scholarly journals Paneth cell–derived growth factors support tumorigenesis in the small intestine

2020 ◽  
Vol 4 (3) ◽  
pp. e202000934
Author(s):  
Qing Chen ◽  
Kohei Suzuki ◽  
Luis Sifuentes-Dominguez ◽  
Naoteru Miyata ◽  
Jie Song ◽  
...  
Keyword(s):  
Small Intestine ◽  
Growth Factors ◽  
Small Bowel ◽  
Genetic Model ◽  
Paneth Cell ◽  
Tumor Formation ◽  
Intestinal Epithelial ◽  
Α Subunit ◽  
Conditional Expression ◽  
Small Intestinal

Paneth cells (PCs) are small intestinal epithelial cells that secrete antimicrobial peptides and growth factors, such as Wnt ligands. Intriguingly, the context in which PC-derived Wnt secretion is relevant in vivo remains unknown as intestinal epithelial ablation of Wnt does not affect homeostatic proliferation or restitution after irradiation injury. Considering the importance of growth factors in tumor development, we explored here the role of PCs in intestinal carcinogenesis using a genetic model of PC depletion through conditional expression of diphtheria toxin-α subunit. PC depletion in ApcMin mice impaired adenoma development in the small intestine and led to decreased Wnt3 expression in small bowel adenomas. To determine if PC-derived Wnt3 was required for adenoma development, we examined tumor formation after PC-specific ablation of Wnt3. We found that this was sufficient to decrease small intestinal adenoma formation; moreover, organoids derived from these tumors displayed slower growth capacity. Overall, we report that PC-derived Wnt3 is required to sustain early tumorigenesis in the small bowel and identify a clear role for PC-derived Wnt production in intestinal pathology.

scholarly journals Intestinal Neurod1 expression impairs paneth cell differentiation and promotes enteroendocrine lineage specification

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hui Joyce Li ◽  
Subir K. Ray ◽  
Ning Pan ◽  
Jody Haigh ◽  
Bernd Fritzsch ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Intestinal Epithelial Cells ◽  
Paneth Cell ◽  
Substantial Reduction ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Intestinal Epithelial ◽  
Conditional Expression

AbstractTranscription factor Neurod1 is required for enteroendocrine progenitor differentiation and maturation. Several earlier studies indicated that ectopic expression of Neurod1 converted non- neuronal cells into neurons. However, the functional consequence of ectopic Neurod1 expression has not been examined in the GI tract, and it is not known whether Neurod1 can similarly switch cell fates in the intestine. We generated a mouse line that would enable us to conditionally express Neurod1 in intestinal epithelial cells at different stages of differentiation. Forced expression of Neurod1 throughout intestinal epithelium increased the number of EECs as well as the expression of EE specific transcription factors and hormones. Furthermore, we observed a substantial reduction of Paneth cell marker expression, although the expressions of enterocyte-, tuft- and goblet-cell specific markers are largely not affected. Our earlier study indicated that Neurog3+ progenitor cells give rise to not only EECs but also Goblet and Paneth cells. Here we show that the conditional expression of Neurod1 restricts Neurog3+ progenitors to adopt Paneth cell fate, and promotes more pronounced EE cell differentiation, while such effects are not seen in more differentiated Neurod1+ cells. Together, our data suggest that forced expression of Neurod1 programs intestinal epithelial cells more towards an EE cell fate at the expense of the Paneth cell lineage and the effect ceases as cells mature to EE cells.

Positional specificity of defensin gene expression reveals Paneth cell heterogeneity in mouse small intestine

1996 ◽  
Vol 271 (1) ◽  
pp. G68-G74 ◽  
Author(s):  
D. Darmoul ◽  
A. J. Ouellette
Keyword(s):  
Gene Expression ◽  
Small Intestine ◽  
Small Bowel ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Northern Blot Hybridization ◽  
Positional Specificity ◽  
Defensin Gene ◽  
Proximal Small Bowel ◽  
Mouse Small Intestine

