Foxo1 controls gut homeostasis and commensalism by regulating mucus secretion

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Zuojia Chen ◽  
Jialie Luo ◽  
Jian Li ◽  
Girak Kim ◽  
Eric S. Chen ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Cell Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Short Chain Fatty Acids ◽  
Mucus Secretion ◽  
Intestinal Epithelial ◽  
Forkhead Box ◽  
Junction Proteins

Mucus produced by goblet cells in the gastrointestinal tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been well studied. Here, we identify that Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in defects in goblet cell autophagy and mucus secretion, leading to an impaired gut microenvironment and dysbiosis. Subsequently, due to changes in microbiota and disruption in microbiome metabolites of short-chain fatty acids, Foxo1 deficiency results in altered organization of tight junction proteins and enhanced susceptibility to intestinal inflammation. Our study demonstrates that Foxo1 is crucial for IECs to establish commensalism and maintain intestinal barrier integrity by regulating goblet cell function.

Red wine extract preserves tight junctions in intestinal epithelial cells under inflammatory conditions: implications for intestinal inflammation

2019 ◽  
Vol 10 (3) ◽  
pp. 1364-1374 ◽  
Author(s):  
Carla Nunes ◽  
Víctor Freitas ◽  
Leonor Almeida ◽  
João Laranjinha
Keyword(s):  
Red Wine ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Tight Junction Proteins ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli ◽  
Wine Polyphenols ◽  
Red Wine Polyphenols ◽  
Junction Proteins

Red wine polyphenols protect the intestinal barrier against inflammatory stimuli by modulating the gene expression of key tight junction proteins.

scholarly journals Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism

2018 ◽  
Vol 115 (43) ◽  
pp. 11036-11041 ◽  
Author(s):  
Yasuharu Nagahama ◽  
Mayuko Shimoda ◽  
Guoliang Mao ◽  
Shailendra Kumar Singh ◽  
Yuuki Kozakai ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Body Weight Loss ◽  
Purine Metabolism ◽  
Intestinal Epithelial ◽  
Beneficial Effects ◽  
Epithelial Regeneration ◽  
Mtorc1 Signaling ◽  
Inflammatory Bowel

Damage to intestinal epithelial cell (IEC) layers during intestinal inflammation is associated with inflammatory bowel disease. Here we show that the endoribonuclease Regnase-1 controls colon epithelial regeneration by regulating protein kinase mTOR (the mechanistic target of rapamycin kinase) and purine metabolism. During dextran sulfate sodium-induced intestinal epithelial injury and acute colitis, Regnase-1∆IEC mice, which lack Regnase-1 specifically in the intestinal epithelium, were resistant to body weight loss, maintained an intact intestinal barrier, and showed increased cell proliferation and decreased epithelial apoptosis. Chronic colitis and tumor progression were also attenuated in Regnase-1∆IEC mice. Regnase-1 predominantly regulates mTORC1 signaling. Metabolic analysis revealed that Regnase-1 participates in purine metabolism and energy metabolism during inflammation. Furthermore, increased expression of ectonucleotidases contributed to the resolution of acute inflammation in Regnase-1∆IEC mice. These findings provide evidence that Regnase-1 deficiency has beneficial effects on the prevention and/or blocking of intestinal inflammatory disorders.

Long noncoding RNA H19 disrupts the intestinal barrier by inhibiting Goblet cell function

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Ting-Xi Yu ◽  
Hee K. Chung ◽  
Lan Xiao ◽  
Shelley R. Wang ◽  
Min S. Kwon ◽  
...  
Keyword(s):  
Goblet Cell ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Function ◽  
Intestinal Barrier

scholarly journals Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
L. Contreras-Ruiz ◽  
A. Ghosh-Mitra ◽  
M. A. Shatos ◽  
D. A. Dartt ◽  
S. Masli
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Cell Function ◽  
Sjögren's Syndrome ◽  
Goblet Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-αand IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

scholarly journals Brain-Derived Neurotrophic Factor Modulates Intestinal Barrier by Inhibiting Intestinal Epithelial Cells Apoptosis in Mice

2018 ◽  
pp. 475-485 ◽  
Author(s):  
D.-Y. ZHAO ◽  
W.-X. ZHANG ◽  
Q.-Q. QI ◽  
X. LONG ◽  
X. LI ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Colonic Mucosa ◽  
Caspase 3 ◽  
Intestinal Epithelial Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Tight Junction Proteins ◽  
Intestinal Barrier Integrity ◽  
Junction Proteins ◽  
Active Caspase

