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Host‐bacteria interactions in the intestine: homeostasis to chronic inflammation

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Abstract In the past decade it has become clear that the gut constitutes an important frontier of the body, which not only regulates the selective entry of nutrients while keeping vigilant against pathogens but also is largely responsible for shaping the immune response to educate the organism to recognize self from non‐self. The very notion of self has undergone a dramatic change, with the acknowledgment that our ‘selves’ include a plethora of microbial species that actively participate in our body's homeostasis. The immune system continuously adapts to the microbiota in a cyclic, dynamic cross talk where intestinal epithelial cells play an important role in instructing noninflammatory responses for a steady‐state control of bacterial growth, or triggering inflammatory mechanisms that can clear the gut from harmful invaders. The system is complex and robust in the sense that many players with partially overlapping roles act to keep the integrity of the intestinal mucosal barrier. Failure of these mechanisms involves genetic and environmental triggers and leads to inflammatory bowel disease. In this review, we seek to collect the state‐of‐the‐art knowledge about how host and microbiota interact to promote gut homeostasis and provide evidences of malfunctioning of the described mechanisms in human inflammatory bowel disease. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Physiology > Organismal Responses to Environment

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Mucosal barrier changes in inflammatory bowel disease. Normal colon is protected by a thick mucus layer (upper scheme; adapted from Ref 15). Normal microbiota occupy up to 10% of mucus and are rarely found close to the mucosal surface. There are no adherent or invasive bacteria, epithelium is integer, and bacterial products can stimulate epithelial cells apically, be captured by dendritic cells (DCs) that extend to the lumen or be translocated through the epithelium. Colitogenic bacteria are competed out by gut commensals. During colitis, the colon has a more than 10‐fold reduced mucus thickness, and mucus can be completely lost in some areas (following a patchy distribution). Increased numbers of bacteria and leukocytes are present in the mucus close to the mucosa, and a high percentage of the epithelium presents adherent bacteria. The control of colitogenic and invasive bacteria expansion is lost. Areas of denuded submucosa are also frequent, allowing direct stimulation of basolateral receptors in epithelial cells and submucosal cells including blood‐recruited DCs or DC precursors by bacteria and bacterial products.

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Intestinal epithelial cells (IECs) play a central role in host–microbiota interaction, promoting the active maintenance of gut homeostasis. Commensal bacteria compounds have been shown both to downmodulate IECs responsiveness to microbial compounds (1) and to enhance epithelial cell survival. Gut microbes may also favor mucus secretion (2), and participate in keeping the integrity of the mucosal barrier. The maintenance of the intestinal noninflammatory environment is ensured by the presence of elevated amounts of transforming growth factor (TGF)‐β, secreted by IECs and IECs‐conditioned dendritic cells (DCs) and T regulatory cells (3–6). IECs can drive the proliferation of preexisting Foxp3+ T regulatory cells of the lamina propria (3), and IECs‐derived TGF‐β production is involved in the generation of mucosal T regulatory cells from naïve T cells (4) or ROR‐γt+ precursors (5) and inhibition of T cell differentiation toward T helper (Th)1 (4) and Th17 (5) phenotypes. Naïve T cell differentiation into T regulatory cells is also fostered by the activity of IECs‐conditioned, thymic stromal lymphopoietin (TSLP)‐activated CD103+ DCs that produce TGF‐β, retinoic acid (RA), and IL‐10 (6). CX3CR1+ DCs, stimulated by bacterial antigens, as well as CD70+ DCs responding to luminal adenosine triphosphate (ATP) released by bacteria, can help driving the differentiation of Th17 cells that may collaborate to restrict bacterial growth in gut's mucosa (7), a response that can be fine‐tuned by the balance between Th17‐driving IL‐6 and IL‐23 and T regulatory‐driving TGF‐β in the mucosal compartment. Finally, TSLP‐activated CD103+ DCs can drive the differentiation of Th2 cells (8), which provide help for soluble immunoglobulin A (SIgA) production. IECs and tissue resident DCs can also collaborate in the steady‐state sensing of microbial antigens and control of gut microbiota's expansion by driving noninflammatory T cell independent Ig class switch and SIgA production by mucosal B cells (9). SIgA can act both by promoting adherent bacteria growth and by restricting the potentially harmful proliferation of gut bacteria (10). Inflammation, with the recruitment of nonconditioned peripheral blood DCs as well as local activation of lamina propria DCs toward a non‐tolerogenic phenotype, can be secondary to mucosal breaching and basolateral activation of pattern recognition receptors in the basolateral membrane of IECs that respond to injury by releasing chemoattractants and pro‐inflammatory mediators (11).

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