Cryptdins are antimicrobial peptides of the defensin family that are expressed specifically by Paneth cells in small intestinal crypts (M.E. Selsted, S.I. Miller, A.H. Henschen, and A.J. Ouellette. J. Cell Biol. 118: 929-936, 1992), and at least 17 cryptdin isoforms have been reported in mouse small intestine (A.J. Ouellette, M.M. Hsieh, M.T. Nosek, D.F. Cano-Gauci, K.M. Huttner, R.N. Buick, and M.E. Selsted. Infect. Immun. 62: 5040-5047, 1994). Analysis of cryptdin gene expression in adult mouse small bowel revealed that the cryptdin-4 isoform is differentially expressed along the proximal-to-distal intestinal axis. By peptide-specific reverse transcriptase-polymerase chain reaction-based assays, cryptdin-4 mRNA was found to be absent from the proximal small bowel, increasing to maximal levels in the ileum. In contrast, intestinal content of cryptdin-1 and -5 mRNAs was equivalent in duodenum, jejunum, and ileum, and Northern blot hybridization experiments were consistent with both sets of data. Similarly, individual crypts isolated from duodenum contain cryptdin-1 mRNA but not cryptdin-4 mRNA. Taken together, the results show that Paneth cells are heterogeneous, depending on their position along the longitudinal axis of the small bowel. The positional specificity of defensin gene expression suggests that cryptdins may be useful markers for investigating the establishment and maintenance of this epithelial lineage in the mouse small intestine.

scholarly journals Immunocytochemical localization of ornithine transcarbamylase in rat intestinal mucosa. Light and electron microscopic study.

1988 ◽  
Vol 36 (1) ◽  
pp. 29-35 ◽  
Author(s):  
Y Hamano ◽  
H Kodama ◽  
M Yanagisawa ◽  
Y Haraguchi ◽  
M Mori ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Small Intestine ◽  
Epithelial Cells ◽  
Light Microscopy ◽  
Intestinal Mucosa ◽  
Intestinal Epithelial Cells ◽  
Protein A ◽  
Intestinal Epithelial ◽  
Electron Microscopic ◽  
Small Intestinal

We investigated light and electron microscopic localization of ornithine transcarbamylase (OTC) in rat intestinal mucosa. In the immunoblotting assay of OTC-related protein, a single protein band with a molecular weight of about 36,500 is observed in extracts of liver and small intestinal mucosa but is not observed in those of stomach and large intestine. For light microscopy, tissue slices of the digestive system were embedded in Epon and stained by using anti-bovine OTC rabbit IgG and the immunoenzyme technique. For electron microscopy, slices of these and the liver tissues were embedded in Lowicryl K4M and stained by the protein A-gold technique. By light microscopy, the absorptive epithelial cells of duodenum, jejunum, and ileum stained positively for OTC, but stomach, large intestine, rectum, and propria mucosa of small intestine were not stained. Electron microscopy showed that gold particles representing the antigenic sites for OTC were confined to the mitochondrial matrix of hepatocytes and small intestinal epithelial cells. However, the enzyme was detected in mitochondria of neither liver endothelial cells, submucosal cells of small intestine, nor large intestinal epithelial cells. Labeling density of mitochondria in the absorptive epithelial cells of duodenum, jejunum, and ileum was about half of that in liver cells.

scholarly journals Update in Small Bowel Physiology: Part 1

1990 ◽  
Vol 4 (6) ◽  
pp. 243-254
Author(s):  
RJ Fingerote ◽  
S Churnratanakul ◽  
M Keelan ◽  
K Madsen ◽  
ABR Thomson
Keyword(s):  
Small Intestine ◽  
Small Bowel ◽  
Human Disease ◽  
Intestinal Function ◽  
The Past ◽  
Recent Advances ◽  
Small Intestinal ◽  
Clinical Advances

The recent advances in clinically important diseases of the small intestine have been reviewed; however, the basis for many of these clinical advances rests with important observations on alterations in the physiology of the small intestine, as well as mechanistic observations of alterations in small intestinal function in models of human disease. In this review a summary of the past year's literature is presented which will draw attention to the considerable areas of progress in small bowel physiology which will soon be translated into an improved understanding of the pathophysiology of a variety of intestinal disorders.

scholarly journals Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8+ T cells

2021 ◽  
Author(s):  
Malte Lehmann ◽  
Kristina Allers ◽  
Claudia Heldt ◽  
Jenny Meinhardt ◽  
Franziska Schmidt ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Complex Disease ◽  
Gastrointestinal Symptoms ◽  
Duodenal Mucosa ◽  
Intestinal Epithelial ◽  
Mass Cytometry ◽  
Upper Airways ◽  
Histomorphological Changes ◽  
Small Intestinal

