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\u27s 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

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Nutritional prevention of cardiovascular diseases : dietary behaviour and polyphenol intakes

La nutrition est l’un des facteurs environnementaux modifiables pouvant avoir un rôle majeur dans la prévention des maladies cardiovasculaires (MCV). Dans ce cadre, un intérêt croissant a été porté ces dernières décennies aux polyphénols, des composés bioactifs potentiellement protecteurs. L’objectif général du travail de cette thèse était l’étude du lien entre la qualité de l’alimentation et les MCV, à partir des données issues des cohortes françaises SU.VI.MAX et NutriNet-Santé. Le premier objectif était d’étudier l’association prospective entre un score individuel mesurant la qualité globale de l’alimentation (score FSA-NPS DI) et le risque de MCV. Le second objectif était d’étudier les associations entre les apports alimentaires en polyphénols et le risque de MCV ainsi que la variation du statut pondéral, en utilisant la table de composition Phenol-Explorer®. Enfin, le troisième objectif était de comparer les consommations et les comportements alimentaires des participants de l’étude NutriNet-Santé présentant une MCV ou un trouble cardiométabolique à des témoins. Concernant le premier objectif, nos résultats indiquaient que des choix alimentaires de moindre qualité nutritionnelle, comme reflété par un score FSA-NPS DI plus élevé, étaient associés à une augmentation de risque de MCV, en particulier chez les individus en surpoids ou obèses dans la cohorte NutriNet-Santé et les fumeurs et ceux ayant un faible niveau d’activité physique dans la cohorte SU.VI.MAX. Concernant le deuxième objectif, nos résultats indiquaient que les anthocyanines, les catéchines, les flavonols, les dihydrochalcones, les dihydroflavonols, les acides hydroxybenzoiques et les stilbènes étaient associés à une moindre survenue des MCV. Nos résultats indiquaient également qu'un apport plus élevé en polyphénols totaux ainsi qu'un apport plus élevé en flavones, flavanones, proanthocyanidines, lignanes et acides hydroxycinnamiques étaient associés à une moindre augmentation de l’adiposité au cours du suivi. Concernant le troisième objectif, nous avons montré, que les adultes, présentant une maladie cardiovasculaire ou cardio-métabolique avaient des comportements moins favorables pour la santé que des témoins du même âge et sexe. Nous avons ainsi mis en évidence les aspects nutritionnels sur lesquels il serait stratégique d’axer en priorité les efforts de prévention et d’accompagnement des patients afin d’améliorer la prise en charge des maladies cardio-métaboliques et cardiovasculaires après leur diagnostic. En conclusion, les résultats de cette thèse ont contribué à une meilleure compréhension du rôle potentiel des facteurs nutritionnels dans l’étiologie des maladies cardiovasculaires via une approche holistique et plus spécifique pour les polyphénols. Cette thèse offre des pistes de réflexion pour les futures stratégies en prévention primaire, secondaire et tertiaire des maladies cardiovasculaires.Nutrition is one of the modifiable environmental factors that may have a major role in the prevention of cardiovascular diseases (CVD). In this context, in etiological epidemiology, there has been a growing interest in polyphenols – bioactive components that are potentially protective. Hence, the general objective of the work presented in this thesis was to study the link between the quality of the diet and CVD, based on data from the French cohorts SU.VI.MAX and NutriNet-Santé.The first objective was to study the prospective association between an individual score measuring the overall quality of the diet (the FSA-NPS DI) and CVD risk, in the context of a French national primary prevention strategy aiming to apply a coloured front-of-package label (the 5C label). The second objective was to examine the association of dietary intakes of different polyphenols with CVD risk and with weight change, using the Phenol-Explorer® composition table. Finally, the third objective was to compare the food and nutrient consumptions and lifestyle behaviours of NutriNet-Santé participants presenting a CVD or a cardiometabolic disorder with those of ‘control’ participants. Concerning the first objective, our results indicated that the choice of foods of a lower nutritional quality, as reflected by a higher FSA-NPS DI score, was associated with an increase in CVD risk – in particular among overweight or obese participants of the NutriNet-Santé cohort, and among participants of the SU.VI.MAX cohort that were smokers or had a low physical activity level. Concerning the second objective, our results indicated that anthocyanins, catechins, flavonols, dihydrochalcones, dihydroflavonols, hydroxybenzoic acids, other phenolic acids and stilbenes were associated with a lower CVD risk. Our results also indicated that a higher intake of total polyphenols as well as a higher intake of falvones, flavanones, proanthocyanins, lignans and hydroxycinnamic acids was associated with a less pronounced increase in body mass index and waist circumference over 6 years. Concerning the third objective, we have shown that adults presenting a CVD or a cardiometabolic disorder had less beneficial behaviours than control participants of the same age and sex, in terms of physical activity, smoking status, and the consumption of alcohol, fruits and vegetables, whole grain cereals, of meat and particularly of processed meat. In addition, we have observed a lower intake of most polyphenol categories among patients. Our results thus provide indications on the nutritional elements that should be at the centre of secondary and tertiary prevention strategies, so as to improve the treatment of CVD and cardiometabolic dysfunctions once that they are diagnosed.To conclude, this thesis contributes to a better understanding of the role of nutritional factors in the development of CVD, using both holistic and specific (through polyphenols) approaches. These results are of interest for future prevention strategies that aime at reducing the risks of CVD through nutrition

