scholarly journals Emc3 maintains intestinal homeostasis by preserving secretory lineages

2021 ◽  
Author(s):  
Meina Huang ◽  
Li Yang ◽  
Ning Jiang ◽  
Quanhui Dai ◽  
Runsheng Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Dominant Role ◽  
Paneth Cell ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Paneth Cells ◽  
Intestinal Barrier Function ◽  
Endoplasmic Reticulum Membrane ◽  
Mucus Production

AbstractIntestinal exocrine secretory lineages, including goblet cells and Paneth cells, provide vital innate host defense to pathogens. However, how these cells are specified and maintained to ensure intestinal barrier function remains poorly defined. Here we show that endoplasmic reticulum membrane protein complex subunit 3 (Emc3) is essential for differentiation and function of exocrine secretory lineages. Deletion of Emc3 in intestinal epithelium decreases mucus production by goblet cells and Paneth cell population, along with gut microbial dysbiosis, which result in spontaneous inflammation and increased susceptibility to DSS-induced colitis. Moreover, Emc3 deletion impairs stem cell niche function of Paneth cells, thus resulting in intestinal organoid culture failure. Mechanistically, Emc3 deficiency leads to increased endoplasmic reticulum (ER) stress. Mitigating ER stress with tauroursodeoxycholate acid alleviates secretory dysfunction and restores organoid formation. Our study identifies a dominant role of Emc3 in maintaining intestinal mucosal homeostasis.

The role of butyrate in surgical and oncological outcomes in colorectal cancer

2021 ◽  
Author(s):  
Roy Hajjar ◽  
Carole S Richard ◽  
Manuela M Santos
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Intestinal Barrier ◽  
Inhibitory Effect ◽  
Intestinal Barrier Function ◽  
Current Evidence ◽  
Mucus Production ◽  
Antineoplastic Effect ◽  
The Impact

Butyrate is a short-chain fatty acid produced by colonic gut bacteria as a result of fermentation of dietary fibers. In the colon, butyrate is a major energy substrate and contributes to the nutritional support and proliferation of a healthy mucosa. It also promotes the intestinal barrier function by enhancing mucus production and tight junctions. In addition to its pro-proliferative effect in healthy colonocytes, butyrate inhibits the proliferation of cancer cells. The antineoplastic effect of butyrate is associated with the inhibitory effect of butyrate on histone deacetylase (HDAC) enzymes, which promote carcinogenesis. Due to the metabolic shift of cancer cells toward glycolysis, unused butyrate accumulates and inhibits procarcinogenic HDACs. In addition, recent studies suggest that butyrate may improve the healing of colonic tissue after surgery in animal models, specifically at the site of reconnection of colonic ends - anastomosis - after surgical resection. Here, we review current evidence on the impact of butyrate on epithelial integrity and colorectal cancer and present current knowledge on data that support its potential applications in surgical practice.

scholarly journals Puerarin improves intestinal barrier function through enhancing goblet cells and mucus barrier

2020 ◽  
Vol 75 ◽  
pp. 104246
Author(s):  
Jiaojiao Li ◽  
Li Zhang ◽  
Yafei Li ◽  
Yi Wu ◽  
Tao Wu ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Intestinal Barrier Function ◽  
Mucus Barrier

scholarly journals Loss of NHE8 expression impairs intestinal mucosal integrity

2015 ◽  
Vol 309 (11) ◽  
pp. G855-G864 ◽  
Author(s):  
Aiping Wang ◽  
Jing Li ◽  
Yang Zhao ◽  
Malin E. V. Johansson ◽  
Hua Xu ◽  
...  
Keyword(s):  
Periodic Acid ◽  
Paneth Cell ◽  
Distal Colon ◽  
Goblet Cells ◽  
Paneth Cells ◽  
Wild Type ◽  
Periodic Acid Schiff ◽  
Mucin Production ◽  
Mucosal Integrity ◽  
Mucin 2

