CD Dynamique nutritionnelle, signatures épigénétiques et microbiote intestinal : Anatomie d'un carrefour de la programmation fœtale de l'obésité pédiatrique

école doctorale

équipe

contexte

Over the last 40 years, there has been a dramatic worldwide increase in obesity, including in children. Obesity is a risk factor for noncommunicable diseases, including metabolic syndrome, type 2 diabetes, non-alcoholic steatohepatitis (NASH), and cardiovascular disease. These diseases are thought to be caused by overconsumption of calories, an unhealthy “Western” diet high in sugar and fat and low in fiber, and a sedentary lifestyle. However, recent evidence also suggests that early factors in life, including low birth weight, vitamin deficiency in mothers during pregnancy, and maternal over-and undernutrition predispose infants to obesity and metabolic syndrome later in life. This is referred to as Developmental origins of chronic health and disease (DOHAD), also called fetal programming, and has been linked to multiple mechanisms, including nutrition-induced changes in epigenetic regulation of gene expression in early life. Fetal programming related to deficiency in methyl donors (vitamin B12 and folate) has been proposed to predispose children to obesity and metabolic syndrome. Epigenetics describes reversible and inheritable genetic modifications that do not change the DNA sequence, namely chromatin structure changes, nucleosome repositioning, DNA methylation, and histone modification. Enzymes carrying out or reversing epigenetic modifications include DNA methyltransferases, histone acetyltransferases and deacetylases, histone methyltransferases and demethylases, lysine acetyltransferases, and lysine demethylases. The sum of epigenetic modifications within a cell is called the epigenome. Through epigenetic mechanisms, gene expression is regulated; hence, they play an essential role in cell differentiation and adaptation to environmental changes, such as the availability of nutrients and chemical exposures. Epigenetic modifications are strongly linked to one-carbon metabolism, in which the universal methyl group donor N-acetyl-S-methionine (SAM), the B-vitamins folate (B9) and cobalamin (B12), and the amino acid methionine play a central role. SAM is produced in the methionine cycle in which its precursor methionine is synthesized by methionine synthase (encoded by MTR) using methylfolate as co-substrate and B12 as co-factor. Deficiency in methyl donors such as folate during pregnancy can result in liver and heart steatosis and neural defects in offspring. Similar effects are produced by silencing of methionine synthase. Hence, varying cellular levels of one-carbon metabolites and their substrates (e.g., carbohydrates) affect the regulation state of genes. DNA regulation is also mediated by the histone deacetylase sirtuin 1 (SIRT1). SIRT1 is crucial in regulating energy metabolism, inflammation, cell stress, and insulin secretion. SIRT1 is protective against metabolic syndrome and insulin resistance and is downregulated in patients with metabolic syndrome and obesity. Both overnutrition and deficiency in methyl donors (B12 and folate) and inherited disorders of cobalamin (B12) metabolism (IECM) are associated with a decrease in SIRT1, in a rat model of foetal progamming produced by the deficiency in methyl donors. The decreased expression and activity of Sirt1 is also associated with the neurological and cardiovascular outcomes in mice with selective gene silencing of Mtr in brain and myocardium. They are reversed by Sirt1 agonists. Interestingly, the rodent KO or nutritional models of fetal programming develop outcomes of metabolic syndrome during aging through epigenomic mechanisms. Epigenome-diet interactions are thought to be causal for fetal programming. For instance, previous studies in the INSERM 1256 NGERE lab have demonstrated that epigenetic changes resulting from maternal over-or undernutrition predisposed the offspring towards obesity. Animal studies suggest that maternal dietary interventions before pregnancy, including vitamin supplementation, can modify epigenetic signatures and reverse fetal programming towards obesity and metabolic syndrome. Besides exposures arising from the diet, environmental chemicals, or drugs, the epigenome has been proposed to be influenced by the gut microbiota, namely, the ecosystem of microbes residing in the human intestine. The human gut microbiota performs essential functions for human health, including maturation of the developing infant's immune system, protection against pathogens, digestion and transformation of dietary nutrients, and synthesis of bioactive metabolites. For example, gut microbes synthesize amino acids, and B vitamins, including B9 and B12. Gut microbes also produce the short-chain fatty acids acetate, propionate, and butyrate, which directly influence gene regulation in the host through at least four independent mechanisms. For instance, butyrate acts as a histone deacetylase inhibitor. Consequently, the gut microbiome modulates global histone acetylation and methylation profiles in multiple host tissues in a diet-dependent manner. Changes in gut microbiome composition have been repeatedly linked to lifestyle-associated metabolic diseases including obesity, type 2 diabetes, and metabolic syndrome. Remarkably, animal models have shown that obesity is transmissible from mother to child via an obesogenic microbiota. A long-term high-fat diet led to alterations of histone methylation and acetylation in intestinal epithelial cells mediated by the gut microbiota, and epigenetic changes could be transferred to germfree animals via a fecal transplant together in combination with a short-term high-fat diet.

spécialité

Sciences de la Vie et de la Santé - BioSE

laboratoire

NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux