The human gut microbiota contributes to type-2 diabetes non-resolution 5-years after Roux-en-Y gastric bypass.

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.

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.

Senescence-associated ß-galactosidase in subcutaneous adipose tissue associates with altered glycaemic status and truncal fat in severe obesity.

AIM/HYPOTHESIS: Altered adipose tissue secretory profile contributes to insulin resistance and type 2 diabetes in obesity. Preclinical studies have identified senescent cells as a cellular source of proinflammatory factors in adipose tissue of obese mice. In humans, potential links with obesity comorbidities are poorly defined. Here, we investigated adipose tissue senescent status and relationships with metabolic complications in human obesity. METHODS: The study includes a prospective cohort of 227 individuals with severe obesity. A photometric method was used to quantify senescence-associated ß-galactosidase (SA-ß-gal) activity in paired subcutaneous and omental adipose tissue biopsies obtained during gastric surgery. Gene and secretory profiling was performed in adipose tissue biopsies and in human primary pre-adipocytes in the presence or absence of senolytic drugs targeting senescent cells. Participants were phenotyped for anthropometric and bioclinical variables, metabolic complications and gastric surgery-induced improvement to address relationships with adipose tissue SA-ß-gal. RESULTS: SA-ß-gal activity was sevenfold higher in subcutaneous than in omental adipose tissue and not associated with BMI or chronological age. Several factors, including insulin-like growth factor binding protein 3 (IGFBP3), plasminogen activator inhibitor 1 (PAI1), C-C motif chemokine ligand 2 (CCL2) and IL-6, were upregulated in subcutaneous adipose tissue in relation with SA-ß-gal (p for linear trend across tertiles <0.05) and in pre-adipocytes cultured with inflammatory macrophage conditioned media. Senolytic treatment reduced SA-ß-gal staining and normalised these alterations. In the whole population, subcutaneous adipose tissue SA-ß-gal activity was positively associated with serum leptin, markers of insulin resistance and increased trunk fat mass. Metabolic complications, including type 2 diabetes and dyslipidaemia, were more prevalent in patients with high levels of SA-ß-gal, but improved with bariatric surgery whatever the initial adipose tissue senescent status. CONCLUSIONS/INTERPRETATION: This study highlights a phenotype of senescence in adipose tissue of severely obese individuals, which characterises prominently subcutaneous fat depots. Subcutaneous adipose tissue senescence is significantly linked to altered glucose metabolism and body fat distribution. Elimination of senescent cells through senolytic treatment could alleviate metabolic complications in severely obese people. Graphical abstract.

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.

Prospective Association between Total and Specific Dietary Polyphenol Intakes and Cardiovascular Disease Risk in the Nutrinet-Santé French Cohort.

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, HRT3vs.T1 = 0.66 (0.52⁻0.83), ptrend = 0.0003; catechins: HRfor a 1-point increment of 10 mg/day = 0.98 (0.96⁻0.99), p = 0.02, HRT3vs.T1 = 0.74 (0.60⁻0.91), ptrend = 0.004; flavonols: HRfor a 1-point increment of 10 mg/day = 0.94 (0.90⁻0.99), p = 0.02, HRT3vs.T1 = 0.75 (0.61⁻0.94), ptrend = 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.

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 contributor 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 would be worth conducting further studies, particularly large prospective and randomised trials. METHODS: A total of 8174 participants from the NutriNet-Santé study who attended a clinical visit and completed an organic food frequency questionnaire were included in this cross-sectional analysis. We evaluated the association between the proportion of organic food in the diet (overall and by food group) and MetS using Poisson regression models while adjusting for potential confounders. RESULTS: Higher organic food consumption was negatively associated with the prevalence of MetS: adjusted prevalence ratio was 0.69 (95% CI 0.61, 0.78) when comparing the third tertile of proportion of organic food in the diet with the first one (p value <0.0001). Higher consumption of organic plant-based foods was also related to a lower probability of having MetS. In addition, when stratifying by lifestyle factors (nutritional quality of the diet, smoking status, and physical activity), a significant negative association was detected in each subgroup (p values <0.05), except among smokers. CONCLUSIONS: Our results showed that a higher organic food consumption was associated with a lower probability of having MetS. Additional prospective studies and randomised trials are required to ascertain the relationship between organic food consumption and metabolic disorders.