The newest member of the Na+/H+ exchanger (NHE) family, NHE8, is abundantly expressed at the apical membrane of the intestinal epithelia. We previously reported that mucin 2 expression was significantly decreased in the colon in NHE8−/− mice, suggesting that NHE8 is involved in intestinal mucosal protection. In this study, we further evaluated the role of NHE8 in intestinal epithelial protection after dextran sodium sulfate (DSS) challenge. Compared with wild-type mice, NHE8−/− mice have increased bacterial adhesion and inflammation, especially in the distal colon. NHE8−/− mice are also susceptible to DSS treatment. Real-time PCR detected a remarkable increase in the expression of IL-1β, IL-6, TNF-α, and IL-4 in DSS-treated NHE8−/− mice compared with DSS-treated wild-type littermates. Immunohistochemistry showed a disorganized epithelial layer in the colon of NHE8−/− mice. Periodic acid-Schiff staining showed a reduction in the number of mature goblet cells and the area of the goblet cell theca in NHE8−/− mice. Phyloxine/tartrazine staining revealed a decrease in functional Paneth cell population in the NHE8−/− small intestinal crypt. The expression of enteric defensins was also decreased in NHE8−/− mice. The reduced mucin production in goblet cells and antimicrobial peptides production in Paneth cells lead to disruption of the intestinal mucosa protection. Therefore, NHE8 may be involved in the establishment of intestinal mucosal integrity by regulating the functions of goblet and Paneth cells.

Colitis Linked to Endoplasmic Reticulum Stress Induces Trypsin Activity Affecting Epithelial Functions

2021 ◽  
Author(s):  
Núria Solà Tapias ◽  
Alexandre Denadai-Souza ◽  
Claire Rolland-Fourcade ◽  
Muriel Quaranta-Nicaise ◽  
Catherine Blanpied ◽  
...  
Keyword(s):  
Er Stress ◽  
Serine Protease ◽  
Barrier Function ◽  
Protease Activity ◽  
Intestinal Epithelial Cells ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Trypsin Activity ◽  
Serine Protease Activity

Abstract Background and Aims Intestinal epithelial cells [IECs] from inflammatory bowel disease [IBD] patients exhibit an excessive induction of endoplasmic reticulum stress [ER stress] linked to altered intestinal barrier function and inflammation. Colonic tissues and the luminal content of IBD patients are also characterized by increased serine protease activity. The possible link between ER stress and serine protease activity in colitis-associated epithelial dysfunctions is unknown. We aimed to study the association between ER stress and serine protease activity in enterocytes and its impact on intestinal functions Methods The impact of ER stress induced by Thapsigargin on serine protease secretion was studied using either human intestinal cell lines or organoids. Moreover, treating human intestinal cells with protease-activated receptor antagonists allowed us to investigate ER stress-resulting molecular mechanisms that induce proteolytic activity and alter intestinal epithelial cell biology. Results Colonic biopsies from IBD patients exhibited increased epithelial trypsin-like activity associated with elevated ER stress. Induction of ER stress in human intestinal epithelial cells displayed enhanced apical trypsin-like activity. ER stress-induced increased trypsin activity destabilized intestinal barrier function by increasing permeability and by controlling inflammatory mediators such as C-X-C chemokine ligand 8 [CXCL8]. The deleterious impact of ER stress-associated trypsin activity was specifically dependent on the activation of protease-activated receptors 2 and 4. Conclusions Excessive ER stress in IECs caused an increased release of trypsin activity that, in turn, altered intestinal barrier function, promoting the development of inflammatory process.

scholarly journals Docosahexaenoic and Eicosapentaenoic Acids Prevent Altered-Muc2 Secretion Induced by Palmitic Acid by Alleviating Endoplasmic Reticulum Stress in LS174T Goblet Cells

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2179
Author(s):  
Quentin Escoula ◽  
Sandrine Bellenger ◽  
Michel Narce ◽  
Jérôme Bellenger
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Goblet Cells ◽  
The Impact

