ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease

Abstract: The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD

Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.

ATG16L1$^{T300A}$, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1$^{ΔIEC}$ mice, and humans homozygous for ATG16L1$^{T300A}$ exhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1$^{ΔIEC}$ mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1$^{ΔIEC}$ mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.This study was supported by the European Research Council under the European Community’s Seventh Framework Program (grant FP7/2007-2013)/ERC, agreement no. 260961 to A. Kaser and grant HORIZON2020/ERC, agreement no. 648889 to A. Kaser), the Wellcome Trust (Investigator Award 106260/Z/14/Z to A. Kaser and Principal Research Fellowship 2008/Z/16/Z to D. Ron), the Cambridge Biomedical Research Centre (A. Kaser), a Medical Research Council PhD for clinicians training fellowship (grant MR/N001893/1 to J. Bhattacharyya), fellowships from the European Crohn’s and Colitis Organization (M. Tschurtschenthaler and T.E. Adolph), the Research Training Group Genes, Environment, and Inflammation supported by the Deutsche Forschungsgemeinschaft (grant RTG 1743/1 to P. Rosenstiel), the SFB877 subproject B9 and CLVIII ExC 306 Inflammation at Interfaces (P. Rosenstiel), and the National Institutes of Health (grants DK044319, DK051362, DK053056, and DK088199 to the Harvard Digestive Diseases Center and grant DK0034854 to R.S. Blumberg)

Cytokines and fatty liver diseases

Cytokines are considered crucial players in inflammatory-associated disorders throughout the body. Fatty liver diseases such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are commonly characterized by lipid accumulation and in a substantial subset of patients with inflammation in the liver. Amount of inflammation affects long-term outcome of liver disease including evolution of liver fibrosis, cirrhosis and hepatocellular carcinoma. Especially the pro-inflammatory cytokines Interleukin (IL)-1 (α and β) and tumor necrosis factor (TNF) α play a central role in many stages of liver diseases mediating fundamental aspects of those diseases including acute phase protein synthesis, lipid metabolism, cholestasis and degree of fibrosis. These key cytokines released mainly by mononuclear cells affect all liver cell types and orchestrate the production of many other mediators relevant in chronic liver diseases. Inflammatory cytokines also regulate crucially the development of insulin resistance, a key component of NAFLD. Blocking these critical mediators of inflammation by specific antibodies, especially TNFα, has so far not been proven successful in alcoholic steatohepatitis, a cytokine-driven disorder. In summary, inflammatory cytokines are continuously present locally and systemically in patients with advanced fatty liver diseases, mediating and affecting the clinical phenotype and many features of these disorders. Keywords: Alcoholic hepatitis (AH), Cytokines, Inflammation, Interleukin (IL)-1, Alcoholic liver disease (ALD), Non-alcoholic fatty liver disease (NAFLD), Tumor necrosis factor (TNF)

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD