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Public dietary guidelines worldwide recommend that dietary saturated fatty acids (SFAs) do not exceed 10% total energy (%TE), and their replacement with unsaturated fatty acids (UFAs) has been shown to help prevent cardiometabolic disease (CMD). However, research on the impact of dietary SFAs on CMD risk mostly relies on indirect evidence either from intervention studies measuring biomarkers of disease risk, such as fasting lipid profiles, or from observational prospective cohort studies with disease outcomes. In addition, emerging research suggests the impact of dietary SFAs on cardiometabolic health might be modulated by novel CMD risk markers identified by omics approaches, differential effects of individual SFAs, and/or specific food matrix effects. In particular, dairy products contribute to 21% of dietary SFAs intakes in UK adults, but their consumption does not seem to be associated with increased CMD risk according to epidemiological studies. In this context, this PhD thesis aimed to (i) investigate the impact of overall and individual dietary SFAs on medium�term CMD risk markers and long-term CMD risk, and (ii) assess the utility of dairy foods, and more particularly dairy fat, for CMD prevention at a population level. I first assessed the plasma lipidome-mediated impact of isoenergetically replacing dietary SFAs with monounsaturated fatty acids (MUFAs) or a mixture of MUFAs and polyunsaturated fatty acids (PUFAs) on CMD risk markers and long-term CMD risk (Chapter 2). To achieve this, joint lipidomics analyses in a subset of n=113 participants from the DIVAS randomised controlled trial (RCT) and a sub-cohort from the EPIC-Potsdam prospective cohort study (specific case-cohorts: n=1,707 and n=775 cases for type 2 diabetes, n=1,886 and n=551 cases for cardiovascular disease [CVD]) were completed. This secondary analysis showed that UFA-rich diets implemented over 16 weeks to reduce dietary SFAs in the DIVAS RCT significantly reduced the plasma concentrations of SFA-containing glycerolipids (i.e. mono-, di-, and triacylglycerols) and sphingolipids which were associated with long-term CVD risk in the EPIC-Potsdam cohort study. In addition, I identified that increased serum concentrations of low�density lipoprotein cholesterol (LDL-C), an established CMD risk marker, were associated with higher plasma levels of glycerolipids containing lauric (12:0) and stearic acids (18:0). The impact of individual SFAs was further assessed at the dietary level by conducting a systematic literature review and meta-analysis of 44 RCTs which substituted individual dietary SFAs with another fatty acid (FA) or a mixture of UFAs (Chapter 3). In quantitative meta-analyses, I observed reductions in LDL-C concentrations after the replacement of palmitic acid (C16:0) with UFAs (-0.36 mmol/L, 95%CI -0.50 to -0.21, I2=96.0%, n=18 RCTs) or oleic acid (C18:1) (-0.16 mmol/L, 95% CI -0.28 to -0.03, I2=89.6%, n=9 RCTs), with a similar impact on total cholesterol and apolipoprotein B concentrations. Furthermore, I identified important research gaps regarding the impact of individual dietary SFAs on novel CMD risk markers (e.g. markers of inflammation, endothelial activation, and glycaemic control) and the specific effect of short-chain SFAs, lauric acid (12:0), and myristic acid (14:0). To assess the practical applications of reducing dietary SFAs in free-living UK adults, we developed a food-based dietary fat exchange model (the RISSCI-1 study), which aimed to replace dietary SFAs with UFAs by replacing high-fat dairy and high-SFA snacks with commercially available lower-fat dairy foods along with high-UFA cooking oil and snacks into the habitual diets of n=109 UK adult men for 4 weeks (Chapter 4). Participants successfully exchanged 10.4%TE of dietary SFAs with 9.7%TE UFAs, with minimal impact on other nutrients. In addition, participants incorporated the intervention food items without changing their overall dietary habits. Importantly, the analysis of plasma phospholipid fatty acids (PL FAs) in the RISSCI-1 study, along with those performed in the SATgen, DIVAS, and RESET dietary fat intervention studies (Chapter 5), revealed contrasted results on the validity of individual plasma PL FAs as proxies for dairy consumption. In particular, circulating odd-chain SFAs and ruminant trans FAs have been commonly use as biomarkers of intakes in epidemiological studies so far, but only modestly correlate with overall dairy intakes in RCTs and do not seem to accurately capture the intakes of low-fat dairy foods (Chapter 1). Finally, a prospective analysis of the NutriNet-Santé cohort study did not reveal statistically significant associations between overall and specific dairy consumption and overall CVD (n=1,952 cases) or coronary heart disease risk (n=1,219 cases) among n=104,805 French adults (Chapter 6). However, we observed a 19% reduction (HR=0.81, 95%CI 0.66 to 0.98, p-trend=0.01) in cerebrovascular disease risk (n=878 cases) associated with higher intakes (i.e. at least 160 g/d) of fermented dairy foods (i.e. yogurt, cheese, and fermented milk) compared to low intakes (i.e. below 57 g/d). Despite being observational, these results generated new hypotheses on the potential beneficial effects of specific dairy food matrices on CMD risk, which may stem from bioactive peptides, calcium, and the fermentation process. Overall, results from this PhD thesis concur with current dietary guidelines on the reduction of dietary SFAs in favour of UFAs and suggest that their deleterious impact on CMD risk may be modulated by their individual structure and/or their effect on the plasma lipidome. Moreover, these findings provide further evidence supporting the presence of beneficial compounds within the dairy food matrix, which may counterbalance the potential deleterious effects of their SFA content. Nonetheless, further interventional and observational studies are warranted to validate these conclusions, and future research is needed to elucidate the physiological mechanisms underlying the complex interactions between dietary SFAs, the dairy food matrix, and the physiological response to dairy consumption.

