Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.

Associations between untargeted plasma metabolomic signatures and gut microbiota composition in the Milieu Intérieur population of healthy adults.

Host-microbial co-metabolism products are being increasingly recognised to play important roles in physiological processes. However, studies undertaking a comprehensive approach to consider host-microbial metabolic relationships remain scarce. Metabolomic analysis yielding detailed information regarding metabolites found in a given biological compartment holds promise for such an approach. This work aimed to explore the associations between host plasma metabolomic signatures and gut microbiota composition in healthy adults of the Milieu Intérieur study. For 846 subjects, gut microbiota composition was profiled through sequencing of the 16S rRNA gene in stools. Metabolomic signatures were generated through proton NMR analysis of plasma. The associations between metabolomic variables and α- and ß-diversity indexes and relative taxa abundances were tested using multi-adjusted partial Spearman correlations, permutational ANOVA and multivariate associations with linear models, respectively. A multiple testing correction was applied (Benjamini-Hochberg, 10 % false discovery rate). Microbial richness was negatively associated with lipid-related signals and positively associated with amino acids, choline, creatinine, glucose and citrate (-0·133 ≤ Spearman's ρ ≤ 0·126). Specific associations between metabolomic signals and abundances of taxa were detected (twenty-five at the genus level and nineteen at the species level): notably, numerous associations were observed for creatinine (positively associated with eleven species and negatively associated with Faecalibacterium prausnitzii). This large-scale population-based study highlights metabolites associated with gut microbial features and provides new insights into the understanding of complex host-gut microbiota metabolic relationships. In particular, our results support the implication of a 'gut-kidney axis'. More studies providing a detailed exploration of these complex interactions and their implications for host health are needed.

Public health potential of guidelines-based dietary scores for non-communicable diseases mortality prevention: simulation study using the Preventable Risk Integrated ModEl (PRIME) model.

OBJECTIVE: Dietary indexes measure the adherence of individuals to a set of nutritional recommendations. However, the health gains associated with adherence to various dietary indexes may vary. Our objective was to compare the magnitude of estimated avoided deaths by chronic diseases obtained by improving diet quality in the French population, measured by a variety of dietary indexes. DESIGN: Simulation study based on observational data. SETTING: Weighted data from a French population-based cohort study. PARTICIPANTS: In participants from the NutriNet-Santé cohort, we computed dietary scores reflecting the adherence to various recommendations (Medi-Lite, Healthy Diet Indicator (HDI), Programme National Nutrition Santé/National Nutrition and Health Program - Guidelines Score, Diet Quality Index (DQI), Alternative Healthy Eating Index (AHEI) and the modified Food Standards Agency nutrient profiling system dietary index (FSAm-NPS DI)). Quintiles of the food groups' consumption and dietary intakes were used as input in a simulation model (Preventable Risk Integrated ModEl (PRIME)), yielding the number of delayed or avoided deaths in nutrition-related non-communicable diseases, comparing between very high or very low nutritional quality of the diet and medium nutritional quality. RESULTS: A modification of dietary intakes from medium quality to very low quality (i.e. from the middle quintile to the quintile with the lowest nutritional quality) was associated with an increased number of deaths ranging from 3485 (95 % uncertainty interval (CI) 4002, 2987) for HDI and 3379 (95 % CI 3881, 2894) for FSAm-NPS DI to 838 (95 % CI 1163, 523) for Medi-Lite. Conversely, a modification of dietary intakes from medium quality to very high quality was associated with a decrease in the number of deaths ranging from 1995 (95 % CI 1676, 2299) for Probability of Adequate Nutrient intake diet, 1986 (95 % CI 1565, 2361) for DQI-International, 1931 (95 % CI 1499, 2316) for FSAm-NPS DI and 858 (95 % CI 499, 1205) for HDI. CONCLUSIONS: Our results provide some insights as the potential impact of following various dietary guidelines to reduce mortality from nutrition-related diseases.

Prospective association between ultra-processed food consumption and incident depressive symptoms in the French NutriNet-Santé cohort.

