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Gut microbiota, innate immunity and endocannabinoid system interactions link metabolic inflammation with the hallmarks of obesity and type 2 diabetes

Final Report Summary - ENIGMO (Gut microbiota, innate immunity and endocannabinoid system interactions link metabolic inflammation with the hallmarks of obesity and type 2 diabetes)

Cardio-metabolic risk factors such as overweight, obesity and type 2 diabetes are characterized by specific alterations in the gut microbiota composition and activity. These metabolic disorders are linked with a higher inflammatory tone and an altered endocannabinoid system (eCB) tone. Besides the composition of the gut microbiota it is also known that hallmarks of the metabolic syndrome such as insulin resistance and inflammation are associated with higher load of bacterial components circulating into the blood (i.e. the metabolic endotoxemia). Because we know that the gut microbes interact with the host via different Toll-Like Receptors (TLR’s), we decided to investigate wether the key signaling adaptor MyD88 (myeloid differentiation primary-response gene 88), that encompass most of the TLR’s were or not involved in the onset of obesity and related disorders. To do so, we have generated different animal models harboring a tissue specific deletion of MyD88. We reasoned that both the intestine and the liver were the first key metabolic organs directly in contact with either bacteria (i.e. the gut) or bacterial components (i.e. the liver). During this ERC project ENIGMO, we discovered that mice lacking MyD88 specifically in the intestinal epithelial cells were partially protected against diet-induced obesity, type 2 diabetes and inflammation, together with a higher energy expenditure. We also found that the deletion of MyD88 modified the gut microbiota, a phenomenon closely linked with changes in the intestinal eCB system tone and antimicrobial peptides production. Next, we found that transferring the gut microbiota in germ free mice also protects against obesity (Everard et al. Nature Communications 2014).
Conversely, the deletion of MyD88 specifically in the hepatocytes induced a higher susceptibility to the development of glucose intolerance, hepatic steatosis and inflammation. Interestingly, this was also associated with a modulation of the microbiota and the overall lipidome and metabolome. Therefore, this study led us to discover that the innate immune system (i.e. in the hepatocyte) is a key actor involved in the regulation of both lipid and glucose metabolism (Duparc et al GUT 2017). Thus, by using two different models of deletion of MyD88 we demonstrated that the innate immune system plays a major role on the regulation of host metabolism not only by dialoguing with the gut microbiota but also by controlling different other biological systems (i.e. lipid, glucose, endocannabinoids, bioactive lipids, inflammation).

We discovered that MyD88 was linked to the eCB system, therefore we also anticipated that the enzyme NAPE-PLD (N-acylphosphatidylethanolamine phospholipase-D) involved in the synthesis of N-acylethanolamines family could be a key determinant in such pathophysiological aspects. For this purpose, we generated two models, one lacking the NAPE-PLD in the intestinal epithelial cells and another in the adipocytes. We found that mice deleted for this enzyme in the adipocytes developed spontaneous obesity, diabetes and inflammation. This was associated with a lower browning/beiging of the adipose tissue (i.e. oxidation of energy), hence contributing to higher fat mass gain. Interestingly, we discovered that this model was also linked with a change in the gut microbiota and transferring the microbiota into germ free mice was associated with a replication of the same phenotype as the one found in the donors (Geurts et al Nature Communications 2015). By deleting the NAPE-PLD in the intestinal epithelial cells, we discovered that the mice become more obese and developed a stronger hepatic steatosis than the wild-type mice. Among the mechanisms, we found that the lack of NAPE-PLD strongly affects the gut to brain axis and eventually the regulation of food intake, by interfering the hypothalamic regulation of energy metabolism.
Finally, we have previously shown that Akkermansia muciniphila, plays a central role in the regulation of host energy metabolism (Everard et al PNAS 2013), in this project, we serendipitously discovered that pasteurizing the bacteria enhanced its activity. We next tested in a pilot-exploratory study its possible administration in humans and safety (PoC ERC Microbes4U). We found that both alive and pasteurized Akkermansia are well-tolerated and safe in humans (Plovier et al Nature Medicine 2017).
Altogether, our data contributed to show the existence of mechanisms linking the innate immune system, the gut microbiota and host metabolism. We have elucidated different fundamental processes shared by different key hallmarks of obesity and related diseases and we provided potential innovative therapeutic tools.