AbstractThe SARS-CoV-2 pandemic has so far claimed over three and a half million lives worldwide. Though the SARS-CoV-2 mediated disease COVID-19 has first been characterized by an infection of the upper airways and the lung, recent evidence suggests a complex disease including gastrointestinal symptoms. Even if a direct viral tropism of intestinal cells has recently been demonstrated, it remains unclear, whether gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or whether they are a consequence of a systemic immune activation and subsequent modulation of the mucosal immune system. To better understand the cause of intestinal symptoms we analyzed biopsies of the small intestine from SARS-CoV-2 infected individuals. Applying qRT-PCR and immunohistochemistry, we detected SARS-CoV-2 RNA and nucleocapsid protein in duodenal mucosa. In addition, applying imaging mass cytometry and immunohistochemistry, we identified histomorphological changes of the epithelium, which were characterized by an accumulation of activated intraepithelial CD8+ T cells as well as epithelial apoptosis and subsequent regenerative proliferation in the small intestine of COVID-19 patients. In summary, our findings indicate that intraepithelial CD8+ T cells are activated upon infection of intestinal epithelial cells with SARS-CoV-2, providing one possible explanation for gastrointestinal symptoms associated with COVID-19.

scholarly journals The small bowel microbiome changes significantly with age and aspects of the ageing process

2022 ◽  
Vol 9 (1) ◽  
pp. 21-23
Author(s):  
Gabriela Leite ◽  
Mark Pimentel ◽  
Gillian M. Barlow ◽  
Ruchi Mathur
Keyword(s):  
Small Intestine ◽  
Small Bowel ◽  
Intestinal Microbiome ◽  
Ageing Process ◽  
Age Related ◽  
Human Ageing ◽  
Stool Samples ◽  
Older Subjects ◽  
Small Intestinal ◽  
Host Metabolism

Gut microbiome changes have been associated with human ageing and implicated in age-related diseases including Alzheimer’s disease and Parkinson’s disease. However, studies to date have used stool samples, which do not represent the entire gut. Although more challenging to access, the small intestine plays critical roles in host metabolism and immune function. In this paper (Leite et al. (2021), Cell Reports, doi: 10.1016/j.celrep.2021.109765), we demonstrate significant differences in the small intestinal microbiome in older subjects, using duodenal aspirates from 251 subjects aged 18-80 years. Differences included significantly decreased microbial diversity in older subjects, driven by increased relative abundance of phylum Proteobacteria, particularly family Enterobacteriaceae and coliform genera Escherichia and Klebsiella. Moreover, while this decreased diversity was associated with the ‘ageing process’ (comprising chronologic age, number of medications, and number of concomitant diseases), changes in certain taxa were found to be associated with number of medications alone (Klebsiella), number of diseases alone (Clostridium, Bilophila), or chronologic age alone (Escherichia, Lactobacillus, Enterococcus). Lastly, many taxa associated with increasing chronologic age were anaerobes. These changes may contribute to changes in human health that occur during the ageing process.

scholarly journals Small intestine barrier function failure induces systemic inflammation in monosodium glutamate-induced chronically obese mice

2019 ◽  
Vol 44 (6) ◽  
pp. 587-594 ◽  
Author(s):  
Kazuhiko Nakadate ◽  
Tomoya Hirakawa ◽  
Sawako Tanaka-Nakadate
Keyword(s):  
Small Intestine ◽  
Epithelial Cells ◽  
Systemic Inflammation ◽  
Intestinal Epithelial Cells ◽  
Monosodium Glutamate ◽  
Intestinal Epithelial ◽  
Obese Mice ◽  
Gastrointestinal Barrier ◽  
Small Intestinal ◽  
Functional Deterioration

Chronic obesity has increased worldwide, in conjunction with type 2 diabetes. Chronic obesity causes systemic inflammation that may result in functional deterioration of the gastrointestinal barrier. However, gastrointestinal conditions associated with chronic obesity have not been comprehensively investigated. The purpose of this study was to evaluate morphological changes in small intestine barrier structures during chronic obesity. A mouse model of chronic obesity induced by monosodium glutamate treatment was established. At postnatal week 15, pathological changes including in small intestinal epithelial cells were analyzed in chronically obese mice compared with controls. Numerous gaps were identified between small intestinal epithelial cells in chronically obese mice, and levels of both desmosomal and tight junction proteins were significantly lower in their small intestinal epithelial cells. Moreover, in chronically obese mice, a significant increase in the number of intestinal inflammatory cells, particularly macrophages, was observed; in addition, blood samples from the mouse model show an increase in markers of inflammation, tumor necrosis factor-alpha and interleukin-1-beta. These findings suggest that functional deterioration of adhesion structures between small intestinal epithelial cells causes gastrointestinal barrier function failure, leading to a rise in intestinal permeability to blood vessels and consequent systemic inflammation, characterized by macrophage infiltration.

