Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control <i>Clostridium difficile</i> colitis

Liu, Ruixue; Moriggl, Richard; Zhang, Dongsheng; Li, Haifeng; Karns, Rebekah; Ruan, Hai Bin; Niu, Haitao; Mayhew, Christopher N.; Watson, Carey L.; Bangar, Hansraj; Cha, Sang‐Wook; Zhang, Tongli; Gilbert, Shila; Li, Na; Helmrath, Michael A.; Wells, James M.; Denson, Lee A.; Han, Xiaonan

doi:10.26508/lsa.201900296

Cited by 19 publications

(22 citation statements)

References 78 publications

(156 reference statements)

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“…difficile infection is also associated with increased mucosal levels of pro-inflammatory cytokines (i.e., IFN-γ and TNF-α), which are capable of disrupting TJ and epithelial integrity in organoids as for C . difficile toxins [ 96 ]. Host STAT5-dependent JAK2 signaling pathway is necessary to initiate the production of anti-inflammatory cytokines and to promote intestinal epithelium repair.…”

Section: Components Of the Intestinal Barriermentioning

confidence: 99%

Gut Microbiota and Intestinal Trans-Epithelial Permeability

Allam-Ndoul

Castonguay-Paradis

Veilleux

2020

IJMS

210

124

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Constant remodeling of tight junctions to regulate trans-epithelial permeability is essential in maintaining intestinal barrier functions and thus preventing diffusion of small molecules and bacteria to host systemic circulation. Gut microbiota dysbiosis and dysfunctional gut barrier have been correlated to a large number of diseases such as obesity, type 2 diabetes and inflammatory bowel disease. This led to the hypothesis that gut bacteria-epithelial cell interactions are key regulators of epithelial permeability through the modulation of tight junctions. Nevertheless, the molecular basis of host-pathogen interactions remains unclear mostly due to the inability of most in vitro models to recreate the differentiated tissue structure and components observed in the normal intestinal epithelium. Recent advances have led to the development of a novel cellular model derived from intestinal epithelial stem cells, the so-called organoids, encompassing all epithelial cell types and reproducing physiological properties of the intestinal tissue. We summarize herein knowledge on molecular aspects of intestinal barrier functions and the involvement of gut bacteria-epithelial cell interactions. This review also focuses on epithelial organoids as a promising model for epithelial barrier functions to study molecular aspects of gut microbiota-host interaction.

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Section: Components Of the Intestinal Barriermentioning

confidence: 99%

Gut Microbiota and Intestinal Trans-Epithelial Permeability

Allam-Ndoul

Castonguay-Paradis

Veilleux

2020

IJMS

210

124

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“…The IL-22/ Stat3 pathway can improve PC function by increasing the protein levels of lysozyme, RegIIIγ and α-cryptdin 5 under parenteral nutrition [119]. The IL-4 treatment can significantly decrease the gene expression levels of Paneth cell marker LYZ and reduce the proliferation of ISCs [120]. In addition, the IκB kinase (IKK)-NF-κB signalling pathway is involved in inflammatory process when its activation caused the depletion of PCs [121].…”

Section: Growth Factor-mediated Signalling Pathways Regulate the Devementioning

confidence: 99%

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

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Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

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“…Multiple pathways, including the Wnt/β-catenin pathway and the expression of their target genes, are essential for maintaining epithelial barrier function and epithelial cell repair after injury. In C. difficile infection, the accumulation of TcdA and TcdB is associated with Wnt/β-catenin pathway inhibition, although this downregulation is induced, at least in part, by different mechanisms, and together with pro-inflammatory cytokine production within the intestinal mucosa, this accumulation likely results in intestinal epithelial stem cell niche degeneration and suppression of repair ( Farin et al, 2014 ; Leslie et al, 2015 ; Liu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…According to our data, increased Wnt3a expression was found in patients with ulcerative colitis compared to the level found in patients with noninflammatory bowel disease, but no difference was found in the expression of a panel of Wnt target genes ( You et al, 2008 ). Although Paneth cells are an important source of Wnt ligands (Wnt3a) needed to sustain the self-renewal of intestinal epithelial stem cells, Paneth cells are impaired upon C. difficile infection ( Liu et al, 2019 ). In the present study, the expression of Wnt3a was found mainly in lamina propria cells, suggesting that immune-induced inflammatory cells are involved in the release of Wnt3a.…”

Section: Discussionmentioning

confidence: 99%

Clostridioides difficile Toxin A-Induced Wnt/β-Catenin Pathway Inhibition Is Mediated by Rac1 Glucosylation

et al. 2020

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Clostridioides difficile toxin A (TcdA) has been shown to inhibit cellular Wnt signaling, the major driving force behind the proliferation of epithelial cells in colonic crypts, likely through the inhibition of β-catenin nuclear translocation. Herein, we aimed to advance the understanding of this mechanism by replicating the findings in vivo and by investigating the specific role of Rac1, a member of the Rho GTPase family, on the inhibition of the Wnt-induced β-catenin nuclear translocation triggered by TcdA. To investigate the effects of TcdA on the Wnt/β-catenin pathway in vivo , we injected the ileal loops of C57BL/6 mice with TcdA [phosphate-buffered saline (PBS) as the control] to induce C. difficile disease-like ileitis. After 4 h post-injection, we obtained ileum tissue samples to assess Wnt signaling activation and cell proliferation through Western blotting, immunohistochemistry, and qPCR. To assess the role of Rac1 on Wnt signaling inhibition by TcdA, we transfected rat intestinal epithelial cells (IEC-6) with either a constitutively active Rac1 plasmid (pcDNA3-EGFP-Rac1-Q61L) or an empty vector, which served as the control. We incubated these cells with Wnt3a-conditioned medium (Wnt3a-CM) to induce Wnt/β-catenin pathway activation, and then challenged the cells with TcdA. We assessed Wnt signaling activation in vitro with TOP/FOPflash luciferase assays, determined nuclear β-catenin translocation by immunofluorescence, measured cyclin D1 protein expression by Western blotting, and quantified cell proliferation by Ki67 immunostaining. In vivo , TcdA decreased β-catenin, cyclin D1, and cMYC expression and inhibited the translocation of β-catenin into the nucleus in the ileum epithelial cells. In addition, TcdA suppressed cell proliferation and increased Wnt3a expression, but did not alter Rac1 gene expression in the ileum tissue. In vitro , constitutively active Rac1 prevented Wnt signaling inhibition by enabling the β-catenin nuclear translocation that had been blocked by TcdA. Our results show that TcdA inhibits Wnt/β-catenin pathway in vivo and demonstrate that this inhibition is likely caused by a Rac1-mediated mechanism.

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Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis

Cited by 19 publications

References 78 publications

Gut Microbiota and Intestinal Trans-Epithelial Permeability

Gut Microbiota and Intestinal Trans-Epithelial Permeability

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Clostridioides difficile Toxin A-Induced Wnt/β-Catenin Pathway Inhibition Is Mediated by Rac1 Glucosylation

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