What changes in intestinal functions occurs when obesity is complicated by metabolic diseases? : some elements of answer by the study of the intestinal transcriptome of severely obese patients of the ABOS cohort

L'obésité et ses complications métaboliques, le diabète de type 2 (DT2) et les maladies du foie gras non alcooliques (NAFLD), touchent des millions de personnes dans le monde. La perte de poids par des changements d'habitudes alimentaires ou par une augmentation de l'activité physique demeure le moyen premier de réduire le risque de mortalité cardiovasculaire chez ces patients. Bien qu'il n'existe pas de traitement médicamenteux à visée amaigrissante, une chirurgie bariatrique est indiquée à poids extrême, quand l'indice de masse corporelle dépasse les 40 kg/m². Dans ces pathologies, une altération de la communication entre l'intestin et le foie a été rapportée, impliquant en particulier une dérégulation des fonctions intestinales. Afin d'étudier plus précisément ce qui différencie l'intestin d'un patient obèse atteint de complications métaboliques de l'intestin d'un patient obèse métaboliquement sain, nous avons eu recours aux patients de la cohorte ABOS (NCT01129297), bio-banque rassemblant les données clinico-biologiques de patients obèses opérés pour chirurgie bariatrique et une collection d'échantillons biologiques dont des biopsies intestinales.Afin d'élucider les mécanismes potentiels différenciant l'intestin du patient atteint de complication métabolique, la fonction d'absorption intestinale par la caractérisation de l'impact de mutations du co-transporteur sodium-glucose SGLT1 décrites comme protectrices vis à vis de l'incidence de l'obésité et du diabète a été étudiée. Ces mutations ont été corrélées à une plus faible absorption du glucose lors d'un test de tolérance oral chez le patient obèse, et se traduisent par une plus faible expression en ARNm de la protéine SGLT1 dans le jéjunum de ces patients.Dans un second temps, par des méthodes avec et sans a priori, le transcriptime intestinal du patient obèse et DT2 et NAFLD a été étudié. Par analyse différentielle du transcriptome intestinal, certains gènes de l'immunité adaptative ont été montrés comme différemment exprimés dans l'intestin du patient diabétique. Aussi, par des méthodes comparatives et des méthodes de clustering sans a priori, l'immunité à médiation T a pu être négativement corrélée à la stéatose hépatique. Enfin, l'exploration de ces altérations des fonctions intestinales sur un modèle murin de NASH avec insulino-résistance, induite par un régime de type high fat high sucrose supplémenté en cholestérol a mis en évidence par cytométrie en flux une diminution de la proportion et un nombre plus faibles de lymphocytes T dans l'intestin de ces souris. L'ensemble de ces travaux montre qu'au sein du phénotype obèse, la fonction de barrière immunologique intestinale est dérégulée.Obesity and its metabolic complications, type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD), affect millions of people worldwide. Weight loss through dietary changes or increased physical activity remains the primary method of lowering the risk of cardiovascular mortality in these patients. Although there is no drug treatment for weight loss, bariatric surgery is indicated when the body mass index exceeds 40 kg/m². An alteration of communication between the intestine and the liver has been reported in these pathologies, implying a deregulation of intestinal functions in this pathological context. We used patients from the ABOS cohort (NCT01129297), a bio-bank gathering clinico-biological data from obese patients operated on for bariatric surgery, and a collection of biological samples including gut biopsies, to study more precisely what differentiates the gut of an obese patient with metabolic complications from the gut of a metabolically healthy obese patient.The function of intestinal absorption was studied to elucidate the potential mechanisms differentiating the gut of the patient with metabolic complications by characterizing the impact of mutations in the sodium-glucose co-transporter SGLT1 described as protective against the incidence of obesity and diabetes. These mutations were linked to lower glucose absorption in an oral tolerance test in obese patients, as well as lower mRNA expression of SGLT1 in their jejunum.In a second step, the intestinal transcriptome of obese, T2DM, and NAFLD patients was studied using both a priori and non-a priori methods. Some adaptive immunity genes were found to be differentially expressed in the diabetic patient's gut via differential analysis of the intestinal transcriptome. T-mediated immunity was also found to be negatively correlated with liver steatosis using comparative and unbiased clustering methods. Finally, flow cytometry revealed a decrease in the proportion and number of T lymphocytes in the intestine of these mice after investigating these changes in intestinal functions in a mouse model of NASH with insulin resistance induced by a high fat high sucrose diet supplemented with cholesterol. This research demonstrates that the intestinal immunological barrier function is dysregulated in the obese phenotype

Intestine-Liver Cross-talk in Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease

International audienceType 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) are pathologies whose prevalence continues to increase worldwide. Both diseases are precipitated by an excessive caloric intake, which promotes insulin resistance and fatty liver. The role of the intestine and its crosstalk with the liver in the development of these metabolic diseases is receiving increasing attention. Alterations in diet-intestinal microbiota interactions lead to the dysregulation of intestinal functions, resulting in altered metabolite and energy substrate production and increased intestinal permeability. Connected through the portal circulation, these changes in intestinal functions impact the liver and other metabolic organs, such as visceral adipose tissue, hence participating in the development of insulin resistance, and worsening T2D and NAFLD. Thus, targeting the intestine may be an efficient therapeutic approach to cure T2D and NAFLD. In this review, we will first introduce the signaling pathways linking T2D and NAFLD. Next, we will address the role of the gut-liver crosstalk in the development of T2D and NAFLD, with a particular focus on the gut microbiota and the molecular pathways behind the increased intestinal permeability and inflammation. Finally, we will summarize the therapeutic strategies which target the gut and its functions and are currently used or under development to treat T2D and NAFLD

The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids.

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes

Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes

Summary: Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET’s primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(18F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug