequencing data. Combining culture-based and molecular techniques, we undertook a detailed investigation of the evidence for bacterial colonization of the healthy middle ear. Middle ear (ME), nasopharynx (NP), and external ear canal (EC) swabs were collected from a total of 25 adult patients undergoing cochlear implant, stapedotomy, or translabyrinthine vestibular schwannoma resection. Diagnostic culture, microscopy, quantitative PCR, and 16S rRNA gene amplicon sequencing were used to assess sample bacterial content. EC and NP microbiota were consistent with previous reports. In contrast, bacterial levels in ME samples were not significantly above those in unused control swabs. Commonly detected taxa were among recognized sequencing contaminants (, , and ). Linear regression of dominant ME taxa confirmed a negative relationship between relative abundance and bacterial load, consistent with contamination. No bacteria were detected by microscopy or diagnostic culture in any middle ear sample. Our findings cast substantial doubt on previous reports identifying a healthy middle ear microbiome using 16S amplicon sequencing. Recent molecular-based studies have suggested that a diverse middle ear microbiome in adults and children can exist in the absence of disease. These studies have been largely unsupported by culture and feature species that commonly contaminate low-biomass sequencing data. While 16S rRNA gene amplicon sequencing has proven to be a highly informative technique in many clinical contexts, it is susceptible to spurious signal arising from sequencing reagent contaminants where sample biomass is low. Combining culture-based and molecular techniques, we undertook a detailed investigation of the evidence for bacterial colonization of the healthy middle ear. In finding no evidence of viable bacterial cells in middle ear samples, our study further underlines the importance of careful consideration of amplicon sequence data derived from very-low-biomass contexts and the value of analytical approaches that combine culture and molecular techniques.
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http://dx.doi.org/10.1128/mSphere.00456-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731531PMC
September 2019

A Network Analysis of Biomarkers for Type 2 Diabetes.

Diabetes 2019 02 8;68(2):281-290. Epub 2018 Nov 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

Numerous studies have investigated individual biomarkers in relation to risk of type 2 diabetes. However, few have considered the interconnectivity of these biomarkers in the etiology of diabetes as well as the potential changes in the biomarker correlation network during diabetes development. We conducted a secondary analysis of 27 plasma biomarkers representing glucose metabolism, inflammation, adipokines, endothelial dysfunction, IGF axis, and iron store plus age and BMI at blood collection from an existing case-control study nested in the Nurses' Health Study (NHS), including 1,303 incident diabetes case subjects and 1,627 healthy women. A correlation network was constructed based on pairwise Spearman correlations of the above factors that were statistically different between case and noncase subjects using permutation tests ( < 0.0005). We further evaluated the network structure separately among diabetes case subjects diagnosed <5, 5-10, and >10 years after blood collection versus noncase subjects. Although pairwise biomarker correlations tended to have similar directions comparing diabetes case subjects to noncase subjects, most correlations were stronger in noncase than in case subjects, with the largest differences observed for the insulin/HbA and leptin/adiponectin correlations. Leptin and soluble leptin receptor were two hubs of the network, with large numbers of different correlations with other biomarkers in case versus noncase subjects. When examining the correlation network by timing of diabetes onset, there were more perturbations in the network for case subjects diagnosed >10 years versus <5 years after blood collection, with consistent differential correlations of insulin and HbA C-peptide was the most highly connected node in the early-stage network, whereas leptin was the hub for mid- or late-stage networks. Our results suggest that perturbations of the diabetes-related biomarker network may occur decades prior to clinical recognition. In addition to the persistent dysregulation between insulin and HbA, our results highlight the central role of the leptin system in diabetes development.
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http://dx.doi.org/10.2337/db18-0892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341308PMC
February 2019

Dietary Gluten Intake and Risk of Microscopic Colitis Among US Women without Celiac Disease: A Prospective Cohort Study.

Am J Gastroenterol 2019 01;114(1):127-134

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Objective: Microscopic colitis is a common cause of chronic watery diarrhea among the elderly. Although the prevalence of celiac disease appears to be higher in patients with microscopic colitis, the relationship between dietary gluten intake and risk of microscopic colitis among individuals without celiac disease has not been explored.

Methods: We conducted a prospective study of 160,744 US women without celiac disease enrolled in the Nurses' Health Study (NHS) and the NHSII. Dietary gluten intake was estimated using validated food frequency questionnaires every 4 years. Microscopic colitis was confirmed through medical records review. We used Cox proportional hazard modeling to estimate the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI).