We aimed to investigate the effects of brain-derived neurotrophic factor (BDNF) on apoptosis of intestinal epithelial cells (IECs) and alterations of intestinal barrier integrity using BDNF knock-out mice model. Colonic tissues from BDNF+/+ mice and BDNF+/- mice were prepared for this study. The integrity of colonic mucosa was evaluated by measuring trans-mucosa electrical resistance and tissue conductance in Ussing chamber. The colonic epithelial structure was analyzed by transmission electron microscopy. Apoptosis involvement was determined with TUNEL staining, active caspase-3 immunostaining and Western blotting for the protein expression of active caspase-3, Bax and Bcl-2. The expression levels and distribution of tight junction proteins were evaluated by immunohistochemistry or Western blots. Compared with BDNF+/+ mice, BDNF+/- mice displayed impaired integrity and ultrastructure alterations in their colonic mucosa, which was characterized by diminished microvilli, mitochondrial swelling and epithelial cells apoptosis. Altered intestinal barrier function was linked to excessive apoptosis of IECs demonstrated by the higher proportion of TUNEL-positive apoptotic cells and enhanced caspase activities in BDNF+/- mice. Increased expression of Bax and claudin-2 proteins and reduced Bcl-2 and tight junction proteins (occludin, ZO-1 and claudin-1) expression were also detected in the colonic mucosa of BDNF+/- mice. BDNF may play a role in the maintenance of intestinal barrier integrity via its anti-apoptotic properties.

scholarly journals Bifidobacterium dentiumFortifies the Intestinal Mucus Layer via Autophagy and Calcium Signaling Pathways

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Melinda A. Engevik ◽  
Berkley Luk ◽  
Alexandra L. Chang-Graham ◽  
Anne Hall ◽  
Beatrice Herrmann ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Signaling Pathways ◽  
Goblet Cell ◽  
Cell Function ◽  
Goblet Cells ◽  
Mucus Layer ◽  
Content Type ◽  
Intestinal Mucus ◽  
Intestinal Mucus Layer

ABSTRACTMuch remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer.Bifidobacteriumspecies colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, selectBifidobacteriumstrains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived speciesBifidobacterium dentiumwould increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans.In silicodata revealed thatB. dentiumlacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating thatB. dentiumcould not use naive mucin glycans as primary carbon sourcesin vitro. To examineB. dentiummucus modulationin vivo, Swiss Webster germfree mice were monoassociated with live or heat-killedB. dentium. LiveB. dentium-monoassociated mice exhibited increased colonic expression of goblet cell markersKrüppel-like factor 4(Klf4),Trefoil factor 3(Tff3),Relm-β,Muc2, and several glycosyltransferases compared to both heat-killedB. dentiumand germfree counterparts. Likewise, liveB. dentium-monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining.In vitro,B. dentium-secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified thatB. dentium-secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates thatB. dentiumis capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production.IMPORTANCEMicrobe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe,Bifidobacterium dentium, which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike otherBifidobacteriumspecies,B. dentiumdoes not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of usingB. dentiumand similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier.

scholarly journals Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

2015 ◽  
Vol 212 (10) ◽  
pp. 1513-1528 ◽  
Author(s):  
Paul R. Giacomin ◽  
Ryan H. Moy ◽  
Mario Noti ◽  
Lisa C. Osborne ◽  
Mark C. Siracusa ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Lymphoid Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Mucosal Surfaces ◽  
Host Mortality ◽  
Group 3

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.

scholarly journals Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Shilong Sun ◽  
Zehua Duan ◽  
Xinyu Wang ◽  
Chengnan Chu ◽  
Chao Yang ◽  
...  
Keyword(s):  
Er Stress ◽  
Intestinal Epithelial Cell ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Neutrophil Extracellular Traps ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Extracellular Traps ◽  
Epithelial Cell Death ◽  
Stress Activation

AbstractIncreased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.

EVALUATING THE ROLE OF GOBLET CELL ASSOCIATED ANTIGEN PASSAGES (GAPS) IN THE DEVELOPMENT OF MUCOSAL IMMUNE TOLERANCE IN THE CFTR KO INTESTINE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S33-S33
Author(s):  
Sarah Young ◽  
Keely McDonald ◽  
Rodney Newberry ◽  
Lane Clarke
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Goblet Cell ◽  
Intestinal Inflammation ◽  
Clinical Signs ◽  
Goblet Cells ◽  
Immunofluorescent Staining ◽  
Gap Formation ◽  
Tolerogenic Dendritic Cells ◽  
Chronic Intestinal Inflammation

