Correction for Cobo et al., “Entamoeba histolytica Alters Ileal Paneth Cell Functions in Intact and Muc2 Mucin Deficiency”

ABSTRACTEnteric α-defensins, termed cryptdins (Crps) in mice, and lysozymes secreted by Paneth cells contribute to innate host defense in the ileum. Antimicrobial factors, including lysozymes and β-defensins, are often embedded in luminal glycosylated colonic Muc2 mucin secreted by goblet cells that form the protective mucus layer critical for gut homeostasis and pathogen invasion. In this study, we investigated ileal innate immunity againstEntamoeba histolytica, the causative agent of intestinal amebiasis, by inoculating parasites in closed ileal loops inMuc2+/+andMuc2−/−littermates and quantifying Paneth cell localization (lysozyme expression) and function (Crp secretion). Relative toMuc2+/+littermates,Muc2−/−littermates showed a disorganized mislocalization of Paneth cells that was diffusely distributed, with elevated lysozyme secretion in the crypts and on villi in response toE. histolytica. Inhibition ofE. histolyticaGal/GalNAc lectin (Gal-lectin) binding with exogenous galactose andEntamoeba histolyticacysteine proteinase 5 (EhCP5)-negativeE. histolyticahad no effect on parasite-induced erratic Paneth cell lysozyme synthesis. Although the basal ileal expression ofCrpgenes was unaffected inMuc2−/−mice in response toE. histolytica, there was a robust release of proinflammatory cytokines and Crp peptide secretions in luminal exudates that was also present in the colon. Interestingly,E. histolytica-secreted cysteine proteinases cleaved the proregion of Crp4 but not the active form. These findings define Muc2 mucin as an essential component of ileal barrier function that regulates the localization and function of Paneth cells critical for host defense against microbes.

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Specific Responses in Rat Small Intestinal Epithelial mRNA Expression and Protein Levels During Chemotherapeutic Damage and Regeneration

Journal of Histochemistry & Cytochemistry ◽

10.1177/002215540205001113 ◽

2002 ◽

Vol 50 (11) ◽

pp. 1525-1536 ◽

Cited By ~ 30

Author(s):

Melissa Verburg ◽

Ingrid B. Renes ◽

Danielle J.P.M. Van Nispen ◽

Sacha Ferdinandusse ◽

Marieke Jorritsma ◽

...

Keyword(s):

Mrna Expression ◽

Goblet Cell ◽

Expression Patterns ◽

Paneth Cell ◽

Cytostatic Drug ◽

Differentiation Markers ◽

Protein Levels ◽

Cell Functions ◽

Enhanced Expression ◽

Small Intestinal

The rapidly dividing small intestinal epithelium is very sensitive to the cytostatic drug methotrexate. We investigated the regulation of epithelial gene expression in rat jejunum during methotrexate-induced damage and regeneration. Ten differentiation markers were localized on tissue sections and quantified at mRNA and protein levels relative to control levels. We analyzed correlations in temporal expression patterns between markers. mRNA expression of enterocyte and goblet cell markers decreased significantly during damage for a specific period. Of these, sucrase-isomaltase (-62%) and CPS (-82%) were correlated. Correlations were also found between lactase (−76%) and SGLT1 (−77%) and between I-FABP (−52%) and L-FABP (-45%). Decreases in GLUT5 (−53%), MUC2 (-43%), and TFF3 (−54%) mRNAs occurred independently of any of the other markers. In contrast, lysozyme mRNA present in Paneth cells increased (+76%). At the protein level, qualitative and quantitative changes were in agreement with mRNA expression, except for Muc2 (+115%) and TFF3 (+81%), which increased significantly during damage, following independent patterns. During regeneration, expression of each marker returned to control levels. The enhanced expression of cytoprotective molecules (Muc2, TFF3, lysozyme) during damage represents maintenance of goblet cell and Paneth cell functions, most likely to protect the epithelium. Decreased expression of enterocyte-specific markers represents decreased enterocyte function, of which fatty acid transporters were least affected.

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Paneth Cells and their Antimicrobials in Intestinal Immunity

Current Pharmaceutical Design ◽

10.2174/1381612824666180327161947 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1121-1129 ◽

Cited By ~ 8

Author(s):

Timon E. Adolph ◽

Lisa Mayr ◽

Felix Grabherr ◽

Herbert Tilg

Keyword(s):

Intestinal Inflammation ◽

Paneth Cell ◽

Paneth Cells ◽

Secretory Cells ◽

Intestinal Epithelial ◽

Intestinal Immunity ◽

Susceptibility To Infection ◽

Cell Functions ◽

Bowel Diseases ◽

Initial Description

Since the initial description of granular-rich small-intestinal crypt-based epithelial cells in 1872, today referred to as Paneth cells, a plethora of recent studies underlined their function in intestinal homeostasis. Paneth cells are evolutionary conserved highly secretory cells that produce antimicrobials to control gut microbial communities. Moreover, Paneth cells emerged as stem cell regulators that translate environmental cues into intestinal epithelial responses. Paneth cell disturbances may instigate intestinal inflammation and provide susceptibility to infection. Altered Paneth cell functions have been associated with a variety of inflammatory disease models and were linked to human intestinal disease processes including inflammatory bowel diseases such as Crohn´s disease and ulcerative colitis. This review summarizes our current understanding of Paneth cells and their antimicrobials in health and disease.

