In 2013, we have identified Akkermansia muciniphila as a key bacteria involved in the control of the gut barrier function and host metabolism (Everard et al PNAS 2013). We demonstrated that A.muciniphila, a mucin-degrading bacteria that resides in the mucus layer and abundantly colonizes it, negatively correlates with body weight and is decreased under high-fat diet. Moreover, daily administration of A. muciniphila to high-fat-diet-induced obese mice for 4 weeks improves metabolic profile, by decreasing weight gain, restoring mucus layer thickness, antimicrobial peptides (Reg3gamma) production and counteracting metabolic endotoxemia and insulin resistance.
Our studies have also indicated that the gut microbiota clearly participate to the control of metabolic endotoxemia and of the release of proinflammatory cytokines (IL1, IL6, MCP1…) in both nutritional and genetic models of obesity.
We discovered that the fatty acids composition may also strongly contribute to the modulation of the abundance of Akkermansia muciniphila. We found that
mice fed with a saturated fatty acid diet (lard-enriched diet) exhibited a significant decrease in Akkermansia muciniphila, whereas omega 3 fatty acids (fish oilenriched diet) dramatically increased Akkermansia muciniphila in the gut. This effect was associated with a better gut barrier function and decreased adipose tissue inflammation, a phenomenon that can be transferred to germ-free recipient mice (Caesar et al. Cell Metabolism 2015).
We have also revealed a link between Akkermansia muciniphila and age, since the intestinal levels of this bacterium declined with age upon a normal diet feeding. We found that high-fat diet feeding strongly influenced adipose tissue profile and intestinal microbiota in a way that mimicked aging, or at least older mice. In the same set of experiments, we found by using multifactorial analysis that these changes in A. muciniphila were robustly linked with the
expression of lipid metabolism and inflammation markers in adipose tissue, as well as several blood markers (i.e., glucose, insulin, triglycerides, leptin) (Schneeberger et al Sci Reports 2015).
In obsese humans, in accordance with the data obtained in rodents, we found that in the basal state, the abundance of Akkermansia muciniphila is inversely related to fasting glucose levels, visceral fat accumulation, and adipocyte diameter in subcutaneous adipose tissue. In addition, upon caloric restriction, obese individuals with higher baseline Akkermansia muciniphila exhibited a greater improved insulin sensitivity as well as an improvement of different markers and other cardiometabolic risk factors (e.g., plasma cholesterol, inflammation) (Dao, Everard et al. GUT 2016).
Thus, all these data suggests that increasing the intestinal levels with nutrients or the administration of Akkermansia muciniphila is of interest and merit further investigation in humans. The team of Prof. Cani is currently investigating this question in obese patients, study started in December 2015 (www.microbes4U.be).
(Patrice D. Cani, Hubert Plovier, Matthias Van Hul, Lucie Geurts, Nathalie M. Delzenne, Céline Druart and Amandine Everard. Nature Reviews Endocrinology dec 2016).
We have previously identified that the endocannabinoid system links the gut microbiota to adipogenesis in both physiological and pathological situations such as obesity and type 2 diabetes. Our novel data pointed out that targeting specifically the endocannabinoid system tone in the adipose tissue may contribute to change host-microbiota interactions (for review Cani et al Nature Reviews Endocrinology 2016). In 2015, we published data showing that deleting NAPE-PLD in the adipose tissue (tissue specific deletion) induces obesity in normal diet-fed mice by promoting fat mass development, insulin resistance and inflammation. We discovered that the deletion of NAPE-PLD in adipocytes induces also a decreased thermogenic programme (i.e., browning/beiging) in adipose tissue. Importantly, we found that NAPE-PLD deletion in adipose tissue induced a profound shift in the gut microbiota compositon and activity.
Finally, we have proven that the microbiota contribute to the phenotype. By transferring the microbiota from mice in which the adipose tissue NAPE-PLD was deleted into germ-free recipient mice replicated the overall phenotype. Taken together, these findings indicate that bioactive lipids produced by adipose tissue contribute to changes in the gut microbiota; these changes then participate in the altered metabolic disorders observed following NAPE-PLD deletion (Geurts et al. Nature Communications 2015). These results provide strong support for the crosstalk between adipose tissue and gut microbiota, with the endocannabinoid system as a potent mediator.
In 2014, we found that a link between the innate immune system from intestinal cells (i.e., the protein MyD88) and energy homeostasis. More precisely, we found that modifying the response of the immune system by deactivating the protein MyD88 in the intestinal cells delay the development of type 2 diabetes induced by a high fat diet, reduces the development of fat mass, reduces the deleterious inflammation observed during obesity and reinforced the gut barrier thereby preventing the leakage of unsuitable bacterial compounds from the intestine to the organism. More importantly, we found that it is experimentally possible, through this modification of the immune system, to induce body weight loss and therefore to have a therapeutic effect despite the fact that the animals were already obese and diabetic. Surprisingly, we found that it is possible to partially protects against obesity and diabetes by transferring (i.e., grafting) the gut microbiota from these mice to axenic mice (i.e., germ free) (Everard et al. Nature Communications 2014). We are currently investigating the role of Myd88 deletion in the hepatocyte and host metabolism (Duparc et al, GUT 2016).