scholarly journals Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats

2012 ◽  
Vol 109 (4) ◽  
pp. 667-677 ◽  
Author(s):  
Aude Bressenot ◽  
Shabnam Pooya ◽  
Carine Bossenmeyer-Pourie ◽  
Guillaume Gauchotte ◽  
Adeline Germain ◽  
...  
Keyword(s):  
Small Intestine ◽  
Small Bowel ◽  
Barrier Function ◽  
Paneth Cell ◽  
Cell Number ◽  
Nuclear Antigen ◽  
Methyl Donors ◽  
Distal Small Bowel ◽  
Proximal Small Bowel ◽  
Enterocyte Differentiation

Dietary methyl donors and their genetic determinants are associated with Crohn's disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 0·30 mm v. controls 0·58 mm; P< 0·001) with increased crypt apoptosis (3·37 v. 0·4 %; P< 0·001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 3·37 % v. controls 0·4 %, P< 0·001) and the Apostain labelling index showed increased crypt apoptosis (3·5 v. 1·4 %; P= 0·018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 52·83 % v. controls 83·17 %; P= 0·048) and proliferating cell nuclear antigen-positive cells (46·25 v. 59 %; P= 0·05). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of β-catenin and a decreased β-catenin–E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 8·66 % v. controls 21·66 %) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 8·66 v. 15·33 %; villus 7 v. 17 %). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats.

scholarly journals Endoscopic Evaluation of the Small Intestine

2002 ◽  
Vol 16 (3) ◽  
pp. 178-185 ◽  
Author(s):  
Steven J Shields ◽  
Jacques van Dam
Keyword(s):  
Small Intestine ◽  
Small Bowel ◽  
Intestinal Bleeding ◽  
Endoscopic Evaluation ◽  
Design And Development ◽  
Intestinal Pathology ◽  
Small Intestinal ◽  
Small Bowel Endoscopy

Technological achievements in the area of endoscope design and development have resulted in instruments capable of advancing beyond the reach of simple gastroscopes. Such instruments, known as enteroscopes, form the bases of small bowel endoscopy. Recent widespread use of enteroscopes have contributed significantly to the understanding of small intestinal pathology and improved the ability to diagnose and treat patients with intestinal bleeding sources.

scholarly journals An INF-STAT Axis Augments Tissue Damage and Inflammation in a Mouse Model of Crohn's Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Iris Stolzer ◽  
Anja Dressel ◽  
Mircea T. Chiriac ◽  
Markus F. Neurath ◽  
Claudia Günther
Keyword(s):  
Cell Death ◽  
Small Intestine ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Cell Function ◽  
Paneth Cell ◽  
Intestinal Epithelial ◽  
Jak Inhibitors ◽  
Inflammatory Bowel ◽  
Epithelial Cell Death

Blocking interferon-function by therapeutic intervention of the JAK-STAT-axis is a novel promising treatment option for inflammatory bowel disease (IBD). Although JAK inhibitors have proven efficacy in patients with active ulcerative colitis (UC), they failed to induce clinical remission in patients with Crohn's disease (CD). This finding strongly implicates a differential contribution of JAK signaling in both entities. Here, we dissected the contribution of different STAT members downstream of JAK to inflammation and barrier dysfunction in a mouse model of Crohn's disease like ileitis and colitis (Casp8ΔIEC mice). Deletion of STAT1 in Casp8ΔIEC mice was associated with reduced cell death and a partial rescue of Paneth cell function in the small intestine. Likewise, organoids derived from the small intestine of these mice were less sensitive to cell death triggered by IBD-key cytokines such as TNFα or IFNs. Further functional in vitro and in vivo analyses revealed the impairment of MLKL-mediated necrosis as a result of deficient STAT1 function, which was in turn associated with improved cell survival. However, a decrease in inflammatory cell death was still associated with mild inflammation in the small intestine. The impact of STAT1 signaling on gastrointestinal inflammation dependent on the localization of inflammation, as STAT1 is essential for intestinal epithelial cell death regulation in the small intestine, whereas it is not the key factor for intestinal epithelial cell death in the context of colitis. Of note, additional deletion of STAT2 was not sufficient to restore Paneth cell function but strongly ameliorated ileitis. In summary, we provide here compelling molecular evidence that STAT1 and STAT2, both contribute to intestinal homeostasis, but have non-redundant functions. Our results further demonstrate that STATs individually affect the distinct pathophysiology of inflammation in the ileum and colon, respectively, which might explain the diverse outcome of JAK inhibitors on inflammatory bowel diseases.

Sign in / Sign up

Export Citation Format

Share Document