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    Insulin signaling as gatekeeper of intestinal barrier function

    Dalale Gueddouri


    Tuesday 9 of March 2021 at 2 pm

    Rosalind Franklin room
    Institut Cochin, 22 rue Méchain, Paris 75014
    (By videoconference for the public)

    Intestinal mucosa 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. A common feature of metabolic diseases is their association with chronic inflammatory processes in various tissues, as well as an increased general risk of infection. This state of metaflammation is thought to result from impaired intestinal mucosal barrier, leading to the translocation of microbial products into the systemic circulation.

    While the mechanistic basis for gut leakiness accompanying the metabolic syndrome has long remained poorly understood, recent evidences indicate that gut epithelial glucose metabolism can be considered as a prime candidate. Thaiss et al indeed proposed that hyperglycemic state leads to GLUT2-mediated glucose transport and metabolism in intestinal epithelial cells and drives intraepithelial gene expression reprograming which markedly interferes with homeostatic gut barrier function and favors susceptibility to enteric infection upon the diabesity cascade.

    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. To address this point, we developed two murine models of insulin resistance: (i) a model of global insulin resistance not associated with obesity, by treatment with an insulin receptor antagonist (S961), (ii) a model of specific and inducible intestinal insulin resistance that do not display concomitant hyperglycemia, by inducible deletion of the insulin receptor in the intestinal epithelium (IRΔGUT).

    Loss of intestinal insulin signaling triggered a significant deterioration of antimicrobial defense by Paneth cells, concomitantly with the onset of a significant dysbiosis as characterized by a bloom of pro-inflammatory Proteobacteria. This was accompanied by an increased susceptibility to infection by enteropathogens and enhanced fecal content of lipocalin 2, a marker of intestinal inflammation. Further examination of IRΔGUT mice pinpointed that insulin controls epithelium renewal capacities, another essential component of intestinal integrity. Ex-vivo growth of intestinal and colonic organoids derived from IRΔGUT mice was indeed significantly altered, suggesting defects in stem cell proliferation and survival. Consequently, IRΔGUT mice exhibited a greater susceptibility to acute colitis induced by DSS treatment, with was associated with major defects in re-epithelialization.

    This study therefore reveals that insulin acts as a gatekeeper of the intestinal by controlling two essential components of the gut epithelial barrier: (i) the bactericidal activity of Paneth cells and (ii) the survival and proliferative capacities of stem cells.