scholarly journals P007 GC1qR driven oxidative phosphorylation is essential for intestinal goblet cell differentiation

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S133-S133
Author(s):  
A SÜNDERHAUF ◽  
M Hicken ◽  
K Skibbe ◽  
H Schlichting ◽  
M Hirose ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Oxidative Phosphorylation ◽  
Goblet Cell ◽  
Intestinal Inflammation ◽  
Control Diet ◽  
Nutritional Intervention ◽  
Mucosal Inflammation ◽  
Mucosal Cell ◽  
Metabolic Switch ◽  
Goblet Cell Differentiation

Abstract Background Induction of goblet cell differentiation during inflammation has been shown to be impaired in ulcerative colitis (UC) but not Crohn’s disease (CD), possibly explaining the intestinal goblet cell and mucus reduction observed in active UC. A metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) is necessary for terminal differentiation of intestinal stem cells towards goblet cells. Interestingly, intestinal energy deficiency in general and reduced level of OXPHOS in specific have been attributed to UC pathogenesis more than 30 years ago. The c1q binding protein (C1QBP; gC1qR) is indispensable for the maintenance of OXPHOS. Nevertheless, experimental evidence linking mitochondrial dysfunction with goblet cell depletion and C1QBP expression are still missing. Methods Goblet cell differentiation was studied in human biopsies from UC patients in remission, in mucus-producing HT29MTX cells and in a conplastic mouse strain with diminished mitochondrial OXPHOS activity. Furthermore, mice were fed an experimental diet to shift cellular energy production from glycolysis to OXPHOS and mucosal cell differentiation was compared with mice on an isocaloric control diet. Results In vitro, siRNA experiments in HT29MTX cells showed that butyrate-induced expression of goblet cell differentiation factor KLF4 is highly dependent on gC1qR expression. Interestingly, the latter was significantly reduced in human ileal and colonic sections of UC patients in remission compared with HN. OXPHOS-deficient conplastic B6-mt FVB mice further confirmed these findings by depicting diminished klf4 expression, lowered goblet cell numbers, a thinned intestinal mucus layer and signs of intestinal inflammation. Finally, via nutritional intervention in C57BL/6 mice we were able to increase gC1qR level and to induce goblet cell differentiation via hath1 and klf4 compared with controls. Conclusion Taken together, we here describe a new pathway linking low intestinal expression of OXPHOS-regulating gC1qR to impaired goblet cell differentiation, mucus reduction and mucosal inflammation, which could be possibly reversed by nutritional intervention.

scholarly journals Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5817
Author(s):  
Kerstin Skibbe ◽  
Ann-Kathrin Brethack ◽  
Annika Sünderhauf ◽  
Mohab Ragab ◽  
Annika Raschdorf ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cancer Progression ◽  
Goblet Cell ◽  
Aerobic Glycolysis ◽  
Control Diet ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
High Amino Acid ◽  
Goblet Cell Differentiation

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3e, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.

Goblet Cell Hyperplasia is not Epithelial-Autonomous in the Cftr Knockout Intestine

2021 ◽  
Author(s):  
Nancy M Walker ◽  
Jinghua Liu ◽  
Sarah M Young ◽  
Rowena A Woode ◽  
Lane L. Clarke
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Ex Vivo ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Cell Numbers ◽  
Markers Of Inflammation ◽  
Tlr4 Agonist ◽  
Goblet Cell Differentiation ◽  
Mucosal Morphology

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2, Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum as compared to wild-type (WT). IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2 and Tlr4 protein expression was increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4 and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.

scholarly journals IL-33 Induces Murine Intestinal Goblet Cell Differentiation Indirectly via Innate Lymphoid Cell IL-13 Secretion

2018 ◽  
Vol 202 (2) ◽  
pp. 598-607 ◽  
Author(s):  
Amanda Waddell ◽  
Jefferson E. Vallance ◽  
Amy Hummel ◽  
Theresa Alenghat ◽  
Michael J. Rosen
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Lymphoid Cell ◽  
Innate Lymphoid Cell ◽  
Goblet Cell Differentiation

scholarly journals P105 Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S188-S188
Author(s):  
J H Kim ◽  
J B Ahn ◽  
D H Kim ◽  
S Kim ◽  
H W Ma ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Immune Responses ◽  
Goblet Cell ◽  
Goblet Cells ◽  
Dependent Manner ◽  
Glutathione S Transferase ◽  
Host Immune Responses ◽  
Interleukin 22 ◽  
Gstt1 Gene ◽  
Goblet Cell Differentiation

Abstract Background The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Oxidative stress plays a key role in the pathogenesis of inflammatory bowel disease (IBD). Although mutation of the GSTT1 gene increases IBD susceptibility, the underlying mechanisms remain unexplained. Methods The Gstt1 gene was intrarectally or intraperitoneally delivered to mice with dextran sodium sulphate (DSS)-induced colitis. The GSTT1 gene was knocked down or knocked out using short interfering RNA or genome editing, respectively. Protein and mRNA expression and differentiation of goblet cells were evaluated. Results We identified decreased expression of GSTT1 in inflamed tissues from IBD patients and mice compared with their control counterparts, respectively. We also noted attenuation of colitis through gene transfer of Gstt1 to DSS-treated mice via the interleukin-22 (IL-22) pathway. GSTT1 was differently regulated by pathogens and host immune responses. Down-regulation of GSTT1 reduced innate defence responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells as well as IBD patients diminished its dimerisation, which was connected to insufficient phosphorylation of signal transducer and activator of transcription 3 and p38/mitogen-activated protein kinase by their common activator, IL-22. Conclusion GSTT1 ameliorated IL-22 in colitis in a dependent manner and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerisation. Our results provide new insights into GSTT1 mutations and their functional consequences in IBDs.

scholarly journals WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

2019 ◽  
Vol 116 (51) ◽  
pp. 25697-25706 ◽  
Author(s):  
Hyun-Taek Kim ◽  
Wenguang Yin ◽  
Yuko Nakamichi ◽  
Paolo Panza ◽  
Beate Grohmann ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Goblet Cell ◽  
Lung Development ◽  
Alveolar Epithelial Cells ◽  
Airway Epithelial ◽  
Cell Hyperplasia ◽  
Mucus Hypersecretion ◽  
Goblet Cell Hyperplasia ◽  
Goblet Cell Differentiation

Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in anN-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development;Rykmutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specificRykdeletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specificRykdeletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.

scholarly journals Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging

2020 ◽  
Vol 117 (35) ◽  
pp. 21519-21526 ◽  
Author(s):  
Domonica N. Powell ◽  
Alyson Swimm ◽  
Robert Sonowal ◽  
Alexis Bretin ◽  
Andrew T. Gewirtz ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Dynamic Structure ◽  
Goblet Cells ◽  
Type I ◽  
Cellular Composition ◽  
Type I Ifn ◽  
Commensal Microbiota ◽  
Goblet Cell Differentiation

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.

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