Are self-reported unhealthy food choices associated with an increased risk of breast cancer? Prospective cohort study using the British Food Standards Agency nutrient profiling system.

OBJECTIVES: French authorities are considering the implementation of a simplified nutrition labelling system on food products to help consumers make healthier food choices. One of the most documented candidates (Five-Colour Nutrition Label/Nutri-score) is based on the British Food Standards Agency Nutrient Profiling System (FSA-NPS), a score calculated for each food/beverage using the 100 g amount of energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits and vegetables. To assess its potential public health relevance, studies were conducted on the association between the nutritional quality of the diet, measured at the individual level by an energy-weighted mean of all FSA-NPS scores of foods usually consumed (FSA-NPS dietary index (FSA-NPS DI)), and the risk of chronic diseases. The present study aimed at investigating the relationship between the FSA-NPS DI and breast cancer risk. DESIGN: Prospective study. SETTING: Population based, NutriNet-Santé cohort, France. PARTICIPANTS: 46 864 women aged ≥35 years who completed ≥3 24-hour dietary records during their first 2 year of follow-up. PRIMARY OUTCOME MEASURE: Associations between FSA-NPS DI and breast cancer risk (555 incident breast cancers diagnosed between 2009 and 2015) were characterised by multivariable-adjusted Cox proportional hazard models. RESULTS: A higher FSA-NPS DI (lower nutritional quality of the diet) was associated with an increased breast cancer risk (HR1-point increment=1.06 (1.02-1.11), p=0.005; HRQ5vs.Q1=1.52 (1.11-2.08), p trend=0.002). Similar trends were observed in premenopausal and postmenopausal women (HR1-point increment=1.09 (1.01-1.18) and 1.05 (1.00-1.11), respectively).This study was based on an observational cohort using self-reported dietary data, thus residual confounding cannot be entirely ruled out. Finally, this holistic approach does not allow investigating which factors in the diet most specifically influence breast cancer risk. CONCLUSIONS: These results suggested that unhealthy food choices, as characterised by the FSA-NPS, may be associated with an increase in breast cancer risk, supporting the potential public health relevance of using this profiling system in the framework of public health nutritional measures.

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

Prospective association between a dietary quality index based on a nutrient profiling system and cardiovascular disease risk.

BACKGROUND: Public health strategies are essential to guide consumers' choices and produce a substantial population impact on cardiovascular disease risk prevention through nutrition. Our aim was to investigate the prospective association between the Food Standards Agency nutrient profiling system dietary index (FSA-NPS DI) and cardiovascular disease risk. The FSA-NPS has been proposed to serve as a basis for a five-colour nutrition label suggested in France to be put on the front of pack of food products. METHODS AND RESULTS: A total of 6515 participants to the SU.VI.MAX cohort (1994-2007), who completed at least six 24-hour dietary records during the first two years of the study, were followed for a median of 12.4 years (25th-75th percentiles: 11.0-12.6). Multivariable Cox proportional hazards models were used to characterise the associations between FSA-NPS DI (continuous and sex-specific quartiles) and the incidence of cardiovascular diseases. Interactions with individual characteristics were tested; 181 major cardiovascular events were reported (59 myocardial infarctions, 43 strokes, 79 anginas). A higher FSA-NPS DI, characterising poorer food choices, was associated with an overall increase in cardiovascular disease risk (HRfor a 1-point increment = 1.14 (1.03-1.27); HRQ4vs.Q1 = 1.61 (1.05-2.47), Ptrend Q4-Q1 = 0.03). This association tended to be stronger in smokers (HRfor a 1-point increment = 1.39 (1.11-1.73); Pinteraction = 0.01) and those less physically active (HRfor a 1-point increment = 1.26 (1.08-1.46); Pinteraction = 0.04). CONCLUSIONS: Our results suggest that poorer food choices, as reflected by a higher FSA-NPS DI, may be associated with a significant increase in cardiovascular risk, especially in at-risk individuals (smokers and physically inactive persons). This score could be a useful tool for public health prevention strategies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00272428.