Solia Adriouch

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.

The intestinal microbiota plays a pivotal role in regulating metabolic processes, and its imbalance is linked to metabolic disorders. Modulating the gut microbiota composition and function through prebiotic supplementation has been repeatedly shown to improve host metabolism. While most studies have focused on the fecal microbiota due to the ease of sampling, fecal samples do not reflect the microbial dynamics throughout the gastrointestinal tract, as regional environmental conditions shape distinct microbiota composition. Given the metabolic significance of the proximal intestine and the potential influence of microbiota on these processes, we characterized the microbiota composition along the gastrointestinal tract in a widely used model for studying host-microbiota interactions: C57Bl6J male mice fed a high-fat diet (HFD) with or without prebiotics supplementation (FOS, fructooligosaccharides). The microbiota composition, determined by long-read Nanopore sequencing, was markedly altered by HFD and FOS supplementation not only in feces but also in the jejunum, ileum and caecum. In contrast to previous observations made in humans, obesity in mice was associated with a decrease in microbiome diversity in the small intestine, highlighting species-specific microbial responses to metabolic challenges. Additionally, the pronounced bifidogenic effect of FOS supplementation in the ileum suggests FOS fermentation in the small intestine in mice, contrary to what has been previously described in humans. Finally, we report a relative homogeneity of microbiome composition along the digestive tract, possibly due to the coprophagic behavior of mice. These findings challenge the translational relevance of rodent models for studying the role of the small intestinal microbiota in human metabolic disease.

The intestinal microbiota is increasingly recognized as a crucial player in the development and maintenance of various chronic conditions, including obesity and associated metabolic diseases. While most research focuses on the fecal microbiota due to its easier accessibility, the small intestine, as a major site for nutrient sensing and absorption, warrants further investigation to determine its microbiota composition and functions. Here, we conducted a clinical research project in 30 age- and sex-matched participants with (n = 15) and without (n = 15) obesity. Duodenojejunal fluid was obtained by aspiration during endoscopy. Phenotyping included clinical variables related to metabolic status, lifestyle, and psychosocial factors using validated questionnaires. We performed metagenomic analyses of the oral, duodenojejunal, and fecal microbiome, alongside metabolomic data from duodenojejunal fluid and feces, integrating these data with clinical and lifestyle information. Our results highlight significant associations between duodenojejunal microbiota composition and usual dietary intake, as well as clinical phenotypes, with larger effect sizes than the associations between these variables and fecal microbiota. Notably, we found that the duodenojejunal microbiota of patients with obesity exhibited higher diversity and showed distinct differences in the abundance of several duodenojejunal microbiota species compared with individuals without obesity. Our findings support the relevance of studying the role of the small intestinal microbiota in the pathogenesis of nutrition-related diseases.

Individual lifestyle factors moderately impact the gut microbiome and host biology. This study explores whether their combined influence significantly alters the gut microbiome and determines the mediating role of the gut microbiome in the links between lifestyle and phenomes. Analyzing 1,643 individuals from the Metacardis European study, we created a non-exhaustive composite lifestyle score (QASD score) incorporating diet quality and diversity, physical activity and smoking. This score shows higher explanatory power for microbiome composition variation compared to individual lifestyle variables. It positively associates with microbiome gene richness, butyrate-producing bacteria, and serum metabolites like Hippurate linked metabolic health. It inversely associates with Clostridium bolteae and Ruminococcus gnavus, serum branched-chain amino acids and dipeptides observed in chronic diseases. Causal inference analyses found 135 cases where the microbiome mediates >20% of QASD score effects on host metabolome. Microbiome gene richness also emerged as a strong mediator in the QASD score’s impact on markers of host glucose metabolism (27.3% of the effect on HOMA- IR), despite bidirectional associations between the microbiome and clinical phenotypes. This study emphasizes the importance of combining lifestyle factors to understand their collective contribution to the gut microbiota and the mediating effects of the gut microbiome on the impact of lifestyle on host metabolic phenotypes and metabolomic profiles.