Little is known of the impact of individual saturated fatty acids (SFAs) and their isoenergetic substitution with other SFAs or unsaturated fatty acids (UFAs) on the prevention of cardiometabolic disease (CMD). This systematic literature review (POSPERO registration: CRD42020084241) assessed the impact of such dietary substitutions on a range of fasting CMD risk markers, including lipid profile, markers of glycemic control and inflammation, and metabolic hormone concentrations. Eligible randomized controlled trials (RCTs) investigated the effect of isoenergetic replacements of individual dietary SFAs for at least 14 days on one or more CMD risk markers in humans. Searches of PubMed, Embase, Scopus and Cochrane CENTRAL databases on 14th February 2021 identified 44 RCTs conducted in participants aged 39.9y (SD 15.2). Studies’ risk of bias was assessed using the Cochrane Risk of Bias tool 2.0 for RCTs. Random-effect meta-analyses assessed the effect of at least three similar dietary substitutions on the same CMD risk marker. Other dietary interventions were described in qualitative syntheses. We observed reductions in low-density lipoprotein cholesterol concentrations after the replacement of palmitic acid (C16:0) with UFA (-0.36 mmol/L, 95%CI [-0.50, -0.21], I2 = 96.0%, n = 18 RCTs) or oleic acid (C18:1) (-0.16 mmol/L, 95% CI [-0.28, -0.03], I2 = 89.6%, n = 9 RCTs), with a similar impact on total cholesterol and apolipoprotein B concentrations. No effects on other CMD risk markers, including high-density lipoprotein cholesterol, triacylglycerol, glucose, insulin, or C-reactive protein concentrations, were evident. Similarly, we found no evidence of a benefit from replacing dietary stearic acid with UFA on CMD risk markers (n = 4 RCTs). In conclusion, the impact of replacing dietary palmitic acid with UFA on lipid biomarkers is aligned with current public health recommendations. However, due to the high heterogeneity and limited studies, relationships between all individual SFAs and biomarkers of cardiometabolic health need further confirmation from RCTs.

National audience; Contexte et objectifs : L’Agence Internationale pour la Recherche sur le Cancer (IARC) a classé la viande rouge et la charcuterie comme cancérigènes probables pour des humains. À l’inverse, divers produits végétaux (fruits, légumes, fibres alimentaires) sont associés à une diminution du risque de cancers avec des niveaux de preuve convaincants. Un score reflétant une alimentation plus riche en produits végétaux et moins riche en produits animaux a récemment été développé et a été associé à une diminution de la mortalité globale chez des sujets à risque cardiovasculaire. Cependant, à notre connaissance, l’association entre ce score et le risque de cancers n’a jamais été explorée. L’objectif de ce travail était d’étudier les associations entre ce score « pro-végétal » et le risque de cancers. Méthodes : Cette étude prospective a inclus 42 544 hommes et femmes, âgés de 45 ans et plus, issus de la cohorte NutriNet-Santé (2009-2016), qui ont complété au moins 3 enregistrements alimentaires de 24h pendant la première année de suivi. Le risque de développer un premier cancer a été estimé par un modèle de Cox multivariable par tertile sexe-spécifique du score « pro-végétal ». Résultats : 1 591 premiers cas de cancers incidents ont été diagnostiqués au cours du suivi, parmi lesquels 487 cas de cancers du sein, 243 cas de cancers de la prostate, 198 cas de cancers digestifs et 68 cas de cancers du poumon. Un score « pro-végétal » plus élevé était associé à une diminution du risque de cancers au global (RRt3vs.t1=0,85; IC 95 % 0,76, 0,97; ptendance=0,01), de cancers digestifs (RRt3vs.t1=0,68; IC 95 % 0,47; 0,99; ptendance =0,04) et de cancers du poumon (RRt3vs.t1=0,47; IC 95 % 0,25, 0,90; ptendance =0,02). Conclusions et perspectives : Cette étude suggère qu’un régime alimentaire plus riche en produits végétaux et moins riche en produits animaux contribuerait à la prévention des cancers.

National audience