BACKGROUND: Ultra-processed food (UPF) consumption has increased over the last decades in Westernized countries. Our objective was to investigate for the first time the association between the proportion of UPF (%UPF) in the diet and incident depressive symptoms in the NutriNet-Santé cohort. METHODS: The sample included 20,380 women and 6350 men (aged 18-86 years) without depressive symptoms at the first Center for Epidemiologic Studies Depression Scale (CES-D) measurement, using validated cut-offs (CES-D score ≥ 17 for men and ≥ 23 for women). The proportion of UPF in the diet was computed for each subject using the NOVA classification applied to dietary intakes collected by repeated 24-h records (mean = 8; SD = 2.3). The association between UPF and depressive symptoms was evaluated using multivariable Cox proportional hazards models. RESULTS: Over a mean follow-up of 5.4 years, 2221 incident cases of depressive symptoms were identified. After accounting for a wide range of potential confounders, an increased risk of depressive symptoms was observed with an increased %UPF in the diet. In the main model adjusted for sociodemographic characteristics, body mass index, and lifestyle factors, the estimated hazard ratio for a 10% increase in UPF was 1.21 (95% confidence interval = 1.15-1.27). Considering %UPF in food groups, the association was significant only for beverages and sauces or added fats. CONCLUSION: Overall, UPF consumption was positively associated with the risk of incident depressive symptoms, suggesting that accounting for this non-nutritional aspect of the diet could be important for mental health promotion.

The Inflammatory Potential of the Diet is Directly Associated with Incident Depressive Symptoms Among French Adults.

BACKGROUND: Low-grade chronic inflammation has been suggested to play a substantial role in the etiology of depression; however, studies on the prospective association between the inflammatory potential of the diet and depression are limited. OBJECTIVE: The aim of this study was to investigate the association between the inflammatory potential of the diet (measured using the Alternate Dietary Inflammatory Index, ADII) and incident depressive symptoms. We also tested the potential modulating effect of sex, age, BMI, and lifestyle indicators. METHODS: The study sample consisted of 26,730 participants (aged 18-86 y) from the NutriNet-Santé study. Baseline ADII was computed using repeated 24-h dietary records collected during the first 2 y of the follow-up. Incident cases of depressive symptoms were defined by a Center for Epidemiologic Studies Depression scale ≥17 for men and ≥23 for women at least once during follow-up. HR and 95% CI were estimated using multivariable Cox proportional hazards models. RESULTS: A total of 2221 incident cases of depressive symptoms were identified over a mean follow-up of 5.4 y. After accounting for a wide range of potential confounders, the highest quartile of the ADII was associated with a 15% (95% CI: 2, 31) increase in the risk of depressive symptoms compared with the lowest quartile. In the stratified analyses, associations were statistically significant only among women (HRquartile4 vs. quartile1: 1.19; 95% CI: 1.02, 1.37), middle-age adults (HRquartile4 vs. quartile1: 1.16; 95% CI: 1.00, 1.35), and participants with a BMI ≥25 (HRquartile4 vs. quartile1: 1.29; 95% CI: 1.04, 1.60). CONCLUSIONS: Overall, a proinflammatory diet was associated with a higher risk of depressive symptoms, especially among women, middle-age adults, and participants with overweight or obesity. These findings contribute to the increasing scientific evidence showing a detrimental role of the proinflammatory diet. The NutriNet-Santé study is registered at clinicaltrials.gov as NCT03335644.

Mucosal-associated invariant T (MAIT) cells are depleted and prone to apoptosis in cardiometabolic disorders.

The disruption of systemic immune homeostasis is a key mediator in the progression of cardiometabolic diseases (CMDs). We aimed to extend knowledge regarding the clinical relevance of CMD-associated variation of circulating mucosal-associated invariant T (MAIT) cell abundance and to explore underlying cellular mechanisms. We analyzed cross-sectional data from 439 participants of the Metagenomics in Cardiometabolic Diseases (MetaCardis) study, stratified into 6 groups: healthy control subjects and patients with metabolic syndrome (MS), obesity, type 2 diabetes mellitus (T2DM), and coronary artery disease (CAD) without, or with congestive heart failure (CAD-CHF). Blood MAIT cell frequency was significantly decreased in all CMD groups, including early (MS) and later (CAD and CAD-CHF) stages of disease progression. Reduced MAIT cell abundance was associated with increased glycosylated hemoglobin, inflammation markers, and deterioration of cardiac function. Glucose dose dependently promoted MAIT cell apoptosis in vitro, independently of anti-CD3 and cytokine-mediated activation. This outcome suggests the prominence of metabolic over an antigenic or cytokine-rich environment to promote MAIT cell reduction in patients with CMD. In summary, all stages of CMDs are characterized by reduced circulating MAIT cells. Chronically elevated blood glucose levels could contribute to this decline. These data extend the pathologic relevance of MAIT cell loss and suggest that MAIT cell abundance may serve as an indicator of cardiometabolic health.-Touch, S., Assmann, K. E., Aron-Wisnewsky, J., Marquet, F., Rouault, C., Fradet, M., Mosbah, H., MetaCardis Consortium, Isnard, R., Helft, G., Lehuen, A., Poitou, C., Clément, K., André, S. Mucosal-associated invariant T (MAIT) cells are depleted and prone to apoptosis in cardiometabolic disorders.

