Nod2: A Critical Regulator of Ileal Microbiota and Crohn’s Disease

Abstract

The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn’s disease (CD). NOD2 plays a key role in the regulation of microbiota in the small intestine. NOD2 is highly expressed in ileal Paneth cells that provide critical mechanism for the regulation of ileal microbiota through the secretion of anti-bacterial compounds. Genome mapping of CD patients revealed that loss of function mutations in NOD2 are associated with ileal CD. Genome-wide association studies further demonstrated that NOD2 is one of the most critical genetic factor linked to ileal CD. The bacterial community in the ileum is indeed dysregulated in Nod2-deficient mice. Nod2-deficient ileal epithelia exhibit impaired ability of killing bacteria. Thus, altered interactions between ileal microbiota and mucosal immunity through NOD2 mutations play significant roles in the disease susceptibility and pathogenesis in CD patients, thereby depicting NOD2 as a critical regulator of ileal microbiota and CD.

LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation

“…Lahiri et al (30) identified LACC1 in both the cytoplasmic and mitochondrial cellular fractions of the cell and report that LACC1 associates with, and is required for, the optimal assembly of NOD2-signaling intermediates following NOD2 stimulation. Given that NOD2 loss of function mutations predispose to Crohn disease (31), these data are consistent with the LACC1 loss of function data reported in this paper.…”

Human β-Defensin 2 Mediated Immune Modulation as Treatment for Experimental Colitis

“…Moreover, in UC compromised mucus production, due to depletion of goblet cells, is a key triggering event in disease pathology, whereas CD is characterized by a defective intestinal barrier, which associates with complex defensin deficiencies based on a variety of mechanisms (6)(7)(8)(9)(10). The best described genetic links to small intestinal CD (11), i.e., NOD2, ATG16L1, XBPD1, are functionally involved in Paneth cell function (12)(13)(14)(15). Paneth cells of the small intestine secrete different antimicrobial peptides into the intestinal lumen.…”

MecCog: A knowledge representation framework for genetic disease mechanism

“…Following this step, the lower abundance of the NOD2-RICK complex alters downstream NF-κB signaling (SSP6àMM6àSSP7) (Caruso et al, 2014;Lécine et al, 2007;Barnich et al, 2005;Girardin et al, 2003), resulting in lower pro-inflammatory cytokine production, so contributing to an altered activation of the immune response (MM10) (Vilela et al, 2012;Park et al, 2007;Strober and Watanabe, 2011;Negroni et al, 2018). The perturbation of the NOD2-ATG16L1 complex affects the xenophagy process (autophagy against bacteria) (MM7) (Travassos et al, 2010) so leading to an increase in the abundance of bacteria in the lamina propria (SSP9) (Sidiq et al, 2016) showing stimulation of NOD2 by MDP binding induces production of defensin HNP-1 (human neutrophil peptide 1) in Caco-2 cells (Yamamoto-Furusho et al, 2010). It has also been shown that the NOD2 1007fs protein fails to induce the production of defensin hBD2 (human β-defensin-2) in several epithelial cell lines (Voss et al, 2006).…”