Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

Suarez, Katherine; Lim, Eileen; Singh, Sujay; Pereira, Matheus P.; Joosen, Linda; Ibeawuchi, Stella‐Rita; Dunkel, Ying; Mittal, Yash; Ho, Samuel B.; Chattopadhyay, Ranajoy; Gumá, Mónica; Boland, Brigid S.; Dulai, Parambir S.; Sandborn, William J.; Ghosh, Pradipta; Das, Soumita

doi:10.1101/280172

Cited by 3 publications

References 55 publications

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NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

Sahan

Venkova

Sayed

et al. 2019

Preprint

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The accumulation of Helicobacter pylori infectioninduced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; this response was more pronounced in Neil2 knockout (KO) mouse cells compared to wild type (WT) cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Interestingly, DNA damage was significantly higher in Neil2 KO mice compared to WT mice. H. pylori-infected Neil2 KO mice showed higher inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of repair genes in gastric specimens showed the reduction of Neil2 level is linked to the GC progression. Taken together, our data suggest that down-regulation of NEIL2 is a plausible mechanism by which H. pylori infection derails DNA damage repair, amplifies the inflammatory response and initiates GCs.

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NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

Sahan

Venkova

Sayed

et al. 2019

Preprint

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Enteroids expressing a disease-associated mutant of EpCAM are a model for congenital tufting enteropathy

Das

Okamoto

Rabalais

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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Congenital tufting enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule ( EPCAM) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAM enteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels. Immunofluorescence microscopy demonstrated the reduced expression of mutant EpCAM. Mutant enteroids had reduced budding potential as well as significantly decreased mRNA expression for epithelial lineage markers ( Mucin 2, lysozyme, sucrase-isomaltase), proliferation marker Ki67, and secretory pathway transcription factors ( Atoh1, Hnf1b). Significantly decreased numbers of Paneth and goblet cells were confirmed by staining. These findings were correlated with intestinal tissue from CTE patients and the mutant mice model that had significantly fewer Paneth and goblet cells than in healthy counterparts. FITC-dextran studies demonstrated significantly impaired barrier function in monolayers derived from mutant enteroids compared with control monolayers. In conclusion, we have established an ex vivo CTE model. The role of EpCAM in the budding potential, differentiation, and barrier function of enteroids is noted. Our study establishes new facets of EpCAM biology that will aid in understanding the pathophysiology of CTE and role of EpCAM in health and disease. NEW & NOTEWORTHY Here, we develop a novel ex vivo enteroid model for congenital tufting enteropathy (CTE) based on epithelial cell adhesion molecule ( EPCAM) gene mutations found in patients. With this model we demonstrate the role of EpCAM in maintaining the functional homeostasis of the intestinal epithelium, including differentiation, proliferation, and barrier integrity. This study further establishes a new direction in EpCAM biology that will help in understanding the detailed pathophysiology of CTE and role of EpCAM.

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The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

et al. 2020

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The gut barrier separates trillions of microbes from the largest immune system in the body; when compromised, a "leaky" gut barrier fuels systemic inflammation, which hastens the progression of chronic diseases. Strategies to detect and repair the leaky gut barrier remain urgent and unmet needs. Recently, a stress-polarity signaling (SPS) pathway has been described in which the metabolic sensor, AMP-kinase acts via its effector, GIV (also known as Girdin) to augment epithelial polarity exclusively under energetic stress and suppresses tumor formation. Using murine and human colon-derived organoids, and enteroid-derived monolayers (EDMs) that are exposed to stressors, we reveal that the SPS-pathway is active in the intestinal epithelium and requires a catalytically active AMP-kinase. Its pharmacologic augmentation resists stress-induced collapse of the epithelium when challenged with microbes or microbial products. In addition, the SPS-pathway is suppressed in the aging gut, and its reactivation in enteroid-derived monolayers reverses aging-associated inflammation and loss of barrier function. It is also silenced during progression of colorectal cancers. These findings reveal the importance of the SPS-pathway in the gut and highlights its therapeutic potential for treating gut barrier dysfunction in aging, cancer, and dysbiosis.

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Dysregulation of the engulfment pathway in the gut fuels Inflammatory Bowel Disease

Cited by 3 publications

References 55 publications

NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

Enteroids expressing a disease-associated mutant of EpCAM are a model for congenital tufting enteropathy

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

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