Association of diet quality and physical activity with healthy ageing in the French NutriNet-Santé cohort.

A growing number of studies have explored overall health during ageing in a holistic manner by investigating multidimensional models of healthy ageing (HA). However, little attention has been given to the role of adherence to national nutrition guidelines in that context. This study aimed to investigate the prospective association between adherence to the French nutrition guidelines and HA. The authors analysed data from 21 407 participants of the NutriNet-Santé study with a median baseline age of 55·6 years (2009-2014) and initially free of major chronic diseases. HA was defined as not developing major chronic disease, no depressive symptoms, no function-limiting pain, independence in instrumental activities of daily living, good physical, cognitive and social functioning, as well as good self-perceived health. Adherence to guidelines of the French Nutrition and Health Programme (Programme National Nutrition Santé or PNNS) was measured via the PNNS Guideline Score (PNNS-GS), using baseline data from repeated 24-h dietary records and physical activity questionnaires. After a median follow-up of 5·7 years, 46·3 % of participants met our HA criteria. Robust-error-variance Poisson regression revealed that higher PNNS-GS scores, reflecting higher adherence to nutrition recommendations (including both diet and physical activity guidelines), were associated with a higher probability to age healthily (relative riskquartile 4 v. quartile 1 = 1·17 (95 % CI 1·12, 1·22)). Supplementary analyses revealed that this association may, to a small part, be mediated by weight status. The results suggest that high adherence to the French national nutrition recommendations may be linked to better overall health throughout ageing.

Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes.

Obesity and its metabolic complications are characterized by subclinical systemic and tissue inflammation. In rodent models of obesity, inflammation and metabolic impairments are linked with intestinal barrier damage. However, whether intestinal permeability is altered in human obesity remains to be investigated. In a cohort of 122 severely obese and non-obese patients, we analyzed intestinal barrier function combining in vivo and ex vivo investigations. We found tight junction impairments in the jejunal epithelium of obese patients, evidenced by a reduction of occludin and tricellulin. Serum levels of zonulin and LPS binding protein, two markers usually associated with intestinal barrier alterations, were also increased in obese patients. Intestinal permeability per se was assessed in vivo by quantification of urinary lactitol/mannitol (L/M) and measured directly ex vivo on jejunal samples in Ussing chambers. In the fasting condition, L/M ratio and jejunal permeability were not significantly different between obese and non-obese patients, but high jejunal permeability to small molecules (0.4 kDa) was associated with systemic inflammation within the obese cohort. Altogether, these results suggest that intestinal barrier function is subtly compromised in obese patients. We thus tested whether this barrier impairment could be exacerbated by dietary lipids. To this end, we challenged jejunal samples with lipid micelles and showed that a single exposure increased permeability to macromolecules (4 kDa). Jejunal permeability after the lipid load was two-fold higher in obese patients compared to non-obese controls and correlated with systemic and intestinal inflammation. Moreover, lipid-induced permeability was an explicative variable of type 2 diabetes. In conclusion, intestinal barrier defects are present in human severe obesity and exacerbated by a lipid challenge. This paves the way to the development of novel therapeutic approaches to modulate intestinal barrier function or personalize nutrition therapy to decrease lipid-induced jejunal leakage in metabolic diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Unsaturated Fatty Acid Intakes During Midlife Are Positively Associated with Later Cognitive Function in Older Adults with Modulating Effects of Antioxidant Supplementation.