Results: We documented 219 incident cases of microscopic colitis over more than 20 years of follow-up encompassing 3,716,718 person-years (crude incidence rate: 5.9/100,000 person-years) in NHS and NHSII. Dietary gluten intake was not associated with risk of microscopic colitis (Ptrend = 0.88). Compared to individuals in the lowest quintile of energy-adjusted gluten intake, the adjusted HR of microscopic colitis was 1.18 (95% CI: 0.77-1.78) for the middle quintile and 1.03 (95% CI: 0.67-1.58) for the highest quintile. Additional adjustment for primary dietary sources of gluten including refined and whole grains did not materially alter the effect estimates (All Ptrend ≥ 0.69). The null association did not differ according to lymphocytic or collagenous subtypes (Pheterogeneity = 0.72) and was not modified by age, smoking status, or body mass index (All Pinteraction ≥ 0.17).

Conclusions: Dietary gluten intake during adulthood was not associated with risk of microscopic colitis among women without celiac disease.
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http://dx.doi.org/10.1038/s41395-018-0267-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329641PMC
January 2019

Prospective study of flavonoid intake and risk of primary open-angle glaucoma.

Acta Ophthalmol 2018 Sep 14;96(6):e692-e700. Epub 2018 Mar 14.

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital/Harvard Medical School, Boston, MA, USA.

Purpose: To evaluate the association between flavonoid intake and incident primary open-angle glaucoma (POAG).

Methods: We followed 65 516 women from the Nurses' Health Study (from 1984) and 42 156 men from the Health Professionals Follow-up Study (from 1986) biennially to 2012, who were 40+ years old, free of POAG, and reported eye examinations. Dietary flavonoid intake was assessed with validated repeated semi-quantitative food frequency questionnaires. Incident POAG cases (n = 1575) were confirmed with medical record review. Cohort-specific multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated and meta-analysed.

Results: Total flavonoid intake was not associated with risk of POAG development [RR for highest (Q5: median ~645 mg/day) versus lowest quintile (Q1: ~130 mg/day) = 0.91 (95% CI = 0.77, 1.08); p for trend (p-trend) = 0.19]; the flavonoid subclasses of flavones, flavanones, polymeric flavanols or anthocyanidins were also not associated (Q5 versus Q1 comparison p-values ≥0.05 and p-trend ≥0.09). Higher intakes of flavonols and monomeric flavanols were nominally associated with lower POAG risk, based on the Q5 versus Q1 comparisons or p-trends. The Q5 versus Q1 comparison RRs were: for flavonols, 0.82 (95% CI = 0.69, 0.97; p-trend = 0.05; ~28 versus ~8 mg/day), and for monomeric flavanols, 0.86 (95% CI = 0.72, 1.02; p-trend=0.04; ~110 versus 10 mg/day). The food/beverage that contributed most to both the variation of flavonols and monomeric flavanols was tea; consuming ~2 cups/day was associated with 18% lower POAG risk (RR=0.82; 95% CI = 0.68, 0.99; p-trend = 0.02).

Conclusion: Total flavonoid intake was not associated with POAG risk. Greater intakes of flavonols and monomeric flavanols and of tea showed suggestive modest associations with lower risk; these results need confirmation.
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http://dx.doi.org/10.1111/aos.13705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138582PMC
September 2018

Metatranscriptome of human faecal microbial communities in a cohort of adult men.

Nat Microbiol 2018 03 15;3(3):356-366. Epub 2018 Jan 15.

Biostatistics Department, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

The gut microbiome is intimately related to human health, but it is not yet known which functional activities are driven by specific microorganisms' ecological configurations or transcription. We report a large-scale investigation of 372 human faecal metatranscriptomes and 929 metagenomes from a subset of 308 men in the Health Professionals Follow-Up Study. We identified a metatranscriptomic 'core' universally transcribed over time and across participants, often by different microorganisms. In contrast to the housekeeping functions enriched in this core, a 'variable' metatranscriptome included specialized pathways that were differentially expressed both across participants and among microorganisms. Finally, longitudinal metagenomic profiles allowed ecological interaction network reconstruction, which remained stable over the six-month timespan, as did strain tracking within and between participants. These results provide an initial characterization of human faecal microbial ecology into core, subject-specific, microorganism-specific and temporally variable transcription, and they differentiate metagenomically versus metatranscriptomically informative aspects of the human faecal microbiome.
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http://dx.doi.org/10.1038/s41564-017-0084-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557121PMC
March 2018

Stability of the human faecal microbiome in a cohort of adult men.

