Mouse intestinal epithelial cells in the deficiency of Foxo1
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178650 | GEO | 2021/06/23
REPOSITORIES: GEO
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Project description:Colonic goblet cells respond to invading enteropathogens by secreting Muc2 mucin and other specific goblet cell proteins that physically entrap and expel microbes away from the epithelium. At present, it is unclear how innate effectors in the gut, including small cationic cathelicidin peptides secreted by the intestinal epithelium and leukocytes, contribute to mucus barrier defense during infections. In this study, we used cathelicidin-deficient (Camp-/-) mice, colonoids, and human colonic LS174T goblet cells to elucidate the mechanisms by which cathelicidin regulates goblet cell secretions in innate host defense against attaching/effacing Citrobacter rodentium. We showed that even though Camp-/- littermates infected with C. rodentium displayed increased fecal shedding and epithelial colonization, Muc2 mucin granules were retained in bloated colonic goblet cells that impaired mucus secretion and expressed less mucus-associated proteins, as quantified by proteomic analysis. C. rodentium infected Camp-/- littermates showed impaired reactive oxygen species (ROS) production and transcriptomic profiling associated with decreased ROS biosynthesis and an increase in ROS negative regulators. Camp-/- bone marrow derived macrophages produced less ROS than their wild-type counterparts. In LS174T goblet cells, human cathelicidin LL-37 promptly induced the secretion of goblet cell-associated TFF3 and RELMβ, which was dependent on ROS production. These findings demonstrate that cathelicidin signaling in colonic goblet cells regulates mucus and mucin-associated protein secretion via an ROS-dependent mechanism to clear bacterial infections and restore gut homeostasis.
2023-05-04 | PXD041957 | Pride
Project description:Background; MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohnâs disease. Methods and Findings; By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions; The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Experiment Overall Design: 3 individual mice from the Eeyore, Winnie or Wild-type strains were compared as groups. An Affymetrix ID was compared between groups if the ID was Present within two of the three mice within each grouping. IDs were compared by calculating the log2 of Group One average signal divided by Group 2 average signal.
2008-04-06 | E-GEOD-9913 | biostudies-arrayexpress
Project description:The intestinal microbiota fundamentally influences the development of a normal intestinal physiology and education and functioning of the mucosal immune system. Using the C. rodentium carrier model of germfree mice (GF), we found that colonization of adult GF with 14 selected commensals (OMM12+MC2) was sufficient to convert a carriers into responders through maturation of intestinal crypts, increasing intestinal angiogenesis and stimulation of the immune system. While the immature colon of C. rodentium infected GF did not allow sufficient extravasation of neutrophils into the gut lumen, colonization with these commensals triggered activation and proliferation of endothelial cells, enabling granulocytes to transmigrate into the gut lumen. Enhanced angiogenesis and morphological maturation development of the intestine was most likely due to sensing of commensals by Paneth cells and subsequent secretion of antimicrobial peptides and angiogenetic factors. This demonstrates the therapeutic value of few commensal bacteria to complete morphological and immunological maturation in of the adult intestinal mucosa enabling rendering this organ immunocompetent against infections and responsive to therapies.
2021-09-09 | GSE180156 | GEO
Project description:Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IkappaBzeta in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating autoimmune inflammatory diseases. Mechanistically, the IkappaBzeta deficiency results in Paneth cell loss and impaired expression of IL-17-inducible genes involved in IgA production. The Paneth cell loss is caused by aberrant activation of IFN-gamma signaling and a failure of IL-17-mediated recovery from IFN-gamma-induced damage. Thus, the IL-17R–IkappaBzeta axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop consisting of the gut microbiota and immune cells
2022-12-07 | GSE188253 | GEO
Project description:Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IkappaBzeta in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating autoimmune inflammatory diseases. Mechanistically, the IkappaBzeta deficiency results in Paneth cell loss and impaired expression of IL-17-inducible genes involved in IgA production. The Paneth cell loss is caused by aberrant activation of IFN-gamma signaling and a failure of IL-17-mediated recovery from IFN-gamma-induced damage. Thus, the IL-17R–IkappaBzeta axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop consisting of the gut microbiota and immune cells
2022-12-07 | GSE188252 | GEO
Project description:Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IkappaBzeta in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating autoimmune inflammatory diseases. Mechanistically, the IkappaBzeta deficiency results in Paneth cell loss and impaired expression of IL-17-inducible genes involved in IgA production. The Paneth cell loss is caused by aberrant activation of IFN-gamma signaling and a failure of IL-17-mediated recovery from IFN-gamma-induced damage. Thus, the IL-17R–IkappaBzeta axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop consisting of the gut microbiota and immune cells
2022-12-07 | GSE188196 | GEO
Project description:The mammalian gastrointestinal tract harbors a diverse microbiota residing in intimate contact with the host immune system. Though most associations are symbiotic or commensal, some resident bacteria (termed pathobionts) have the potential to induce disease in immunocompromised hosts. Type VI secretion systems (T6SSs) have recently emerged as a novel mechanism for forging microbial-host interactions during infection. We reveal here a unique protective role for the T6SS of Helicobacter hepaticus, a Gram-negative bacterium of the murine intestinal microbiota. The T6SS of H. hepaticus targets effector substrates to intestinal epithelial cells (IECs). Mutants in T6SSs display higher intracellular and cell-associated numbers upon incubation with IECs, and exhibit increased bacterial colonization of the gastrointestinal tract compared to wild-type bacteria. The T6SS accordingly directs an anti-inflammatory gene expression profile in IECs co-cultured with H. hepaticus. Remarkably, T6SS mutants induce an exacerbated pro-inflammatory response in an experimental model of colitis. CD4+ T cells isolated from T6SS mutant-colonized animals produce increased T-helper 17 (Th17) cytokines in response to IECs presenting H. hepaticus antigens. These data demonstrate that H. hepaticus intimately interacts with IECs and employs type VI secretion to establish a balanced host relationship by limiting microbial colonization and intestinal inflammation. We propose that altering host-bacterial equilibriums that lead to dysbiosis of the microbiota contributes to human disorders such as inflammatory bowel disease and colon cancer.