Background: Given the drastic demographic changes characterized as "population aging," the disease burden related to dementia is a major public health problem. The scientific literature documenting the link between mono- and polyunsaturated fatty acids (MUFAs, PUFAs) and cognitive function during aging is plentiful, but findings are inconsistent. Objectives: We aimed to evaluate the association between intakes of unsaturated fatty acids at midlife and cognitive performance 13 y later in French adults, and to test for a modulating effect of antioxidant supplementation. Methods: Fatty acid intakes were estimated with the use of repeated 24-h records (1994-1996) among 3362 subjects (mean ± SD age: 65.5 ± 4.6 y) of the SU.VI.MAX (Supplementation with Antioxidant Vitamins and Minerals) study, including an intervention phase (1994-2002) during which participants were randomly assigned to an "antioxidant supplementation" or placebo group. Cognitive performance was assessed at follow-up only (in 2007-2009) via a battery of 6 standardized neuropsychological tests. A global cognitive score was calculated as the sum of T-scores of the 6 tests. Multivariable-adjusted regression analyses were performed to provide regression coefficients and 95% CIs. Results: In multivariable models, total MUFAs, total PUFAs, and n-6 PUFAs (ω-6 PUFAs) were positively associated with overall cognitive functioning. n-3 PUFA (ω-3 PUFA) intakes showed positive associations among supplemented participants only (mean difference Tertile3 versus Tertile1: 1.40; 95% CI: 0.30, 2.51; P-trend = 0.01, P-interaction = 0.01). A detrimental role of arachidonic acid for cognitive functioning was only detected in the placebo group (mean difference Tertile3 versus Tertile1: -1.38; 95% CI: -2.57, -0.18; P-trend = 0.02, P-interaction = 0.07). Conclusion: Whereas higher total MUFA and n-6 PUFA intakes may be generally beneficial for maintaining cognitive health during aging, a higher consumption of n-3 fatty acids may only be beneficial among individuals with an adequate antioxidant status. These findings underline the importance of not only focusing on specific nutrients for dementia prevention, but also considering the complex interaction between consumed nutrients. This trial was registered at clinicaltrials.gov as NCT00272428.

The Inflammatory Potential of the Diet at Midlife Is Associated with Later Healthy Aging in French Adults.

Background: While low-grade chronic inflammation has been suggested as a major modulator of healthy aging (HA), no study has yet investigated the link between the inflammatory potential of the diet and multidimensional concepts of HA. Objective: We aimed to evaluate the association between the inflammatory potential of the diet at midlife, as measured by the Dietary Inflammatory Index (DII), and HA assessed 13 y later. Methods: We analyzed data from 2796 participants in the French Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study aged 45-60 y at baseline (1994-1995) and initially free of diabetes, cardiovascular disease, and cancer. During the trial phase of the study (1994-2002), participants received either a placebo or a daily nutritional dose of antioxidant supplement (120 mg vitamin C, 6 mg ß-carotene, 30 mg vitamin E, 100 µg Se, 20 mg Zn). HA was assessed in 2007-2009, and defined as having no major chronic disease, good physical and cognitive functioning, independence in daily activities, no depressive symptoms, good social health, good overall self-perceived health, and no function-limiting pain. The DII was calculated based on repeated baseline 24-h dietary records. Its association with HA was assessed by robust-error-variance Poisson regression, providing RR estimates. Results: After adjustment for potential confounders, higher DII scores (reflecting a more proinflammatory diet), were associated with a decreased likelihood of HA: RRtertile 3/tertile 1 = 0.85 (95% CI: 0.74, 0.99); P-trend = 0.03. Secondary analyses revealed that this association was only significant among participants who had been in the placebo group during the trial phase: RRtertile 3/tertile 1 = 0.80 (95% CI: 0.64, 1.00); P-trend = 0.04. Conclusions: This study suggests that a proinflammatory diet may lower the probability of overall HA. The SU.VI.MAX trial was registered at www.clinicaltrials.gov as NCT00272428.

Prospective association between adherence to dietary recommendations and incident depressive symptoms in the French NutriNet-Santé cohort.

