Microbial Influences in Inflammatory Bowel Diseases R. Balfour Sartor  Gastroenterology  Volume 134, Issue 2, Pages 577-594 (February 2008) DOI: 10.1053/j.gastro.2007.11.059 Copyright © 2008 AGA Institute Terms and Conditions

Figure 1 Composition and luminal concentrations of dominant microbial species in various regions of the gastrointestinal tract. Gastroenterology 2008 134, 577-594DOI: (10.1053/j.gastro.2007.11.059) Copyright © 2008 AGA Institute Terms and Conditions

Figure 2 Recognition of bacterial ligands by membrane-bound toll-like receptors (TLR) and nod-like receptors (NLR), with signaling through conserved pathways such as NF-κB and mitogen-activated protein kinases (MAPK) signal transduction pathways. Gastroenterology 2008 134, 577-594DOI: (10.1053/j.gastro.2007.11.059) Copyright © 2008 AGA Institute Terms and Conditions

Figure 3 Potential mechanisms by which enteric bacteria and fungi induce chronic immune-mediated intestinal injury. (A) Pathogenic bacteria. A traditional pathogen or functional alterations in commensal bacteria (increased epithelial adherence, invasion, resistance to killing) can lead to increased bacterial stimulation of innate and adaptive immune responses. (B) Abnormal microbial composition. Decreased concentrations of protective bacteria that produce SCFA such as butyrate can enhance mucosal permeability. Conversely, increased concentrations of aggressive bacteria increase the amount of adjuvants and antigens that induce pathogenic immune responses or increase production of toxic metabolites such as hydrogen sulfide (H2S) that increase mucosal permeability and block butyrate metabolism. (C) Defective host containment of commensal bacteria. Defective secretion of antimicrobial peptides or secretory IgA can lead to mucosal bacterial overgrowth, whereas defective killing of phagocytosed bacteria can lead to persistent intracellular bacteria and ineffective clearance of bacterial antigens. Increased mucosal permeability can result in overwhelming exposure of bacterial TLR ligands and antigens that activate pathogenic innate and T-cell immune responses. (D) Defective host immunoregulation. Ineffective down-regulation of innate immune responses, either in epithelial or antigen-presenting cells (APC), can induce inflammatory responses through secretion of chemokines or proinflammatory cytokines. Dysfunction of regulatory T cells or APC can lead to overly aggressive T responses (loss of tolerance) to ubiquitous microbial antigens or induction of cross-reactive autoimmune responses because of molecular mimicry between host and microbial antigens. Gastroenterology 2008 134, 577-594DOI: (10.1053/j.gastro.2007.11.059) Copyright © 2008 AGA Institute Terms and Conditions

Figure 4 Pathogenesis of epithelial attachment and tissue injury with adherent/invasive E coli (AIEC). AIEC induce carcinoembryonic antigen cell adhesion molecule (CEACAM) 6, either directly or by stimulating production of TNF and interferon γ (IFNγ), and attach, invade, and stimulate macrophages and T cells in the lamina propria. Modified from Abraham C and Cho J, N Engl J Med 2007;357:708–710. Gastroenterology 2008 134, 577-594DOI: (10.1053/j.gastro.2007.11.059) Copyright © 2008 AGA Institute Terms and Conditions

Figure 5 Contrast of bacterial/epithelial and epithelial/immune interactions in mucosal homeostasis vs IBD. (A) The normal intestine has limited, controlled uptake of microbial antigens; exclusion of viable organisms; a state of nonresponsiveness of epithelial, innate, and adaptive immune cells; and secretion of IL-10 and TGF-β. (B) In IBD, functionally abnormal bacteria attach to and invade epithelial cells in the absence of secreted antimicrobial peptides (defensins) and persist within epithelial cells and phagocytic cells if intracellular killing is defective. Stimulation of Th1/Th17 cells by persistent secretion of IL-12, IL-23, IL-6, and TNF leads to chronic tissue injury and epithelial damage, which is perpetuated by ongoing translocation of enteric bacteria, microbial antigens, and TLR ligands. Gastroenterology 2008 134, 577-594DOI: (10.1053/j.gastro.2007.11.059) Copyright © 2008 AGA Institute Terms and Conditions