Combination of Healthy Lifestyle Factors on the Risk of Hypertension in a Large Cohort of French Adults

Background: Healthy lifestyle factors are widely recommended for hypertension prevention and control. Nevertheless, little is known about their combined impact on hypertension, in the general population. Our aim was to compute a Healthy Lifestyle Index (HLI) comprising the main non-pharmacological measures usually recommended to improve hypertension prevention: normal weight, regular physical activity, limited alcohol consumption, adoption of a healthy diet; to evaluate their combined impact on hypertension incidence. Methods: We prospectively followed the incidence of hypertension among 80,426 French adults participating in the NutriNet-Santé cohort study. Self-reported dietary, socio-demographic, lifestyle and health data were assessed at baseline and yearly using a dedicated website; the association between HLI and hypertension risk was assessed by multivariable Cox proportional hazards models adjusted for age, sex, family history of hypertension, socio-demographic and lifestyle factors. Hypothetical Population Attributable Risks associated to each factor were estimated. Results: During a median follow-up of 3.5 years (IQR: 1.5-5.3), 2413 incident cases of hypertension were identified. Compared with no or one healthy lifestyle factor, the hazard ratios (HR) for hypertension were 0.76 (95% CI, 0.67-0.85) for two factors, 0.47 (95% CI, 0.42-0.53) for three factors and 0.35 (95% CI, 0.30-0.41) for all healthy lifestyle factors (p-trend <0.0001). Compared with adhering to 0, 1, 2 or 3 healthy lifestyles, adhering to all of them was found associated with a reduction of the hypertension risk of half (HR = 0.55 (95% CI, 0.46-0.65)). Conclusion: Active promotion of healthy lifestyle factors at population level is a key leverage to fight the hypertension epidemic

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-Sante study with a median baseline age of 55 center dot 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 Sante 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 center dot 7 years, 46 center dot 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 risk(quartile 4 v. quartile 1) = 1 center dot 17 (95 % CI 1 center dot 12, 1 center dot 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

Relationship between sensory liking for fat, sweet or salt and cardiometabolic diseases: mediating effects of diet and weight status

Original contribution.International audiencePurpose Previous works have been suggested that individual sensory liking is a predictor of dietary intake and weight status, and may consequently influence development of cardiometabolic diseases (CMDs). We investigated the association between sensory liking for fat-and-salt, fat-and-sweet, sweet or salt and the onset of hypertension, diabetes and cardiovascular diseases (CVDs) over 6 years in adults, and the mediating effects of dietary intake and body mass index (BMI). Methods We examined the CMDs risk among 41,332 (for CVD and diabetes) and 37,936 (for hypertension) French adults (NutriNet-Santé cohort). Liking scores, individual characteristics, diet and anthropometry were assessed at baseline using questionnaires. Health events were collected during 6 years. Associations between sensory liking and CMDs risk, and the mediating effect of diet and BMI, were assessed using Cox proportional hazards models. Results Sensory liking for fat-and-salt was associated with an increased risk of diabetes, hypertension and CVD [hazard ratios (HR) for 1-point increment of the sensory score: HR 1.30 (95% CI 1.18, 1.43), HR 1.08 (1.04, 1.13) and HR 1.10 (1.02, 1.19), respectively]. BMI and dietary intake both explained 93%, 98% and 70%, of the overall variation of liking for fat-and-salt liking in diabetes, hypertension and CVD, respectively. Liking for fat-and-sweet and liking for salt were also associated with an increased risk of diabetes [HR 1.09 (1.01, 1.17) and HR 1.09 (1.01, 1.18), respectively], whereas liking for sweet was associated with a decreased risk [HR 0.76 (0.69, 0.84)]. Conclusions Higher liking for fat-and-salt is significantly associated with CMDs risk, largely explained by dietary intake and BMI. Our findings may help to guide effective targeted measures in prevention