Abstract Greater than 70,000 individuals worldwide are living with the monogenetic disease cystic fibrosis (CF). The development of chronic intestinal inflammation, with clinical signs resembling inflammatory bowel disease-like conditions, is a common yet poorly understood occurrence in CF patients. This inflammation is typically neutrophilic in human and animal models with a heightened basal pro-inflammatory cytokine release. Prior research utilizing intestinal organoids (enteroids) cultured from Cftr knockout mice has shown that goblet cells in the CF mouse intestine demonstrate defective clearance of mucin granules and abnormal mucus retention. Goblet cell-associated antigen passages (GAPs), located in the small intestine and colon, deliver intraluminal antigens to antigen-presenting dendritic cells in the submucosa. This mechanism serves as an important step in the development and maintenance of tolerogenic dendritic cell populations expressing receptors to luminal antigens with involvement of regulatory T cell activation and release of IL-10. We hypothesized that mucus plugging of goblet cells in the CF intestine leads to defective GAP formation and a consequent decrease in the expansion of tolerogenic dendritic cells. To test this hypothesis, Cftrtm1Unc (Cftr KO) and wild type (WT) sex-matched littermate pairs (n=2) maintained on a commercially available liquid diet (Peptamen®) were anesthetized with ketamine/xylazine for a laparotomy to inject a luminal fluorescent 10kD dextran dye into the mid-jejunum. After 30 min, the mice were euthanized with CO2, and the intestine was collected for immunofluorescent staining to evaluate GAP formation. In the WT intestine, the dextran dye was observed within goblet cells outlined by CK18 immunofluorescence, a goblet cell marker. Punctate dextran dye was observed in the submucosa, suggestive of dendritic cell uptake. In contrast, the Cftr KO mice demonstrated defective GAP formation, i.e., without dye penetration of goblet cells, and the lack of punctate dextran fluorescence in the submucosa. To evaluate the population of tolerogenic dendritic cells, small intestinal segments from Cftr KO-WT sex-matched littermate pairs (3-female and 2-male pairs) were collected for FACS sorting of submucosal CD103+ (tolerogenic) and CD103- (pro-inflammatory) dendritic cells. The WT mice had a significantly higher population of CD103+ tolerogenic dendritic cells compared to the CF mice (WT: 20.5+/-2, CF: 9.2+/-3, P < 0.006). A trend towards an increase in CD103- dendritic cells was seen in the CF intestine. In summary, the CF mice were found to have defective intraluminal antigen transfer through the GAP pathway and a significant decrease in tolerogenic dendritic cells in the intestine.

scholarly journals Intestinal barrier breakdown and mucosal microbiota disturbance in neuromyelitis optical spectrum disorder

2020 ◽  
Author(s):  
Chunping Cui ◽  
Sha Tan ◽  
Li Tao ◽  
Junli Gong ◽  
Yanyu Chang ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Water Channel ◽  
Intestinal Barrier ◽  
Inflammatory Cells ◽  
Amplicon Sequencing ◽  
Spectrum Disorder ◽  
Pathophysiological Mechanism ◽  
Intestinal Dysbiosis ◽  
Barrier Breakdown ◽  
Junction Proteins

Abstract Background and purpose The mechanism underlying the pathology of neuromyelitis optica spectrum disorder (NMOSD) remains unclear even though increased expression of the water channel protein aquaporin-4 (AQP4) on astrocytes plays an important role. Our previous study revealed that dysbiosis was detected in the faecal microbiota of NMOSD patients. In this study, we further investigated whether the intestinal barrier and mucosal flora balance were also interrupted in NMOSD patients. Methods Sigmoid mucosal biopsies were collected via endoscopy from six patients with NMOSD and compared with those from three patients with multiple sclerosis (MS) and five healthy controls (HCs). These samples were processed for electron microscopy and immunohistochemistry to investigate changes in ultrastructure and in the number and size of intestinal inflammatory cells. Changes in mucosal flora were also analysed by high-throughput 16S ribosomal RNA gene amplicon sequencing. Results The intercellular space between epithelia of the colonic mucosa became wider in MS and NMOSD patients compared to the HCs (P < 0.01), and the expression of tight junction proteins in MS and NMOSD patients significantly decreased compared to that in the HCs. Activation of microphages with many inclusions inside the cytoplasm and enlarged plasmocytes with more particles were found in the NMOSD group. Quantitative analysis showed that the percentage of small-size CD 38 + and CD138 + cells was lower but that of larger-size cells became higher in NMOSD patients, and 16S data showed that the abundance of Streptococcus and Granulicatella was dramatically increased in NMOSD patients. Conclusions NMOSD patients exhibited a disrupted intestinal barrier and intestinal dysbiosis and activation of intestinal inflammation, which suggested a potential pathophysiological mechanism of NMOSD underlying intestinal inflammation.

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