Roux-en-Y gastric bypass (RYGB) is efficient at inducing drastic albeit variable weight loss and type-2 diabetes (T2D) improvements in patients with severe obesity and T2D. We hypothesized a causal implication of the gut microbiota (GM) in these metabolic benefits, as RYGB is known to deeply impact its composition. In a cohort of 100 patients with baseline T2D who underwent RYGB and were followed for 5-years, we used a hierarchical clustering approach to stratify subjects based on the severity of their T2D (Severe vs Mild) throughout the follow-up. We identified via nanopore-based GM sequencing that the more severe cases of unresolved T2D were associated with a major increase of the class Bacteroidia, including 12 species comprising Phocaeicola dorei, Bacteroides fragilis, and Bacteroides caecimuris. A key observation is that patients who underwent major metabolic improvements do not harbor this enrichment in Bacteroidia, as those who presented mild cases of T2D at all times. In a separate group of 36 patients with similar baseline clinical characteristics and preoperative GM sequencing, we showed that this increase in Bacteroidia was already present at baseline in the most severe cases of T2D. To explore the causal relationship linking this enrichment in Bacteroidia and metabolic alterations, we selected 13 patients across T2D severity clusters at 5-years and performed fecal matter transplants in mice. Our results show that 14 weeks after the transplantations, mice colonized with the GM of Severe donors have impaired glucose tolerance and insulin sensitivity as compared to Mild-recipients, all in the absence of any difference in body weight and composition. GM sequencing of the recipient animals revealed that the hallmark T2D-severity associated bacterial features were transferred and were associated with the animals’ metabolic alterations. Therefore, our results further establish the GM as a key contributor to long-term glucose metabolism improvements (or lack thereof) after RYGB.

Background: Protein intake has been associated with the development of pre-diabetes (pre-T2D) and type 2 diabetes (T2D). The gut microbiota has the capacity to produce harmful metabolites derived from dietary protein. Furthermore, both the gut microbiota composition and metabolic status (e.g., insulin resistance) can be modulated by diet and ethnicity. However, to date most studies have predominantly focused on carbohydrate and fiber intake with regards to metabolic status and gut microbiota composition. Objectives: To determine the associations between dietary protein intake, gut microbiota composition, and metabolic status in different ethnicities. Methods: Separate cross-sectional analysis of two European cohorts (MetaCardis, n = 1759; HELIUS, n = 1528) including controls, patients with pre-T2D, and patients with T2D of Caucasian/non-Caucasian origin with nutritional data obtained from Food Frequency Questionnaires and gut microbiota composition. Results: In both cohorts, animal (but not plant) protein intake was associated with pre-T2D status and T2D status after adjustment for confounders. There was no significant association between protein intake (total, animal, or plant) with either gut microbiota alpha diversity or beta diversity, regardless of ethnicity. At the species level, we identified taxonomical signatures associated with animal protein intake that overlapped in both cohorts with different abundances according to metabolic status and ethnicity. Conclusions: Animal protein intake is associated with pre-T2D and T2D status but not with gut microbiota beta or alpha diversity, regardless of ethnicity. Gut microbial taxonomical signatures were identified, which could function as potential modulators in the association between dietary protein intake and metabolic status.

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.

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 risk_{quartile 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.

Background: Epidemiological and experimental evidence support a protective effect of dietary polyphenols on chronic diseases, but high quality longitudinal data are needed, including details on categories of polyphenols. Our objective was to investigate the prospective association between total and individual classes and subclasses of dietary polyphenols and the risk of major cardiovascular disease in the NutriNet-Santé cohort. Methods: A total of 84,158 participants, who completed at least three 24 h dietary records, were included between May 2009 and June 2017. Individual polyphenols intakes were obtained by matching food consumption data from the 24 h dietary records with the Phenol-Explorer polyphenol composition database. Multivariable Cox proportional hazards models were used to characterize the associations between dietary polyphenols and the incidence of cardiovascular diseases, comparing tertile T3 vs. T1 of classes and subclasses of polyphenols. Results: Over a median of 4.9 years of follow-up, 602 major cardiovascular events were diagnosed. Intakes of anthocyanins, catechins, and flavonols were strongly inversely associated with cardiovascular disease risk (anthocyanins: Hazard Ratio (HR)_{for a 1-point increment of 10 mg/day} = 0.98 (0.96–0.99, p = 0.03, HR_T3vs.T1 = 0.66 (0.52–0.83), p_trend = 0.0003; catechins: HR_{for a 1-point increment of 10 mg/day} = 0.98 (0.96–0.99), p = 0.02, HR_T3vs.T1 = 0.74 (0.60–0.91), p_trend = 0.004; flavonols: HR_{for a 1-point increment of 10 mg/day} = 0.94 (0.90–0.99), p = 0.02, HR_T3vs.T1 = 0.75 (0.61–0.94), p_trend = 0.006). Intakes of dihydrochalcones, proanthocyaninidins, dihydroflavonols, hydroxybenzoic acids, and stilbenes were also associated with a decrease (13%, 19%, 24%, 24%, and 27%, respectively) in cardiovascular disease risk, when comparing tertile T3 to T1. Conclusions: Higher intakes of polyphenols, especially of anthocyanins, catechins, and flavonols, were associated with a statistically significant decreased cardiovascular disease risk.

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-Santé. 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.