The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases  Benoit Chassaing, Arlette Darfeuille–Michaud  Gastroenterology  Volume 140, Issue 6, Pages 1720-1728.e3 (May 2011) DOI: 10.1053/j.gastro.2011.01.054 Copyright © 2011 AGA Institute Terms and Conditions

Figure 1 The microbiota and host genetic and environmental factors contribute to pathogenesis of Crohn's disease. (Left panel) In healthy individuals, commensal and anti-inflammatory bacteria interact with the GI mucosa to maintain homeostasis. This involves recognition of pathogen-associated molecular pattern (PAMPs) derived from microbes by intestinal mucosa and a physiologic host response involving IgA and IgG and α- and β-defensins. The microbial community prevents the proinflammatory effects of harmful bacteria that are present and mediate tolerance. (Right panel) In patients with IBD, abnormal interaction between host cells and microbes perturb homeostasis, leading to intestinal inflammation. Inflammation could arise from host genetic factors that affect barrier functions, innate and adaptative immunity, and qualitative and/or quantitative changes in the composition of the microbiota. Gastroenterology 2011 140, 1720-1728.e3DOI: (10.1053/j.gastro.2011.01.054) Copyright © 2011 AGA Institute Terms and Conditions

Figure 2 AIEC infection and loop of colonization and inflammation. In the early phase of CD development (left panel), extracellular AIEC (in green) adhere to the healthy ileal mucosa via type 1 pili recognizing CEACAM6 abnormally expressed by intestinal cells in CD patients. AIEC are able to invade intestinal epithelial cells and breach the intestinal barrier, allowing them to gain access to the lamina propria. By having access to the basolateral membrane, AIEC bacteria can induce IL-8 and CCL20 secretion by intestinal epithelial cells through the interaction between flagellin and Toll-like receptor 5, leading to the recruitment of neutrophils and dendritic cells. After phagocytosis by macrophages/dendritic cells, intracellular AIEC (in orange) replicate in a large vacuole, inducing production of TNF-α and IL-12, which activates Th1 cells to produce IFN-γ. In inflamed ileal mucosa (right panel) expression of CEACAM6 is increased in response to TNF-α and IFN-γ stimulation and AIEC infection of intestinal epithelial cells, creating loop of colonization and inflammation that leads to chronic disease with the secretion of proinflammatory cytokines IL-6, IL-12, IL-23, and IL-17. Gastroenterology 2011 140, 1720-1728.e3DOI: (10.1053/j.gastro.2011.01.054) Copyright © 2011 AGA Institute Terms and Conditions

Figure 3 Four contributing ways of AIEC to CD. (A) AIEC colonize the GI tract using type 1 pili variants to adhere to the ileal mucosa. The type 1 pili variants bind to mannose residues of CEACAM6, which is expressed at high levels on the apical surface of ileal epithelial cells in patients with ileal CD. (B) The ER stress response protein Gp96 is overexpressed on the apical surface of ileal epithelial cells in patients with CD. Gp96 acts as a host-cell receptor for outer membrane vesicles released by AIEC, promoting AIEC invasion of the mucosa. (C) Intracellular AIEC bacteria replicate uncontrollably in host cells with autophagy defects caused by variants of ATG16L1, IRGM, or NOD2. (D) In patients with CD, variants in NOD2 increase the numbers of membranous/microfold cells. AIEC express long polar fimbriae, which allows the bacteria to interact with Peyer's patches and to translocate across monolayers of membranous/microfold cells. Gastroenterology 2011 140, 1720-1728.e3DOI: (10.1053/j.gastro.2011.01.054) Copyright © 2011 AGA Institute Terms and Conditions

Gastroenterology 2011 140, 1720-1728. e3DOI: (10. 1053/j. gastro. 2011 Copyright © 2011 AGA Institute Terms and Conditions

Gastroenterology 2011 140, 1720-1728. e3DOI: (10. 1053/j. gastro. 2011 Copyright © 2011 AGA Institute Terms and Conditions