A posteriori healthier dietary patterns and several nutrients have been associated with lower risks of depression in various studies; however, evidence is lacking with regard to the prospective association between adherence to nutritional recommendations (food-based and nutrient-based recommendations) and incident depression or depressive symptoms. In this study, we investigate such associations in the NutriNet Santé cohort. The study sample included 26 225 participants (aged 18-86 years) who were initially free of depressive symptoms. Adherence to nutritional recommendations was measured by four scores namely modified French Programme National Nutrition Santé-Guideline Score (mPNNS-GS), Alternative Healthy Eating Index-2010 (AHEI-2010), Probability of Adequate Nutrient Intake Dietary Score (PANDiet) and Diet Quality Index-International (DQI-I), using non-consecutive dietary record data during the first 2 years of follow-up (mean number of recording days=8, sd 2). Depressive symptoms were defined by a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥17 for men and ≥23 for women. We used Cox proportional hazards models to estimate hazard ratios and 95 % CI, modelling the dietary scores as standardised continuous variables and as tertiles. Over a mean follow-up of 6 years, we identified 2166 incident cases of depressive symptoms. All dietary scores with the exception of the AHEI-2010 were significantly inversely associated with incident depressive symptoms. In the fully adjusted model, an increase of 1 sd in the mPNNS-GS, PANDiet and DQI-I was, respectively, associated with an 8 % (95 % CI 4, 13), 5 % (95 % CI 1, 9) and 9 % (95 % CI 5, 13) reduction in the risk of depressive symptoms. Overall, these findings suggest that diet in accordance with national or international guidelines could have beneficial effects with regard to mental health.

Prospective association between adherence to the Mediterranean diet and risk of depressive symptoms in the French SU.VI.MAX cohort.

PURPOSE: This study examines whether adherence to the Mediterranean Diet (MD) measured by several dietary indexes was associated with incident depressive symptoms in a large French cohort. METHODS: The study sample consisted of 3523 participants from the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort who had at least three dietary records at baseline during the first 2 years of follow-up (1994-1996), free of depression at the beginning of the study (1996-1997) and available Center for Epidemiologic Studies Depression Scale (CES-D) data at the end of follow-up (2007-2009). The rMED was computed. Incident depressive symptoms were defined by a CES-D score ≥17 for men and ≥23 for women in 2007-2009. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using multivariable logistic regression models. Several sensitivity analyses were performed. RESULTS: In the present study, 172 incident cases of depressive symptoms were identified during the follow-up (mean = 12.6 years). After adjustment for a wide range of potential confounders, adherence to the rMED score (continuous variable) was significantly associated with incident depressive symptoms in men (OR 0.91; 95% CI 0.83-0.99; p = 0.03), but not in women. Use of the Literature-Based Adherence Score to the Mediterranean Diet (LAMD) and the classic MD score (MDS) provide similar findings. CONCLUSIONS: In the current study, higher adherence to the Mediterranean Diet at midlife was associated with a lower risk of incident depressive symptoms, particularly in men, increasing scientific evidence for a beneficial role of Mediterranean Diet on health. Further investigations in particular among women are needed.

The Inflammatory Potential of the Diet Is Associated with Depressive Symptoms in Different Subgroups of the General Population.

Background: Low-grade chronic inflammation, which can be modulated by diet, has been suggested as an important risk factor for depression, but few studies have investigated the association between the inflammatory potential of the diet and depression.Objective: We investigated the prospective association between the inflammatory potential of the diet, measured by the Dietary Inflammatory Index (DII), and incident depressive symptoms and tested the potential modulating effect of sex, age, physical activity, and smoking status.Methods: This study included 3523 participants (aged 35-60 y) from the SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) cohort, who were initially free of depressive symptoms. Baseline DII (1994-1996) was computed by using repeated 24-h dietary records. Incident depressive symptoms were defined by a Center for Epidemiologic Studies-Depression Scale score ≥17 for men and ≥23 for women in 2007-2009. We used multivariable logistic regression models to estimate ORs and 95% CIs, and modeled the DII as a continuous variable and as sex-specific quartiles.Results: A total of 172 cases of incident depressive symptoms were identified over a mean follow-up of 12.6 y. The DII was not associated with incident depressive symptoms in the full sample. In sex-specific models, men with a higher DII had a higher risk of incident depressive symptoms (quartile 4 compared with quartile 1-OR: 2.32; 95% CI: 1.01, 5.35), but the association was only marginally significant (P-trend = 0.06). When analyses were performed across smoking status, current and former smokers with a higher DII had a higher risk of incident depressive symptoms (quartile 4 compared with quartile 1-OR: 2.21; 95% CI: 1.08, 4.52). A positive association was also observed among less physically active participants (quartile 4 compared with quartile 1-OR: 2.07; 95% CI: 1.05, 4.07).Conclusion: The promotion of a healthy diet with anti-inflammatory properties may help to prevent depressive symptoms, particularly among men, smokers, or physically inactive individuals. This trial was registered at clinicaltrials.gov as NCT0027242.

