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Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [RNA-seq]

ABSTRACT: To determine how constitutively active autophagy in Becn1F121A mice affects the colonic tissue, we performed a transcriptional analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE220457 | GEO | 2023/02/03

REPOSITORIES: GEO

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Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [16S]

Project description:To determine how constitutively active autophagy in Becn1F121A mice affects the fecal microbiota, we performed a 16s analysis.

2023-02-03 | GSE220883 | GEO

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress.

Project description:Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.

| S-EPMC10016318 | biostudies-literature

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress super

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-03 | GSE220884 | GEO

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress super

Project description:Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress super

| PRJNA911802 | ENA

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [16S]

Project description:Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [16S]

| PRJNA911803 | ENA

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [RNA-seq]

Project description:Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress [RNA-seq]

| PRJNA909805 | ENA

Cathelicidin deficiency disrupts goblet cell mucus secretion but not mucus associated proteins in Citrobacter rodentium-induced colitis

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

Clearance of small intestinal crypts involves goblet cell mucus secretion by intracellular granule rupture and enterocyte ion transport.

Project description:Goblet cells in the small intestinal crypts contain large numbers of mucin granules that are rapidly discharged to clean bacteria from the crypt. Because acetylcholine released by neuronal and nonneuronal cells controls many aspects of intestinal epithelial function, we used tissue explants and organoids to investigate the response of the small intestinal crypt to cholinergic stimulation. The activation of muscarinic acetylcholine receptors initiated a coordinated and rapid emptying of crypt goblet cells that flushed the crypt contents into the intestinal lumen. Cholinergic stimulation induced an expansion of the granule contents followed by intracellular rupture of the mucin granules. The mucus expanded intracellularly before the rupture of the goblet cell apical membrane and continued to expand after its release into the crypt lumen. The goblet cells recovered from membrane rupture and replenished their stores of mucin granules. Mucus secretion from the goblet cells depended on Ca2+ signaling and the expansion of the mucus in the crypt depended on gap junctions and on ion and water transport by enterocytes adjacent to the goblet cells. This distinctive mode of mucus secretion, which we refer to as "expanding secretion," efficiently cleans the small intestine crypt through coordinated mucus, ion, and fluid secretion by goblet cells and enterocytes.

| S-EPMC9749883 | biostudies-literature

NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion.

Project description:Mucus production by goblet cells of the large intestine serves as a crucial antimicrobial protective mechanism at the interface between the eukaryotic and prokaryotic cells of the mammalian intestinal ecosystem. However, the regulatory pathways involved in goblet cell-induced mucus secretion remain largely unknown. Here, we demonstrate that the NLRP6 inflammasome, a recently described regulator of colonic microbiota composition and biogeographical distribution, is a critical orchestrator of goblet cell mucin granule exocytosis. NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion into the large intestinal lumen. Consequently, NLRP6 inflammasome-deficient mice are unable to clear enteric pathogens from the mucosal surface, rendering them highly susceptible to persistent infection. This study identifies an innate immune regulatory pathway governing goblet cell mucus secretion, linking nonhematopoietic inflammasome signaling to autophagy and highlighting the goblet cell as a critical innate immune player in the control of intestinal host-microbial mutualism. PAPERCLIP:

| S-EPMC4017640 | biostudies-literature

Novel Human NKCC1 Mutations Cause Defects in Goblet Cell Mucus Secretion and Chronic Inflammation.

Project description:Background & aimsInfections resulting from intestinal yeast and bacteria affect a large number of patients with deficits in absorptive or secretory epithelial transport mechanisms. The basolateral Na+-K+-2Cl- cotransporter (NKCC1) has been implicated in intestinal epithelial fluid secretion. Two patients with deleterious heterozygous (NKCC1-DFX, DFX for Asp-Phe-stop codon) or homozygous (Kilquist) mutations in SLC12A2 (NKCC1) suffered from gastrointestinal deficits. Because of chronic infections, the colon and the small intestine of the NKCC1-DFX patient were resected surgically.MethodsTo investigate how NKCC1 affects the integrity and function of the gut epithelia, we used a mouse model recapitulating the NKCC1-DFX patient mutation. Electron microscopy and immunostaining were used to analyze the integrity of the colonic mucus layers and immune cell infiltration. Fluorescence in situ hybridization was performed on the distal colon sections to measure bacteria translocation to the mucosa and submucosa. Citrobacter rodentium was used to measure mouse ability to clear enteric infection. A multiplex cytokine assay was used to analyze mouse inflammatory response to infection.ResultsWe show that NKCC1-DFX expression causes defective goblet cell mucus granule exocytosis, leading to secretion of intact granules into the lumen of the large intestine. In addition, NKCC1-DFX colon submucosal glands secrete mucus that remained attached to the epithelium. Importantly, expression of the mutant NKCC1 or complete loss of NKCC1 function leads to aggravated inflammatory response to C rodentium infection. Compared with wild-type, NKCC1-DFX mice showed decreased expression of claudin-2, a tight junction protein involved in paracellular Na+ and water transport and enteric infection clearance.ConclusionsOur data indicate that NKCC1-DFX impairs gut barrier function by affecting mucus secretion and immune properties.

| S-EPMC6957845 | biostudies-literature

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