Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease

Abstract

The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…Consistent with the genetic impairment of Atg16l1 and Atg7, Deuring et al 99 illustrated that markers of ER stress are significantly elevated in the Paneth cells of patients suffering from Crohn disease with homozygosity or heterozygosity for the ATG16L1 risk allele, even during quiescent disease stages. Further, ileal biopsy samples from Crohn disease patients with ERstressed Paneth cells exhibit a higher incidence of AIEC and an increased risk for ileal disease, fistulizing disease, and the need for intestinal surgery.…”

“…98 In another study on T300A Crohn disease patients, a significantly increased presence of AIEC was observed in Paneth cells. 99 Therefore, as a result of this deficiency in bacterial clearance, the ATG16L1 risk variant has been associated with shifts in the microbial compositions of the intestine 100 and, additionally, has been related to the presence of bacterial DNA and an increased formation of antibacterial antibodies in patients with Crohn disease. 101,102 Of interest, bacterial DNA has been correlated with higher disease activity/flares and elevated levels of TNF.…”

“…Further, ileal biopsy samples from Crohn disease patients with ERstressed Paneth cells exhibit a higher incidence of AIEC and an increased risk for ileal disease, fistulizing disease, and the need for intestinal surgery. 99 Thus, both ER stress responses and autophagy seem to be crucial regulatory mechanisms in intestinal homeostasis and pathogenic inflammation in Crohn disease. Recently, other genes related to ER stress were found to be associated with Crohn disease, which further highlights the importance of this pathophysiological mechanism for IBD.…”

L’autophagie garante de l’immunité et de l’inflammation

“…La nature des cargos ciblés et dégradés par l'autophagie semble directement liée à l'état d'activation du [41]. Les cellules de Paneth des patients porteurs de ce polymorphisme présentent une persistance accrue de ces bactéries [42]. Leurs cellules dendritiques ont également un défaut d'autophagie conduisant à une perte d'activité bactéricide et lymphocyte, ce qui permet à la cellule d'adapter son métabolisme à ses besoins [25].…”

Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

“…Paneth cells in CD patients also show elevated endoplasmic reticulum stress, which could also be due to defective autophagy (Adolph et al, 2013;Deuring et al, 2014).…”