scholarly journals Loss of intestinalO-glycans promotes spontaneous duodenal tumors

2016 ◽  
Vol 311 (1) ◽  
pp. G74-G83 ◽  
Author(s):  
Nan Gao ◽  
Kirk Bergstrom ◽  
Jianxin Fu ◽  
Biao Xie ◽  
Weichang Chen ◽  
...  
Keyword(s):  
Small Intestine ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Duodenal Mucosa ◽  
Intestinal Epithelial ◽  
Double Knockout ◽  
Adult Mice ◽  
Epithelial Homeostasis ◽  
Mucus Barrier

Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1−/−; C3GnT−/−or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.

The Role of Serotonin in Intestinal Epithelial Homeostasis

2010 ◽  
Vol 158 (2) ◽  
pp. 186
Author(s):  
E.R. Gross ◽  
A.R. Ruiz-Elizalde ◽  
Z.V. Gertsberg ◽  
M.D. Gershon ◽  
R.A. Cowles
Keyword(s):  
Intestinal Epithelial ◽  
Epithelial Homeostasis

scholarly journals Role of Intestinal Epithelial Cells in Immune Effects Mediated by Gram-Positive Probiotic Bacteria: Involvement of Toll-Like Receptors

2005 ◽  
Vol 12 (9) ◽  
pp. 1075-1084 ◽  
Author(s):  
Gabriel Vinderola ◽  
Chantal Matar ◽  
Gabriela Perdigon
Keyword(s):  
Small Intestine ◽  
B Cells ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Primary Cultures ◽  
Clonal Expansion ◽  
Probiotic Bacteria ◽  
Intestinal Epithelial ◽  
Toll Like Receptors

ABSTRACT The mechanisms by which probiotic bacteria exert their effects on the immune system are not completely understood, but the epithelium may be a crucial player in the orchestration of the effects induced. In a previous work, we observed that some orally administered strains of lactic acid bacteria (LAB) increased the number of immunoglobulin A (IgA)-producing cells in the small intestine without a concomitant increase in the CD4+ T-cell population, indicating that some LAB strains induce clonal expansion only of B cells triggered to produce IgA. The present work aimed to study the cytokines induced by the interaction of probiotic LAB with murine intestinal epithelial cells (IEC) in healthy animals. We focused our investigation mainly on the secretion of interleukin 6 (IL-6) necessary for the clonal expansion of B cells previously observed with probiotic bacteria. The role of Toll-like receptors (TLRs) in such interaction was also addressed. The cytokines released by primary cultures of IEC in animals fed with Lactobacillus casei CRL 431 or Lactobacillus helveticus R389 were determined. Cytokines were also determined in the supernatants of primary cultures of IEC of unfed animals challenged with different concentrations of viable or nonviable lactobacilli and Escherichia coli, previously blocked or not with anti-TLR2 and anti-TLR4. We concluded that the small intestine is the place where a major distinction would occur between probiotic LAB and pathogens. This distinction comprises the type of cytokines released and the magnitude of the response, cutting across the line that separates IL-6 necessary for B-cell differentiation, which was the case with probiotic lactobacilli, from inflammatory levels of IL-6 for pathogens.

scholarly journals Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine

2006 ◽  
Vol 26 (13) ◽  
pp. 4949-4957 ◽  
Author(s):  
Andrea Haegebarth ◽  
Wenjun Bie ◽  
Ruyan Yang ◽  
Susan E. Crawford ◽  
Valeri Vasioukhin ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Fatty Acid Binding ◽  
Protein Tyrosine ◽  
Adult Mice ◽  
Enterocyte Differentiation

ABSTRACT Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6 −/− mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear β-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.

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 c-Myc Is Required for the Formation of Intestinal Crypts but Dispensable for Homeostasis of the Adult Intestinal Epithelium

2005 ◽  
Vol 25 (17) ◽  
pp. 7868-7878 ◽  
Author(s):  
Michael D. Bettess ◽  
Nicole Dubois ◽  
Mark J. Murphy ◽  
Christelle Dubey ◽  
Catherine Roger ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Epithelium ◽  
Cell Types ◽  
Molecular Evidence ◽  
Normal Numbers ◽  
Normal Epithelium ◽  
Independent Manner ◽  
Adult Mice ◽  
Canonical Wnt

ABSTRACT In self-renewing tissues such as the skin epidermis and the bone marrow, Myc proteins control differentiation of stem cells and proliferation of progenitor cell types. In the epithelium of the small intestine, we show that c-Myc and N-Myc are expressed in a differential manner. Whereas c-Myc is expressed in the proliferating transient-amplifying compartment of the crypts, N-Myc is restricted to the differentiated villus epithelium and a single cell located near the crypt base. c-Myc has been implicated as a critical target of the canonical Wnt pathway, which is essential for formation and maintenance of the intestinal mucosa. To genetically assess the role of c-Myc during development and homeostasis of the mammalian intestine we induced deletion of the c-myc flox allele in the villi and intestinal stem cell-bearing crypts of juvenile and adult mice, via tamoxifen-induced activation of the CreERT2 recombinase, driven by the villin promoter. Absence of c-Myc activity in the juvenile mucosa at the onset of crypt morphogenesis leads to a failure to form normal numbers of crypts in the small intestine. However, all mice recover from this insult to form and maintain a normal epithelium in the absence of c-Myc activity and without apparent compensation by N-Myc or L-Myc. This study provides genetic and molecular evidence that proliferation and expansion of progenitors necessary to maintain the adult intestinal epithelium can unexpectedly occur in a Myc-independent manner.

