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Oxygen metabolism and innate immune responses in the gut.

ABSTRACT: Epithelial cells of the mucosa provide a first line of defense to prevent the inappropriate translocation of luminal antigens, and therefore contribute significantly to nonspecific innate immunity. In the gastrointestinal (GI) tract, barrier is provided by multiple components of the mucosa, including mucus production, epithelial junctional complexes, and the production of antimicrobial molecules. In recent years, it is better appreciated that tissue oxygen metabolism is key to homeostasis in the mucosa. The intestine, for example, maintains a low baseline Po2 level due to high rates of metabolism, countercurrent blood flow, and the presence of a steep oxygen gradient across the luminal aspect of tissue surface. As a result, hypoxia and hypoxia-inducible factor (HIF)-dependent signaling exists even in the healthy, unperturbed intestinal mucosa. In a number of examples, HIF has been demonstrated both to promote barrier function during homeostasis and to promote resolution of active inflammation. Hypoxia-elicited factors that contribute to innate responses in the mucosa include the transcriptional regulation of mucin genes, junction proteins, and autophagic flux. Here, we review current literature related to hypoxia and innate immunity in health and during mucosal inflammation.

SUBMITTER: Colgan SP

PROVIDER: S-EPMC5792101 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Oxygen metabolism and innate immune responses in the gut.

Colgan Sean P SP Campbell Eric L EL

Journal of applied physiology (Bethesda, Md. : 1985) 20170713 5

Epithelial cells of the mucosa provide a first line of defense to prevent the inappropriate translocation of luminal antigens, and therefore contribute significantly to nonspecific innate immunity. In the gastrointestinal (GI) tract, barrier is provided by multiple components of the mucosa, including mucus production, epithelial junctional complexes, and the production of antimicrobial molecules. In recent years, it is better appreciated that tissue oxygen metabolism is key to homeostasis in the ...[more]

PMID: 28705991

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Project description:BackgroundEarly microbial colonization of the gut reduces the incidence of infectious, inflammatory and autoimmune diseases. Recent population studies reveal that childhood hygiene is a significant risk factor for development of inflammatory bowel disease, thereby reinforcing the hygiene hypothesis and the potential importance of microbial colonization during early life. The extent to which early-life environment impacts on microbial diversity of the adult gut and subsequent immune processes has not been comprehensively investigated thus far. We addressed this important question using the pig as a model to evaluate the impact of early-life environment on microbe/host gut interactions during development.ResultsGenetically-related piglets were housed in either indoor or outdoor environments or in experimental isolators. Analysis of over 3,000 16S rRNA sequences revealed major differences in mucosa-adherent microbial diversity in the ileum of adult pigs attributable to differences in early-life environment. Pigs housed in a natural outdoor environment showed a dominance of Firmicutes, in particular Lactobacillus, whereas animals housed in a hygienic indoor environment had reduced Lactobacillus and higher numbers of potentially pathogenic phylotypes. Our analysis revealed a strong negative correlation between the abundance of Firmicutes and pathogenic bacterial populations in the gut. These differences were exaggerated in animals housed in experimental isolators. Affymetrix microarray technology and Real-time Polymerase Chain Reaction revealed significant gut-specific gene responses also related to early-life environment. Significantly, indoor-housed pigs displayed increased expression of Type 1 interferon genes, Major Histocompatibility Complex class I and several chemokines. Gene Ontology and pathway analysis further confirmed these results.ConclusionEarly-life environment significantly affects both microbial composition of the adult gut and mucosal innate immune function. We observed that a microbiota dominated by lactobacilli may function to maintain mucosal immune homeostasis and limit pathogen colonization.

Project description:BackgroundLeptospira interrogans is the major causative agent of leptospirosis. Phagocytosis plays important roles in the innate immune responses to L. interrogans infection, and L. interrogans can evade the killing of phagocytes. However, little is known about the adaptation of L. interrogans during this process.Methodology/principal findingsTo better understand the interaction of pathogenic Leptospira and innate immunity, we employed microarray and comparative genomics analyzing the responses of L. interrogans to macrophage-derived cells. During this process, L. interrogans altered expressions of many genes involved in carbohydrate and lipid metabolism, energy production, signal transduction, transcription and translation, oxygen tolerance, and outer membrane proteins. Among them, the catalase gene expression was significantly up-regulated, suggesting it may contribute to resisting the oxidative pressure of the macrophages. The expressions of several major outer membrane protein (OMP) genes (e.g., ompL1, lipL32, lipL41, lipL48 and ompL47) were dramatically down-regulated (10-50 folds), consistent with previous observations that the major OMPs are differentially regulated in vivo. The persistent down-regulations of these major OMPs were validated by immunoblotting. Furthermore, to gain initial insight into the gene regulation mechanisms in L. interrogans, we re-defined the transcription factors (TFs) in the genome and identified the major OmpR TF gene (LB333) that is concurrently regulated with the major OMP genes, suggesting a potential role of LB333 in OMPs regulation.Conclusions/significanceThis is the first report on global responses of pathogenic Leptospira to innate immunity, which revealed that the down-regulation of the major OMPs may be an immune evasion strategy of L. interrogans, and a putative TF may be involved in governing these down-regulations. Alterations of the leptospiral OMPs up interaction with host antigen-presenting cells (APCs) provide critical information for selection of vaccine candidates. In addition, genome-wide annotation and comparative analysis of TFs set a foundation for further studying regulatory networks in Leptospira spp.

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Oxygen metabolism and innate immune responses in the gut.

Publications

Oxygen metabolism and innate immune responses in the gut.

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