Nat Microbiol 2018 03 15;3(3):347-355. Epub 2018 Jan 15.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Characterizing the stability of the gut microbiome is important to exploit it as a therapeutic target and diagnostic biomarker. We metagenomically and metatranscriptomically sequenced the faecal microbiomes of 308 participants in the Health Professionals Follow-Up Study. Participants provided four stool samples-one pair collected 24-72 h apart and a second pair ~6 months later. Within-person taxonomic and functional variation was consistently lower than between-person variation over time. In contrast, metatranscriptomic profiles were comparably variable within and between subjects due to higher within-subject longitudinal variation. Metagenomic instability accounted for ~74% of corresponding metatranscriptomic instability. The rest was probably attributable to sources such as regulation. Among the pathways that were differentially regulated, most were consistently over- or under-transcribed at each time point. Together, these results suggest that a single measurement of the faecal microbiome can provide long-term information regarding organismal composition and functional potential, but repeated or short-term measures may be necessary for dynamic features identified by metatranscriptomics.
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http://dx.doi.org/10.1038/s41564-017-0096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016839PMC
March 2018

Identifying the metabolomic fingerprint of high and low flavonoid consumers.

J Nutr Sci 2017 14;6:e34. Epub 2017 Jul 14.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

High flavonoid consumption can improve vascular health. Exploring flavonoid-metabolome relationships in population-based settings is challenging, as: (i) there are numerous confounders of the flavonoid-metabolome relationship; and (ii) the set of dependent metabolite variables are inter-related, highly variable and multidimensional. The Metabolite Fingerprint Score has been developed as a means of approaching such data. This study aims to compare its performance with that of more traditional methods, in identifying the metabolomic fingerprint of high and low flavonoid consumers. This study did not aim to identify biomarkers of intake, but rather to explore how systemic metabolism differs in high and low flavonoid consumers. Using liquid chromatography-tandem MS, 174 circulating plasma metabolites were profiled in 584 men and women who had complete flavonoid intake assessment. Participants were randomised to one of two datasets: (a) training dataset, to determine the models for the discrimination variables ( 399); and (b) validation dataset, to test the capacity of the variables to differentiate higher from lower total flavonoid consumers ( 185). The stepwise and full canonical variables did not discriminate in the validation dataset. The Metabolite Fingerprint Score successfully identified a unique pattern of metabolites that discriminated high from low flavonoid consumers in the validation dataset in a multivariate-adjusted setting, and provides insight into the relationship of flavonoids with systemic lipid metabolism. Given increasing use of metabolomics data in dietary association studies, and the difficulty in validating findings using untargeted metabolomics, this paper is of timely importance to the field of nutrition. However, further validation studies are required.
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http://dx.doi.org/10.1017/jns.2017.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672306PMC
July 2017

Association of flavonoid-rich foods and flavonoids with risk of all-cause mortality.

Br J Nutr 2017 May 13;117(10):1470-1477. Epub 2017 Jun 13.

1Department of Nutrition,Harvard T. H. Chan School of Public Health,Boston,MA 02115,USA.

Flavonoids are bioactive compounds found in foods such as tea, red wine, fruits and vegetables. Higher intakes of specific flavonoids, and flavonoid-rich foods, have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoid-rich foods, and flavonoids, in preventing all-cause mortality remains uncertain. As such, we examined the association of intake of flavonoid-rich foods and flavonoids with subsequent mortality among 93 145 young and middle-aged women in the Nurses' Health Study II. During 1 838 946 person-years of follow-up, 1808 participants died. When compared with non-consumers, frequent consumers of red wine, tea, peppers, blueberries and strawberries were at reduced risk of all-cause mortality (P<0·05), with the strongest associations observed for red wine and tea; multivariable-adjusted hazard ratios 0·60 (95 % CI 0·49, 0·74) and 0·73 (95 % CI 0·65, 0·83), respectively. Conversely, frequent grapefruit consumers were at increased risk of all-cause mortality, compared with their non-grapefruit consuming counterparts (P<0·05). When compared with those in the lowest consumption quintile, participants in the highest quintile of total-flavonoid intake were at reduced risk of all-cause mortality in the age-adjusted model; 0·81 (95 % CI 0·71, 0·93). However, this association was attenuated following multivariable adjustment; 0·92 (95 % CI 0·80, 1·06). Similar results were observed for consumption of flavan-3-ols, proanthocyanidins and anthocyanins. Flavonols, flavanones and flavones were not associated with all-cause mortality in any model. Despite null associations at the compound level and select foods, higher consumption of red wine, tea, peppers, blueberries and strawberries, was associated with reduced risk of total and cause-specific mortality. These findings support the rationale for making food-based dietary recommendations.
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http://dx.doi.org/10.1017/S0007114517001325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233415PMC
May 2017
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