scholarly journals SETDB1 is required for intestinal epithelial differentiation and the prevention of intestinal inflammation

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321339 ◽  
Author(s):  
Lea Južnić ◽  
Kenneth Peuker ◽  
Anne Strigli ◽  
Mario Brosch ◽  
Alexander Herrmann ◽  
...  
Keyword(s):  
Rare Variants ◽  
Intestinal Inflammation ◽  
Specific Activity ◽  
Critical Role ◽  
Epithelial Differentiation ◽  
Endogenous Retroviruses ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Epithelial Homeostasis

ObjectiveThe intestinal epithelium is a rapidly renewing tissue which plays central roles in nutrient uptake, barrier function and the prevention of intestinal inflammation. Control of epithelial differentiation is essential to these processes and is dependent on cell type-specific activity of transcription factors which bind to accessible chromatin. Here, we studied the role of SET Domain Bifurcated Histone Lysine Methyltransferase 1, also known as ESET (SETDB1), a histone H3K9 methyltransferase, in intestinal epithelial homeostasis and IBD.DesignWe investigated mice with constitutive and inducible intestinal epithelial deletion of Setdb1, studied the expression of SETDB1 in patients with IBD and mouse models of IBD, and investigated the abundance of SETDB1 variants in healthy individuals and patients with IBD.ResultsDeletion of intestinal epithelial Setdb1 in mice was associated with defects in intestinal epithelial differentiation, barrier disruption, inflammation and mortality. Mechanistic studies showed that loss of SETDB1 leads to de-silencing of endogenous retroviruses, DNA damage and intestinal epithelial cell death. Predicted loss-of-function variants in human SETDB1 were considerably less frequently observed than expected, consistent with a critical role of SETDB1 in human biology. While the vast majority of patients with IBD showed unimpaired mucosal SETDB1 expression, comparison of IBD and non-IBD exomes revealed over-representation of individual rare missense variants in SETDB1 in IBD, some of which are predicted to be associated with loss of function and may contribute to the pathogenesis of intestinal inflammation.ConclusionSETDB1 plays an essential role in intestinal epithelial homeostasis. Future work is required to investigate whether rare variants in SETDB1 contribute to the pathogenesis of IBD.

Role of 14-3-3ζ Signaling in the Regulation of Intestinal Epithelial Homeostasis

2014 ◽  
Vol 186 (2) ◽  
pp. 679
Author(s):  
N. Hansraj ◽  
J.N. Rao ◽  
D.J. Turner ◽  
J. Wang
Keyword(s):  
Intestinal Epithelial ◽  
Epithelial Homeostasis

scholarly journals Role of eicosanoids on intestinal epithelial homeostasis

2010 ◽  
Vol 80 (4) ◽  
pp. 431-438 ◽  
Author(s):  
Rut Ferrer ◽  
Juan J. Moreno
Keyword(s):  
Intestinal Epithelial ◽  
Epithelial Homeostasis

Cooperation between MYC and BCL2 to Induce Lymphoma Is Uncovered in an Adult Context.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1530-1530
Author(s):  
Alice C. Fan ◽  
Sylvie Giuriato ◽  
Charles Feng ◽  
Rose Ann Padua ◽  
Dean Felsher
Keyword(s):  
Tumor Development ◽  
Regulatory System ◽  
Developmental Context ◽  
Adult Mice ◽  
Tet System ◽  
Tetracycline Regulatory System ◽  
Mean Time ◽  
Inhibition Of Differentiation

Abstract MYC overexpression is thought to induce tumorigenesis through a variety of different mechanisms including the induction of proliferation, inhibition of differentiation and disruption of genomic stability. Conventional transgenic systems that have been used to study the role of oncogenes in tumorigenesis continuously overexpress transgenes and hence preclude the investigation of the initial and age specific consequences of oncogene activation. To investigate the developmental specific consequences of MYC overexpression in the pathogenesis of lymphoma in vivo, we used transgenic mice in which the MYC proto-oncogene is conditionally regulated via the Tetracycline Regulatory System (Tet system). The ability of MYC to induce lymphomagenesis was found to be inversely correlated with the age of the host at the time of MYC activation. When MYC was activated constitutively, the mean time until tumor development was 13 weeks. When MYC was activated at increasing developmental ages of 3 and 5 weeks, identical tumors arose, but with an increased mean tumor latency. When MYC was activated at 7 weeks, an age equivalent to an adult mouse, no tumors developed even after 40 weeks of observation. However, we found that in adult mice, if both MYC and BCL2 are overexpressed at 7 weeks of age, mice succumbed to lymphoma with a mean latency of 27 weeks. Surprisingly, we could not find evidence that MYC overexpression induces apoptosis or that BCL2 overexpression reduced apoptosis. We conclude that the ability of MYC to induce lymphomagenesis is highly dependent on the developmental context. MYC and BCL2 cooperate to permit tumorigenesis in adult mice. Since lymphoma occurs generally as a disease in adults, this suggests that previous reports may have greatly overestimated the ability of MYC activation to induce tumorigenesis and underestimated the potential cooperation between MYC and BCL2 oncogenes. Our results also suggest that BCL2 may cooperate with MYC to induce lymphomagenesis through additional mechanisms other than preventing MYC from inducing apoptosis.

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