Compliance with Nutritional and Lifestyle Recommendations in 13,000 Patients with a Cardiometabolic Disease from the Nutrinet-Sante Study

International audienceBackground: A healthy diet has been shown to prevent cardiovascular diseases complications. The objective of this study was to assess dietary intakes and compliance with nutritional and lifestyle recommendations in French adults diagnosed with hypertension, diabetes, dyslipidaemia or cardiovascular disease compared with healthy individuals. Methods: Data was collected from 26,570 subjects aged 35 to 70 years (13,285 patients and 13,285 controls matched by sex and age) of the French cohort NutriNet-Sante. Dietary intakes were assessed using three 24-h records. Mean food and nutrient intakes of patients were compared to those of healthy subjects using multivariable mixed logistic and linear regressions. Results: Compared to healthy controls, adults reporting cardiometabolic diseases had lower intakes of sweetened products, higher intakes of fish and seafood and a better compliance with dairy products. However, overall, they reported unhealthier lifestyles and dietary habits. Indeed, they were less often physically active and had similar habits regarding alcohol and tobacco consumption. They also had lower intakes of fruit, higher intakes of meat, processed meat and added fats. It is noteworthy that diabetic subjects tended to show the highest compliance with certain dietary recommendations (vegetables, pulses and whole grain products). Conclusion: Our study brings into focus the fact that some nutritional aspects still need to be improved among individuals with a cardiometabolic disease. We should encourage higher intakes of fruits and vegetables, whole grain products, and lower intakes of meat and sodium, as well as healthy lifestyle (physical activity, no-smoking and limited intake of alcohol) in order to encourage a healthier management after being diagnosed

Compliance with Nutritional and Lifestyle Recommendations in 13,000 Patients with a Cardiometabolic Disease from the Nutrinet-Sante Study

Background: A healthy diet has been shown to prevent cardiovascular diseases complications. The objective of this study was to assess dietary intakes and compliance with nutritional and lifestyle recommendations in French adults diagnosed with hypertension, diabetes, dyslipidaemia or cardiovascular disease compared with healthy individuals. Methods: Data was collected from 26,570 subjects aged 35 to 70 years (13,285 patients and 13,285 controls matched by sex and age) of the French cohort NutriNet-Sante. Dietary intakes were assessed using three 24-h records. Mean food and nutrient intakes of patients were compared to those of healthy subjects using multivariable mixed logistic and linear regressions. Results: Compared to healthy controls, adults reporting cardiometabolic diseases had lower intakes of sweetened products, higher intakes of fish and seafood and a better compliance with dairy products. However, overall, they reported unhealthier lifestyles and dietary habits. Indeed, they were less often physically active and had similar habits regarding alcohol and tobacco consumption. They also had lower intakes of fruit, higher intakes of meat, processed meat and added fats. It is noteworthy that diabetic subjects tended to show the highest compliance with certain dietary recommendations (vegetables, pulses and whole grain products). Conclusion: Our study brings into focus the fact that some nutritional aspects still need to be improved among individuals with a cardiometabolic disease. We should encourage higher intakes of fruits and vegetables, whole grain products, and lower intakes of meat and sodium, as well as healthy lifestyle (physical activity, no-smoking and limited intake of alcohol) in order to encourage a healthier management after being diagnosed

Association between organic food consumption and Metabolic Syndrome: cross-sectional results from the NutriNet-Santé study

Purpose : Metabolic Syndrome (MetS), a multicomponent condition, is a cardiovascular disease predictor. Although exposure to agricultural pesticides has been suggested as a potential contribut or to the rising rates of obesity, type 2 diabetes and other features of metabolic disorders, no studies have focused on the association between consumption of organic food (produced without synthetic pesticides) and MetS. We aimed to investigate the cross-sectional association between organic food consumption and MetS in French adults to determine whether it wou ld be worth conducting further studies, particularly large prospective and randomised trial