Prospective association between consumption frequency of organic food and body weight change, risk of overweight or obesity: results from the NutriNet-Santé Study.

A lower BMI has been reported among consumers of organic foods, but this relationship has never been examined in a prospective design study. Our aim was to prospectively investigate the association between frequency of organic food consumption and weight change. We analysed data from 62 224 participants of the NutriNet-Santé cohort (78 % women, mean age=45 years) with information on consumption frequency of organic foods, dietary intake and repeated anthropometric data. For sixteen products, participants reported their consumption frequency of labelled organic foods (never, occasionally, most of the time). An organic score (OS) with a maximum of thirty-two points was computed. The associations of the OS (modeled as quartiles (Q)) with change in BMI during follow-up (on average 3·1 years) and with the risk of overweight and obesity were estimated by ANCOVA and multivariable logistic regression. A lower BMI increase was observed across quartiles of the OS (mean difference Q4 v. Q1=-0·16 (95 % CI -0·32, -0·01). An increase in the OS was associated with a lower risk of overweight and obesity (among non-overweight and non-obese participants at inclusion): OR for Q4 v. Q1 were 0·77 (95 % CI 0·68, 0·86) and 0·69 (95 % CI 0·58, 0·82), respectively. Concerning obesity risk, the association was stronger among participants with higher adherence to nutritional guidelines. This study supports a strong protective role of consumption frequency of organic foods with regard to the risk of overweight and obesity that depends on overall dietary quality. Upon confirmation, these results may contribute to fine-tune nutritional guidelines by accounting for farming practices in food production.

Long-term associations between inflammatory dietary scores in relation to long-term C-reactive protein status measured 12 years later: findings from the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) cohort.

Chronic low-grade inflammation has been recognised as a key underlying mechanism for several chronic diseases, including cancer and CVD. Nutrition represents a host of key modifiable factors that influence chronic inflammation. Dietary inflammatory scores were developed to assess the inflammatory potential of the diet and have been associated with inflammatory biomarkers in cross-sectional and short-term longitudinal studies. The objective of this study was to investigate the relationship between the dietary inflammatory index (DII), the alternate dietary inflammatory index (ADII) and long-term C-reactive protein (CRP). We also tested age as an effect modifier of this relationship. Participants were selected in the Supplémentation en Vitamines et Minéraux Antioxydants study, which included subjects aged 45-60 years old for men and 35-60 years old for women in 1994. Participants with ≥3 24-h dietary records at baseline and a CRP measurement at the 12-year follow-up evaluation were included in the present study (n 1980). The relationships between the DII and ADII and elevated CRP (>3 mg/l) were investigated using logistic multivariable regression. All analyses were stratified by age (cut-off at median age=50 years old). The overall associations between DII and ADII and long-term CRP were not statistically significant (P trend across tertiles=0·16 for DII and 0·10 for ADII). A quantitative interaction was found between ADII score and age (P=0·16 for ADII, 0·36 for DII). In stratified analyses the ADII was significantly prospectively associated with CRP only in younger participants: OR tertile 3 v. tertile 1: 1·79 (95 % CI 1·04, 3·07). Pro-inflammatory diets may have long-term effect on CRP only in younger subjects.

Long-term association between the dietary inflammatory index and cognitive functioning: findings from the SU.VI.MAX study.

