CE14 - Physiologie et physiopathologie

Epithelial insulin sensitivity as a gatekeeper of the gut barrier ? – GutBarrIR

Submission summary

A common feature of metabolic diseases, including obesity, associated insulin resistance and subsequent T2D, is their association with chronic inflammatory processes in various tissues, as well as an increased general risk of infection. While the mechanistic bases of this metaflammation state have been partly uncovered, recent evidences have shed light on the intestinal contribution to this feature. Under physiological conditions, the intestinal mucosa indeed forms a selective barrier, which ingeniously allows an efficient transcellular transport of nutrients while rigorously excluding the paracellular flow of immune-stimulatory bacterial products across the epithelium. By contrast, an early increase of intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation have been suggested to pave the road to the subclinical inflammatory state that accompanies the diabesity cascade. While a comprehensive mapping of the molecular mechanisms that elicit or sustain such defective epithelial integrity has long remained poorly understood, microbial imbalance, food composition and hyperglycemia have been lately proposed to be at play.

Because hyperglycemia and loss of insulin action are often two sides of the same coin, we hypothesize that, beyond hyperglycemia, defective intestinal insulin signaling could directly impair epithelial integrity upon diabetic conditions. Preliminary results from the GutBarrIR consortium indeed reveal that intestinal insulin sensitivity, which is decreased upon obesity, controls two essential components of the epithelial gut barrier: bactericidal and renewal capacities. This pinpoints blunted local insulin action per se (independently of hyperglycemia or adiposity) as a prime candidate in the potential triggers of gut leakiness, metabolic endotoxemia and metaflammation observed during the metabolic syndrome. Therefore, our proposal aims at investigating the role of intestinal epithelial insulin receptor as a gatekeeper of the gut barrier, by deciphering its contribution to antimicrobial defenses and epithelium renewal capacities. More precisely, we will: (i) evaluate the molecular mechanisms underlying functional defects of anti-microbial producing Paneth cells upon gut insulin resistance, (ii) determine whether altered gut microbiota and associated immune response contribute to impaired intestinal permeability following blunted intestinal IR signaling, and (iii) assess whether insulin signaling represents an intestinal stem cell intrinsic mechanism for gut barrier integrity maintenance in mouse and human.

The success of this proposal relies on the development, through pharmacological and genetic approaches, of original mouse models of either global or gut specific insulin action deficiency that do not display parallel hyperglycemia or obesity. Our project also implies the use of human gut organoids, which represent an excellent alternative for animal models to pre-screen selective pharmacological targeting of insulin receptor downstream pathways and will help to translate our results into clinic. This will allow the specific exploration of the molecular and cellular mechanisms mediating gut barrier impairment upon local insulin signaling loss, which is central to the design of preventive and therapeutic strategies. Rather than a triggering factor, we assume that loss of insulin action might aggravate the chronic low-grade inflammation during progressive weight gain. Moreover, we anticipate that while insulin signaling could represent a mechanism to coordinate food ingestion and epithelial protection under physiological conditions, loss of insulin action selectively in the gut could weaken host defense and represent a risk factor for intestinal inflammatory or infectious injuries under diabetic conditions. Moreover, outcomes of the GurBarrIR program might also open up promising perspectives in the context of inflammatory bowel diseases therapies.

Project coordination

Sandra Guilmeau (Institut Cochin)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM INSERM U1016 - Institut Cochin
Inserm - IRSD Inserm Occitanie Pyrénées
Institut Cochin
NUMECAN Nutrition, métabolismes et cancer

Help of the ANR 400,248 euros
Beginning and duration of the scientific project: January 2021 - 36 Months

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