BACTERIA TO TREAT TYPE 2 DIABETES | Akkermansia Muciniphila
Article Summary :
Obesity, flabbiness and type 2 diabetes are associated with low-grade inflammation. Among the new mechanisms, the link with intestinal bacteria seems more and more convincing. This intestinal microbiota would play a key role in triggering inflammation and insulin resistance via different mechanisms, such as the translocation of bacteria or even bacterial compounds with the development of metabolic endotoxemia. Certain intestinal bacteria could also contribute in a deleterious or, on the contrary, beneficial way to the improvement of carbohydrate homeostasis. Among the potential candidates, the role of Akkermansia muciniphila is currently being investigated.
Obesity and overweight are classically associated with low-grade inflammation. This inflammation contributes to the development of insulin resistance, type 2 diabetes, and other cardio-metabolic complications. Over the past decade, many studies have associated the intestinal microbiota (formerly called: intestinal flora) with the development of these metabolic disorders (1,2). Over the past twenty years, our laboratory has contributed to a better understanding and elucidation of how the intestinal microbiota manages to dialogue with our body and contributes to the development of obesity and its associated metabolic disorders (insulin resistance, type 2, metabolic inflammation, non-alcoholic fatty liver disease (NASH)) (3-5)
Among the candidates involved in this inflammation, we have proposed that constituents of the wall of intestinal bacteria (gram-negative), such as lipopolysaccharides (LPS) (also called endotoxins), would play an essential role in the triggering of some of these disorders (6 ). LPS are powerful pro-inflammatory molecules, continuously produced by the intestinal microbiota and whose absorption is directly linked to the ingestion of dietary lipids (3,7). Indeed, intestinal bacteria would contribute to the inflammation associated with metabolic disorders by mechanisms involving, in particular, an increase in plasma LPS levels, which we have defined as “metabolic endotoxemia” (3).
The existence of metabolic endotoxemia and its role in triggering inflammation and insulin resistance associated with obesity and type-2 diabetes was first demonstrated experimentally in animals. Still, it was later largely confirmed in humans (3.7-9). From an experimental point of view, we demonstrated that a chronic infusion of LPS mimicking metabolic endotoxemia induces inflammation and insulin resistance associated with hepatic steatosis.
In addition, the invalidation of the LPS receptor (CD14/Toll-like receptor 4 (TLR-4)) protects against the development of various metabolic disorders induced by LPS or a high-fat diet.
Dialogues Between Bacteria and Host Cells
More recently, we demonstrated that the established dialogue between gut bacteria and host gut cells plays a prime role in the development of obesity and diabetes. By specifically inactivating (in gut epithelial cells) an innate immune system protein called MyD881 can reduce inflammation, insulin resistance, and type-2 diabetes associated with a high-fat diet ( 10). This protection is directly dependent on the composition and activity of intestinal bacteria, thus suggesting that intestinal cells play a key role in the systemic response to components of the intestinal microbiota.
In this context, the barrier function of the intestine is essential in order to limit as much as possible the passage of undesirable compounds from the intestinal lumen to the blood circulation and the tissues of the host. The effectiveness of this intestinal barrier is ensured by different cell types and different mechanisms (tight junction proteins, mucus layer, antimicrobial proteins and immunoglobulins, etc.) (10).
Among the mechanisms potentially involved in the bacteria-host dialogue, we found that the gut microbiota interacts closely with the endocannabinoid (eCB) system and its bioactive lipids (11,12). Indeed, the eCB system is involved in the control of the barrier function of the intestine, and certain bacteria (or intestinal microbiota) would be associated either with protection or, on the contrary, with the triggering of disorders of the intestinal barrier for review (6).
More recently, we discovered that the eCB system in adipose tissue, specifically the enzyme for the synthesis of N-acyl ethanolamines (NAPE-PLD), plays a key role in the regulation of energy metabolism (11). This substance (enzyme) is involved in the synthesis of bioactive molecules, some of which are already known for their effects on inflammation and appetite regulation.
Using genetic tools, we discovered that eliminating the enzyme specifically in adipocytes leads to obesity and insulin resistance. This is associated with an almost complete disappearance of beige cells, thus indicating an inability to oxidize fat. The absence of NAPE-PLD in this organ also prevents the development of beige cells during exposure to cold, preventing the mice from expending energy to produce heat.
Our work shows that animals without NAPE-PLD in adipose tissue develop inflammation associated with metabolic endotoxemia. In agreement with this observation, the composition of the bacteria in the intestine of these animals is also different.
This surprising result, therefore, suggests that adipose tissue interacts with the intestine and bacteria. Our work suggests that certain bioactive lipids may modify metabolism through a microbiota-host metabolic dialogue. But this dialogue does not only take place in the direction of adipose tissue to the intestine. Indeed, transferring gut bacteria from these mice into axenic animals causes a decrease in browning/beiging and fat oxidation, thus suggesting that gut bacteria would be able to control the metabolism of adipose tissue.
MyD88, or Myeloid Differentiation Primary Response Gene 88, is Involved in the Signaling Pathway of Most TLRs.
A place of choice for certain candidates?
Various studies have shown an association between intestinal microbiota composition, body weight, hyperglycemia, and type-2 diabetes. Many metagenomic analyzes show that certain bacteria or bacterial families. They increase or decrease in the feces of type-2 diabetic patients compared to non-diabetic individuals. Still, there is no reliable “listing” to suggest a causal link between these observations and the onset of diabetes.
On the other hand, there is another bacterium called Akkermansia muciniphila which is interesting in the context of metabolic disorders. Indeed, this bacterium has been associated with energy and carbohydrate metabolism on several occasions. For example, we found this bacterium was less present in obese and type 2 diabetic mice, regardless of the model, i.e., genetic or nutritional (13,14). Next, we demonstrated that the administration of Akkermansia muciniphila to obese and diabetic animals reduced body weight gain, improved blood sugar and insulin resistance, strengthened the intestinal barrier, and decreased metabolic inflammation (14); other teams have recently confirmed these observations (15,16).
In humans, various studies have shown that the presence of Akkermansia muciniphila was inversely correlated with body weight or blood sugar (17-19). Note, however, that the abundance of this bacterium is increased by taking metformin, which makes it a confounding factor during its investigation in the intestine of type-2 diabetic patients (20,21).
Our recent work has shown that the abundance of Akkermansia muciniphila could predict a patient’s response and metabolic improvements following a low-calorie diet. Specifically, subjects with more Akkermansia muciniphila before the nutritional intervention will show the greatest improvement in insulin sensitivity, greater decrease in total and LDL cholesterol, and waist circumference. Akkermansia muciniphila was also inversely correlated with fasting blood glucose but also with other parameters, such as the hip-to-waist ratio and the size of adipocytes in subcutaneous adipose tissue (17).
To date, no intervention study has been able to demonstrate whether this bacterium has any potential health benefits. This hypothesis is currently being investigated at the Cliniques Universitaires Saint-Luc in collaboration with Professors Jean-Paul Thissen, Michel Hermans, Dominique Maiter and Doctor Audrey Loumaye.
In conclusion, a lot of work is underway, and over a relatively short period of a decade, a significant number of advances have been made. Obviously, the influence of the intestinal microbiota on carbohydrate and energy homeostasis is complex and multifactorial. However, some leads could be suggested for the specific management of metabolic syndrome. Current research encourages the development of new therapeutic targets that will be personalized. Both targets, such as immunity or even different bacterial metabolites, are of particular interest.
Gut microbiota, diabetes, inflammation, Akkermansia muciniphila, Health
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