Diets high in saturated fatty acids (FA) represent a risk factor for the development of obesity and associated metabolic disorders, partly through their impact on the epithelial cell barrier integrity. We hypothesized that unsaturated FA could alleviate saturated FA-induced endoplasmic reticulum (ER) stress occurring in intestinal secretory goblet cells, and consequently the reduced synthesis and secretion of mucins that form the protective mucus barrier. To investigate this hypothesis, we treated well-differentiated human colonic LS174T goblet cells with palmitic acid (PAL)—the most commonly used inducer of lipotoxicity in in vitro systems—or n-9, n-6, or n-3 unsaturated fatty acids alone or in co-treatment with PAL, and measured the impact of such treatments on ER stress and Muc2 production. Our results showed that only eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids protect goblet cells against ER stress-mediated altered Muc2 secretion induced by PAL, whereas neither linolenic acid nor n-9 and n-6 FA are able to provide such protection. We conclude that EPA and DHA could represent potential therapeutic nutrients against the detrimental lipotoxicity of saturated fatty acids, associated with type 2 diabetes and obesity or inflammatory bowel disease. These in vitro data remain to be explored in vivo in a context of dietary obesity.

scholarly journals The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

2020 ◽  
Vol 11 ◽  
Author(s):  
Han Cheng ◽  
Xiaokun Gang ◽  
Guangyu He ◽  
Yujia Liu ◽  
Yingxuan Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Insulin Signaling ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Glucose Sensing ◽  
Hepatic Insulin Resistance ◽  
Endoplasmic Reticulum Membrane ◽  
Hepatic Insulin Signaling

Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.

BODIPY–Coumarin Conjugate as an Endoplasmic Reticulum Membrane Fluidity Sensor and Its Application to ER Stress Models

2015 ◽  
Vol 26 (12) ◽  
pp. 2474-2480 ◽  
Author(s):  
Hoyeon Lee ◽  
Zhigang Yang ◽  
Youngjin Wi ◽  
Tae Woo Kim ◽  
Peter Verwilst ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Membrane Fluidity ◽  
Endoplasmic Reticulum Membrane ◽  
Stress Models

scholarly journals The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion

2018 ◽  
Vol 315 (2) ◽  
pp. G195-G205 ◽  
Author(s):  
Martin Stahl ◽  
Sarah Tremblay ◽  
Marinieve Montero ◽  
Wayne Vogl ◽  
Lijun Xia ◽  
...  
Keyword(s):  
Cell Function ◽  
Paneth Cell ◽  
Goblet Cells ◽  
Paneth Cells ◽  
Phenotypic Differences ◽  
Cell Functions ◽  
First Time ◽  
Electron Lucent ◽  
Granule Release

Paneth cells are a key subset of secretory epithelial cells found at the base of small intestinal crypts. Unlike intestinal goblet cells, which secrete the mucin Muc2, Paneth cells are best known for producing an array of antimicrobial factors. We unexpectedly identified Muc2 staining localized around Paneth cell granules. Electron microscopy (EM) confirmed an electron lucent halo around these granules, which was lost in Paneth cells from Muc2-deficient (−/−) mice. EM and immunostaining for lysozyme revealed that Muc2−/− Paneth cells contained larger, more densely packed granules within their cytoplasm, and we detected defects in the transcription of key antimicrobial genes in the ileal tissues of Muc2−/− mice. Enteroids derived from the small intestine of wild-type and Muc2−/− mice revealed phenotypic differences in Paneth cells similar to those seen in vivo. Moreover, lysozyme-containing granule release from Muc2−/− enteroid Paneth cells was shown to be impaired. Surprisingly, Paneth cells within human ileal and duodenal tissues were found to be Muc2 negative. Thus Muc2 plays an important role in murine Paneth cells, suggesting links in function with goblet cells; however human Paneth cells lack Muc2, highlighting that caution should be applied when linking murine to human Paneth cell functions. NEW & NOTEWORTHY We demonstrate for the first time that murine Paneth cell granules possess a halo comprised of the mucin Muc2. The presence of Muc2 exerts an impact on Paneth cell granule size and number and facilitates the release and dispersal of antimicrobials into the mucus layer. Interestingly, despite the importance of Muc2 in murine Paneth cell function, our analysis of Muc2 in human intestinal tissues revealed no trace of Muc2 expression by human Paneth cells.

scholarly journals Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice

2020 ◽  
Vol 3 (6) ◽  
pp. e201900592
Author(s):  
Yu Shimizu ◽  
Kiminori Nakamura ◽  
Aki Yoshii ◽  
Yuki Yokoi ◽  
Mani Kikuchi ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Er Stress ◽  
Disease Progression ◽  
Intestinal Microbiota ◽  
Disulfide Bonds ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Lumen ◽  
Reduced Form

Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

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