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Obesity and Type-2 Diabetes: Cells at the Junction of Microbiota and Inflammation?

 

[Communiqué de presse disponible en français]

Joint press release (ICAN, CNRS, INSERM, UPMC, Université Paris Descartes)

Paris, Monday, March 9, 2015 – Researchers at the Cochin Institute (CNRS/Inserm/Paris Descartes University) and the Institute of Cardiometabolism And Nutrition – ICAN (Inserm/UPMC/AP-HP) have discovered that a class of inflammatory cells, lymphocytes MAIT1, is deregulated in patients with type-2 diabetes and obesity. For these individuals, bariatric surgery (or gastric bypass)2, which relieves inflammation, restores the normal functioning of MAIT cells. Already known to be activated by certain bacterial populations and to promote inflammation, these cells could explain the link between the observed changes in the intestinal flora (microbiota) and the inflammatory nature of the disease. This work is published March 9, 2015 in The Journal of Clinical Investigation (JCI).

Type-2 diabetes3 and obesity are severe and closely-linked pathologies which have been growing worldwide, including in France4. These diseases with multiple causes (diet change, lack of physical activity, interacting with genetic predispositions) are associated with chronic inflammation induced by the immune system, which is abnormally activated. This inflammation is not only present in the blood but also in the organs involved in the metabolic control of the body such as the liver and adipose tissue. It contributes to the loss of control of blood sugar levels. In addition, recent studies show that the intestinal bacterial flora of diabetic and obese patients is altered substantially.

However, the link between changes in the intestinal flora and chronic inflammation observed in these disorders is poorly understood. Incidentally, some inflammatory cells, i.e. individual T lymphocytes called MAIT, are activated by various bacteria. Research teams coordinated by Karine Clément and Agnès Lehuen therefore analysed whether these cells were altered in patients with type-2 diabetes or obesity.

Their results reveal that these MAIT cells are indeed strongly altered: their number is greatly reduced in the blood of patients. They are even undetectable in one quarter of obese patients. The adipose tissue of diabetic and obese patients, however, contains much larger amounts of MAIT cells than in healthy subjects. They are also activated in an exacerbated manner, producing large amounts of cytokines (inflammatory molecules).

In addition, after obesity surgery (gastric bypass), known to improve diabetes and inflammation, the number of MAIT cells in the blood increases and returns to the levels observed in non-obese, non-diabetic individuals. Similarly, the production of cytokines by MAIT cells is greatly reduced after this surgery.

These results highlight a strong association between MAIT cells and metabolic dysfunction. They suggest that these cells are involved in the development of type-2 diabetes and obesity. The researchers speculate that they may be activated by changing the intestinal flora (microbiota) of patients, and increase inflammation this way. The next step is to check the connection between the MAIT cells and microbiota. For example, do patients who have no circulating MAIT cells have a different microbiota from those for whom we still detect these cells in the blood? To answer such questions, scientists plan to sequence the microbiota of obese patients before and after surgery.

This project, bringing together the team of Agnès Lehuen at the Cochin Institute and the team of Karine Clément at ICAN Pitié-Salpêtrière, was supported by the Inflamex5 Labex, the DHU-AUTHORS, a hospital clinical research program (AP-HP, Microbaria) and the Métacardis European project. It was designed and run with the support of ANR (ObeMAIT project).

(1) MAIT: Mucosal Associated Invariant T-cells

(2) The gastric bypass technique consists of bypassing much of the stomach by reducing it to a small bag connected to the small intestine, thereby decreasing the amount of food ingested and assimilated.

(3) Type-2 diabetes, or noninsulin-dependent diabetes, is the most common form of diabetes, in which hyperglycemia is caused by the decrease of sensitivity of cells to insulin (insulin resistance). It appears in particular as a result of obesity or lack of physical activity.

(4) In France, the last OBEPI survey (2012) shows that across regions, 14 to 20% of the French are obese and 5-9% have type-2 diabetes. The number of people with severe obesity increased by a factor of 3 in 12 years (1% of the French in 2012 are massively obese and 30% of them are diabetics).

(5) ICAN and the Inflamex Labex have been founded and supported by the government-sponsored Investment for the Future Program.

In obese individuals, the modification of the intestinal microbiota and the loss of intestinal integrity disrupt homeostasis and function of MAIT cells, which produce large quantities of IL-17 cytokine, an inflammatory molecule. MAIT cells found in lower amounts in the blood of obese individuals are recruited in their adipose tissue, where they increase inflammation. Scientists have also observed an increased turnover of MAIT cells in adipose tissue, marked by a high level of proliferation and cell death. © ICAN & Cochin Institute.

ICAN : Translational Research in Action

This study was performed, in part, from obese and diabetic patients, candidates for bariatric surgery. These patients (more than 1500) are followed at the Institute of Cardiometabolism and Nutrition ICAN (Nutrition Service, AP-HP, Hôpital Pitié-Salpêtrière).

The observed metabolic improvements after bariatric surgery are due in part to changes in the microbiota.

The Institut hospitalo-universitaire (IHU) ICAN develops an ambitious project that aims to better understand these changes and identify markers that predict weight loss and metabolic improvements, as in the case of diabetes. These programs are also extended to academic and industrial partnerships.

Bibliography

Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients
Isabelle Magalhaes, Karine Pingris Christine Poitou, Stephanie Bessoles, Nicolas Venteclef Badr KIAF, Lucie Beaudoin, Jennifer Da Silva, Omran Allatif Jamie Rossjohn Lars Kjer-Nielsen, Jim McCluskey, Séverine Ledoux, Lawrence Genser, Adriana Torcivia, Claire Soudais Olivier Lantz, Christian Boitard, Judith Aron-Wisnewski, Etienne Larger, Karine Clement and Agnes Lehuen
The Journal of Clinical Investigation, March 9th, 2015.
doi:10.1172/JCI78941

Contacts

CNRS: Agnes Lehuen, PhD l +33 176 535 590 l +33 609 452 469 l agnes.lehuen@inserm.fr
ICAN: Karine Clement, MD, PhD  l +33 142 177 928 l k.clement@ican-institute.org
CNRS Press Officer: Véronique Etienne l +33 144 965 137 l veronique.etienne@cnrs-dir.fr
ICAN Press Officer: Sylvain Gilat, PhD l +33 183 798 900 l s.gilat@ican-institute.org