Metabolic disorders induced by nutritional deficiency in n-3 polyunsaturated fatty acid or magnesium : potential implication of the gut microbiota

Abstract

The prevalence of obesity is increasing worldwide. Among environmental factors, involved in this phenomenon, the nutritional dys-balance plays a major role. Surprisingly, the excess of calorie intake is often associated with specific nutritional deficiencies. Moreover, recent data suggest that the gut microbiota is a novel partner to take into account when evaluating the regulation of host energy metabolism by the nutrients provided in the diet. In the context of this thesis, we have focused our work on the assessment of two nutritional deficiencies often occurring in western countries and which have been associated with diabetes, inflammation and/or obesity: namely, magnesium (Mg) and n-3 polyunsaturated fatty acid (PUFA) deficiencies. We have characterized the metabolic alterations occurring in animal models mimicking those deficiencies and we have tested the hypothesis that perturbations of the gut microbiota contribute to the metabolic alterations occurring in deficient mice. We have shown for the first time that Mg deficiency, independent of any other changes in nutrient intake, modulates the concentration of bifidobacteria in the gut in a time dependent manner. A short term (4 days) Mg-deficiency leads to a drop of bifidobacteria, which is associated with intestinal and hepatic inflammation and with a loss of gut barrier integrity. A restoration of the gut microbial changes occurs spontaneously after a few days (21 days), which allows to normalize the metabolic alterations. In the second part of the thesis, we have developed mouse models of n-3 PUFA depletion: one long term (depletion installed for two generations) and one short term (depletion installed for three months). Both long-term and short-term n-3 PUFA depletions induce hepatic steatosis, alterations in glucose metabolism and a metabolic stress in the liver tissue. Moreover, mice depleted in n-3 PUFA for two generations exhibit a lower body weight. A microarray analysis performed in the liver of mice depleted in n-3 PUFA for three months revealed a higher expression of several factors involved in fatty acid and cholesterol synthesis and a lower expression of factors involved in fatty acid oxidation. These metabolic alterations occur together with a modification in the gut microbiota composition, characterized by a lower content in lactobacilli and a higher content in bifidobacteria in long-term depleted mice and characterized by a higher Roseburia spp. content in short-term depleted mice. Supplementation with a prebiotic called fructooligosaccharides (FOS) leads to differential effects depending on the model of n-3 PUFA depletion. In mice depleted for two generations, after FOS feeding, we observed an increased body weight and an improvement of the catabolic state, whereas there was no effect on hepatic steatosis. In mice depleted for three months, FOS supplementation restored the hepatic lipid deposition, mainly by activating fatty acid oxidative pathways and by lessening cholesterol synthesis. In conclusion, a nutritional deficiency in n-3 PUFA or in Mg modulates the gut microbiota composition. In Mg deficiency, a spontaneous adaptation of the gut microbiota composition is observed progressively and is associated with a restoration of the inflammatory state. In n-3 PUFA-depleted mice, changing the gut microbiota composition by FOS supplementation leads to an improvement of several metabolic alterations induced by the depletion. These results support the idea that gut microbiota affects the health of the host and should be taken into account in the treatment of inflammatory conditions and hepatic steatosis.(FARM 3) -- UCL, 201