2010-06-01 | GSE20434 | GEO
Project description:Background MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. MUC2 homo-oligomerizes intracellularly into large secreted polymers which give mucus its viscous properties. The inflammatory bowel disease (IBD) ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, whereas goblet cells and the mucus layer are increased in the other major inflammatory bowel disease, Crohn’s disease. Methods and Findings By murine N-ethyl-N-nitrosourea-mutagenesis we identified two distinct non-complementing missense mutations in Muc2 exons encoding N- and C-terminal homo-oligomerization domains causing an ulcerative colitis-like phenotype. Both strains developed mild spontaneous distal intestinal inflammation, chronic diarrhea, rectal bleeding and prolapse, increased susceptibility to acute and chronic colitis induced by a luminal toxin, aberrant Muc2 biosynthesis, smaller goblet cell thecae (less stored mucin) and a diminished mucus barrier. Enhanced local production of IL-1beta, TNF-alpha and IFN-gamma was seen in the distal colon. The number of leukocytes within mesenteric lymph nodes was increased five-fold and leukocytes cultured in vitro produced both Th1 and Th2 cytokines (IFN-gamma, TNF-alpha and IL-13). Intestinal permeability was increased and the luminal bacterial flora were more heavily coated with immunoglobulin as occurs in IBD. This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis and wound repair. Expression of mutated Muc2 oligomerization domains in vitro demonstrated that aberrant Muc2 oligomerization underlies the ER stress. These models show that mutations in Muc2 oligomerization domains can lead to aberrant assembly of the Muc2 complex leading to ER stress, a depleted mucus barrier and intestinal inflammation. In ulcerative colitis we demonstrate similar accumulation of non-glycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in non-inflamed intestinal tissue. Conclusions The observations that mucin misfolding and ER stress lead directly to intestinal inflammation and that ER stress and goblet cell pathology occur in ulcerative colitis suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of colitis. Keywords: Single gene, multiple mutant comparison
2008-03-01 | GSE9913 | GEO
Project description:Chronic inflammatory bowel disease (IBD) causes disability, suffering and risk of colon cancer in over 30 million people globally. Here, we investigate 3 kindreds of IBD with mutations in the N-acetylgalactosamide alpha-2,6-sialyltransferase 1/ST6GALNAC1 (ST6) glycosyltransferase gene that is uniquely expressed in the goblet cells (GCs). These mutations cause defective sialic acid (SA) conjugation, elimination of the onco-antigen S-Tn (Sialyl-Tn), and altered glycosylation of the MUC2 protein, a key component of intestinal mucus. Decreased MUC2 sialylation increases susceptibility to bacterial proteolytic degradation and compromises the gastrointestinal (GI) mucus barrier. Mice harboring the patient ST6 mutations recapitulate human colitis and reveal that defective sialylation causes dysbiosis, butyrate overproduction, and impaired GI stem cell proliferation during injury. Thus, this new genetic disease illustrates how sialylation controls host-microbe homeostasis and reveals several new potential approaches to IBD treatment.
2022-03-17 | PXD028239 | Pride
Project description:The mechanisms by which the mouse pathogen Citrobacter rodentium triggers effacement of the brush border microvilli, colitis, hyperplasia and dysbiosis remain poorly understood. We investigated the impact of C. rodentium infection on the proteomic and metabolic landscapes of intestinal epithelial cells (IECs) in vivo using isobaric labeling proteomics and targeted metabolomics. We found that infection depletes proteins involved in butyrate uptake, glycolysis, TCA cycle, lipid metabolism and oxidative phosphorylation with aparallel, increased production of creatine/phosphocreatine and cholesterol. The evolving ecological niche within the infected gut was concomitant with a reduction in butyrate-producing commensal bacteria and expansion of Proteobacteria that can metabolize cholesterol. These changes coincide with the modulation of IEC transcription factors by C. rodentium, specifically phosphorylation of Kdm5a, demethylation of histone H3 (Lys-4) and cleavage of Srebp2. Taken together our results show that whilst engaging with the host in a race to control innate immune responses, C. rodentium and the changing microbiota shape the metabolism flow in IECs.
2018-01-10 | PXD005004 | Pride