PURPOSE: Inflammation is a ubiquitous underlying mechanism of the links between diet and cognitive functioning. No study has yet evaluated the overall inflammatory potential of the diet, using the dietary inflammatory index (DII), in relation to cognitive functioning. In a French cohort of middle-aged adults, we evaluated the association between the DII, assessed in midlife, and cognitive performance evaluated 13 years later. METHODS: The DII is a literature-derived dietary index developed to determine the inflammatory potential of diet. The DII was estimated at baseline (1994-1996) among 3080 subjects of the SU.VI.MAX (supplementation with antioxidant vitamins and minerals) cohort. Cognitive performance was assessed in 2007-2009 via a battery of standardized neuropsychological tests. Principal component analysis was performed to extract a summary score of cognitive performance. Multivariable-adjusted linear regression analyses were performed to provide regression coefficients and 95 % confidence intervals (95 % CI). RESULTS: In a multivariate model, a strong inverse association was observed between a higher DII (reflecting a more inflammatory diet) and overall cognitive functioning (mean difference Q4 vs. Q1 = -1.76; 95 % CI = -2.81, -0.72, P for trend =0.002). With regard to specific cognitive domains, similar associations were observed with scores reflecting verbal memory, but not executive functioning. CONCLUSION: This study suggests that a pro-inflammatory diet at midlife might be associated with subsequent lower cognitive functioning. A diet exhibiting anti-inflammatory properties may help to maintain cognitive health during aging. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (number NCT00272428).

Plasma vitamin D status and recurrent depressive symptoms in the French SU.VI.MAX cohort.

PURPOSE: Depression is a major public health issue because it is a common cause of disability worldwide. It has been suggested that an optimal vitamin D status may be related to fewer depressive symptoms, but findings are inconsistent. We aimed to investigate the association between plasma vitamin D at midlife and recurrent depressive symptoms and to test for a modulating effect by overall dietary quality. METHODS: The relationship between plasma 25-hydroxyvitamin D (25(OH)D) and recurrent depressive symptoms was evaluated among 1196 participants of the Supplémentation en Vitamines et Minéraux Antioxydants cohort with available data on the Center for Epidemiologic Studies-Depression Scale (CES-D) at baseline (1996-1997) and follow-up (2007-2009). Recurrent depressive symptoms were defined as a CES-D score ≥16 at baseline and follow-up. Prevalence ratios (PR) and 95 % confidence intervals (95 %-CI) were estimated using extensively adjusted Poisson regression models. Dietary quality was estimated using an index measuring adherence to the French national recommendations. RESULTS: Having 25(OH)D concentrations above 10 ng/mL was related to a lower probability of recurrent depressive symptoms: PR (95 %-CI) = 0.48 (0.33; 0.69); P < 0.0001). When comparing individuals with concentrations < versus ≥20 or < versus ≥30 ng/mL, no significant results were obtained. In contrast, among individuals with low dietary quality, a better vitamin D status was related to a lower probability of recurrent depressive symptoms independently of the applied cutoff. CONCLUSIONS: Plasma vitamin D might have a preventive role against recurrent depressive symptoms, notably among individuals with poor dietary quality. Our findings are relevant for the development of depression prevention programs.

Adherence to dietary guidelines as a protective factor against chronic or recurrent depressive symptoms in the French SU.VI.MAX cohort.

Several studies have suggested that a healthier overall diet was associated with a lower risk of depression, which is one of the main causes of disability worldwide. Our objective was to investigate the prospective association of adherence to dietary guidelines at midlife, measured by the French Programme National Nutrition Santé-Guideline Score (PNNS-GS), with chronic or recurrent depressive symptoms. The association between the PNNS-GS and chronic or recurrent depressive symptoms was evaluated among participants of the French Supplémentation en Vitamines et Minéraux AntioXydants (SU.VI.MAX) cohort with available data on the PNNS-GS at baseline (1994-1996) and on the Center for Epidemiologic Studies-Depression Scale (CES-D) in 1996-1997 and follow-up (2007-2009) (n=3328). Chronic or recurrent depressive symptoms were defined by a CES-D score ≥16 at baseline and follow-up. Odds ratios (OR) and 95%-confidence intervals (95%-CI) were estimated across quartiles (Q) of the PNNS-GS, using logistic regression models. In our study, 10.1% of the participants (n=335) had chronic or recurrent depressive symptoms. After adjustment for potential confounders, the PNNS-GS was inversely associated with chronic or recurrent depressive symptoms: ORQ4 vs. Q1: 0.42 (95%-CI: 0.29, 0.60). Modelling the PNNS-GS as a continuous variable yielded similar results: OR for a 1-point increment in the PNNS-GS: 0.86 (95%-CI: 0.80, 0.92). In conclusion, higher adherence to French dietary guidelines at midlife was associated with a lower rate of chronic or recurrent depressive symptoms, which suggests that these recommendations may be highly relevant, not only to avoid chronic diseases, but also for the overall well-being.