Browsing by Subject "Colitis"
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Item Bacterial colitis(1980-09-11) Dietschy, John M.Item Changes in the Gut Metabolic Landscape Drive Inflammation-Associated Dysbiosis and Host Responses(2020-12-01T06:00:00.000Z) Hughes, Elizabeth Rose; Sperandio, Vanessa; Pfeiffer, Julie K.; Alto, Neal; Winter, Sebastian E.Intestinal inflammation is frequently associated with alterations in composition of gut microbial communities, termed dysbiosis. Inflammation-associated dysbiosis is characterized by an expansion of facultative anaerobic bacteria in the Proteobacteria phylum, such as Escherichia coli. A dysbiotic microbiota has been linked to increased disease severity in the context of inflammatory bowel disease. However, the mechanisms responsible for inflammation-associated dysbiosis and its impact on disease are incompletely understood. Utilizing bioinformatic analyses of gut microbiota composition and mechanistic studies with Escherichia coli as a model organism in murine models, we uncovered two metabolic pathways that are unique to intestinal inflammation and responsible for changes in microbiota composition. Aerobic respiration coupled with formate oxidation, and utilization of molecular hydrogen fuel expansion of Escherichia coli populations during intestinal inflammation. The impact of oxygen leakage into the gut lumen on obligate anaerobic bacterial metabolism was additionally investigated. In vitro metabolite measurements and use of bacterial genetics indicated formate production increased in Bacteroides exposed to low oxygen levels. Formate measurements and exogenous delivery of formate in mice suggested that intestinal formate levels increase during inflammation and may exacerbate disease. However, further study is required. In conclusion, we identified key changes that occur during non-infectious inflammation in the gut metabolic landscape, illustrating the importance of understanding bacterial metabolism in order to understand host-microbiota interactions.Item A Chemically Induced Colitis Screen Reveals the Necessity for Membrane Traffic in Intestinal Homeostasis(2019-03-21) McAlpine, William Elliott; Winter, Sebastian E.; Beutler, Bruce; Burstein, Ezra; Schmid, Sandra; Scherer, PhilippInflammatory bowel disease is most commonly a complex disorder caused by the interaction of environmental and genetic aberrations. Under normal conditions, a genetic program actively prevents inflammatory bowel disease, preventing invasion of microbes without permitting severe inflammation of the gut. To identify genes that maintain this balance, we performed a sensitized screen of 49,420 third generation (G3) germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires, bearing 104,658 coding/splicing mutations. We induced mild mucosal damage in these mice by orally administering dextran sodium sulfate (DSS) and found mutations that led to diarrhea and weight loss under these conditions. Causative mutations were mapped concurrently with screening using an automated mapping procedure. Among 114 DSS phenotypes identified and mapped, 36 have been validated by CRISPR/Cas9 targeting. Three vesicle trafficking genes, Myo1d, Smcr8, and Tvp23b, were selected for mechanistic evaluation. MYO1D is a class I myosin that binds both actin and lipid. MYO1D localizes to the basolateral membrane of enterocytes and functions in the intestinal epithelium to protect against colitis. SMCR8, along with C9ORF72 and WDR41, is a member of a tripartite complex that functions as a guanine exchange factor. SMCR8 localizes to the lysosome, and its absence results in perturbations to endocytic and phagocytic pathways. Hyperactivation of endosomal Toll-like receptors in Smcr8-/- mice causes spontaneous inflammation, and hyperactivation of multiple pathways contributes to DSS susceptibility. TVP23B is a trans-Golgi protein that binds YIPF6. Both TVP23B and YIPF6 are necessary for the formation of secretory granules in goblet and Paneth cells of the intestinal epithelium. These studies reveal non-redundant molecules required for the return of normal physiologic balance within the intestine after DSS insult.Item LRBA Restricts Murine Colitis by Regulating Interferon Responses and Autophagy(2018-11-27) Wang, Kuan-Wen; Pascual, Juan M.; Malter, James; Chen, Zhijian J.; Beutler, BruceLrba encodes lipopolysaccharide-responsive and beige like anchor (LRBA) protein, which was originally identified as an LPS-inducible gene in immune cells. LRBA putatively regulates the recycling and degradation of proteins critical for immune quiescence in human lymphocytes. However, recent studies showed that Lrba-deficient rodents had normal adaptive immune responses. Mutations in Lrba are associated with the immune deficiency, autoimmunity, and inflammatory bowel diseases (IBDs) in human; however it is unclear how LRBA regulates intestinal homeostasis and the cellular mechanisms it involves in. Here, I showed that LRBA is critical for both adaptive and innate immunity by regulating T cell, dendritic cells and intestinal epithelial cells to control inflammation. Lrba-deficient (Lrba-/-) mice showed a murine model colitis-DSS-induced colitis, and LRBA expression was essential in the hematopoietic (in both adaptive and non-adaptive) and non-hematopoietic compartment to prevent colitis susceptibility. LRBA regulates T cell homeostasis and activation, and Lrba-/- T cells skew to more effector subsets, especially Th1 and Th17 condition, but not to naïve and regulatory subsets (naïve T and regulatory T cells) in splenocytes and colon lamina propria lymphocytes. Furthermore, Lrba-/- naïve T cells showed a greater potential to become activated, lead to intestinal inflammation. Moreover, the possible mechanism that LRBA regulates T cell function is through PI3K/AKT/mTOR signaling. Bone marrow-derived dendritic cells (BMDCs) from Lrba-/- mice contribute to intestinal inflammation in an adaptive immune cells-independent manner. Lrba-/- BMDCs displayed an accumulated endosomal Toll-like receptor (TLR) ligands in the lysosomes, and led to excessive interferons (IFNs) signaling in response to endosomal TLR stimulation through IRF3/7 pathway that was PI3K/AKT/mTOR pathway-dependent. Furthermore, blocking the endosomal TLRs translocation to endolysosome/lysosome by genetically disturbs UNC93B1 to reduce enhanced IFN signaling that partially ameliorated the experimentally-induced colitis severity. Accumulated autophagosomes was observed in both BMDCs and intestinal epithelial cells in LRBA deficient condition. The possibly impaired autophagosome-lysosome fusion led to the defect of autophagy might be the reason for accumulated autophagosomes, further exaggerated a potential intracellular cell stress from dysfunctional organelles to dampen the inflammation from the dysregulated endosomal TLR signaling. Taking together, the possibility of LRBA functions in the process of vesicle fusion (endosome-autophagosome-lysosome) that suggests LRBA could be as a new potential linker between innate endosomal TLR signaling, adaptive immune functions and autophagy. Therefore, deficiency of LRBA can lead to excessive inflammatory responses and induction of colitis.Item Ulcerative colitis(1961-08-24) UnknownItem Understanding and improving inflammatory bowel disease care in 2022: the gut and beyond(2022-06-24) Fudman, David