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Bile Acids Regulate Intestinal Paneth Cell Functions and Contribute to Gut Dysbiosis Induced by High Fat Feeding

Gastroenterology ◽

10.1016/s0016-5085(17)30927-7 ◽

2017 ◽

Vol 152 (5) ◽

pp. S184

Author(s):

Hui Zhou ◽

Merritt Gillilland ◽

Jun Gao ◽

Shi-Yi Zhou ◽

Guanpo Zhang ◽

...

Keyword(s):

Bile Acids ◽

Paneth Cell ◽

High Fat ◽

Cell Functions ◽

Gut Dysbiosis ◽

Fat Feeding

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R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease

Journal of Experimental Medicine ◽

10.1084/jem.20170418 ◽

2017 ◽

Vol 214 (12) ◽

pp. 3507-3518 ◽

Cited By ~ 35

Author(s):

Eiko Hayase ◽

Daigo Hashimoto ◽

Kiminori Nakamura ◽

Clara Noizat ◽

Reiki Ogasawara ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Fecal Microbiota Transplantation ◽

Paneth Cell ◽

Fecal Microbiota ◽

Paneth Cells ◽

Host Disease ◽

Graft Versus Host ◽

Cell Functions ◽

Therapeutic Benefits ◽

Physiological Approach

The intestinal microbial ecosystem is actively regulated by Paneth cell–derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host–microbiota cross talk toward therapeutic benefits.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00264.2017 ◽

2018 ◽

Vol 315 (2) ◽

pp. G195-G205 ◽

Cited By ~ 2

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.

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Evaluation of Amoebicidal Potential of Paneth Cell Cryptdin-2 against Entamoeba histolytica

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0001386 ◽

2011 ◽

Vol 5 (12) ◽

pp. e1386 ◽

Cited By ~ 11

Author(s):

Simran Preet ◽

Sanjay Bharati ◽

Geeta Shukla ◽

Ashwani Koul ◽

Praveen Rishi

Keyword(s):

Entamoeba Histolytica ◽

Paneth Cell

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Impaired 25-hydroxylation of vitamin D in liver injury suppresses intestinal Paneth cell defensins, leading to gut dysbiosis and liver fibrogenesis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00021.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. G685-G695

Author(s):

Pengfei Wu ◽

Ruofei Zhang ◽

Mei Luo ◽

Tianci Zhang ◽

Lisha Pan ◽

...

Keyword(s):

Vitamin D ◽

Innate Immunity ◽

Small Intestine ◽

Liver Diseases ◽

Paneth Cell ◽

Intestinal Immunity ◽

Cell Functions ◽

Gut Dysbiosis ◽

Liver Fibrogenesis

Vitamin D deficiency is coprevalent with various liver diseases, indicating the role of vitamin D in maintaining liver homeostasis. In this study, we observed that the hepatic 25-hydroxylation of VD is critical for intestinal innate immunity through VD signaling in the small intestine for maintaining Paneth cell functions. Conversely, failure of biogenesis of VD in the liver impairs intestinal immunity, leading to gut dysbiosis and endotoxemia, which promotes liver fibrogenesis.

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IFN-γ mediates Paneth cell death via suppression of mTOR

eLife ◽

10.7554/elife.60478 ◽

2021 ◽

Vol 10 ◽

Author(s):

Alessandra Araujo ◽

Alexandra Safronova ◽

Elise Burger ◽

Américo López-Yglesias ◽

Shilpi Giri ◽

...

Keyword(s):

Cell Death ◽

Intestinal Inflammation ◽

Paneth Cell ◽

Paneth Cells ◽

Cell Integrity ◽

Host Protection ◽

Cell Functions ◽

Cell Death Pathways ◽

Inflammatory Conditions ◽

Ifn Γ

Paneth cells constitutively produce antimicrobial peptides and growth factors that allow for intestinal homeostasis, host protection and intestinal stem cell replication. Paneth cells rely heavily on the glycolytic metabolic program, which is in part controlled by the kinase complex Mechanistic target of rapamycin (mTORC1). Yet, little is known about mTOR importance in Paneth cell integrity under steady state and inflammatory conditions. Our results demonstrate that IFN-γ, a crucial mediator of the intestinal inflammation, acts directly on murine Paneth cells to alter their mitochondrial integrity and membrane potential, resulting in an mTORC1-dependent cell death mechanism distinct from canonical cell death pathways including apoptosis, necroptosis, and pyroptosis. These results were established with the purified cytokine and a physiologically relevant common Th1-inducing human parasite Toxoplasma gondii. Given the crucial role for IFN-γ, which is a cytokine frequently associated with the development of inflammatory bowel disease (IBD) and compromised Paneth cell functions, the identified mechanisms underlying mTORC1-dependent Paneth cell death downstream of IFN-γ may provide promising novel approaches for treating intestinal inflammation.

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