Paternal chronic colitis causes epigenetic inheritance of susceptibility to colitis.

Inflammatory bowel disease (IBD) arises by unknown environmental triggers in genetically susceptible individuals. Epigenetic regulation of gene expression may integrate internal and external influences and may thereby modulate disease susceptibility. Epigenetic modification may also affect the germ-line and in certain contexts can be inherited to offspring. This study investigates epigenetic alterations consequent to experimental murine colitis induced by dextran sodium sulphate (DSS), and their paternal transmission to offspring. Genome-wide methylome- and transcriptome-profiling of intestinal epithelial cells (IECs) and sperm cells of males of the F0 generation, which received either DSS and consequently developed colitis (F0(DSS)), or non-supplemented tap water (F0(Ctrl)) and hence remained healthy, and of their F1 offspring was performed using reduced representation bisulfite sequencing (RRBS) and RNA-sequencing (RNA-Seq), respectively. Offspring of F0(DSS) males exhibited aberrant methylation and expression patterns of multiple genes, including Igf1r and Nr4a2, which are involved in energy metabolism. Importantly, DSS colitis in F0(DSS) mice was associated with decreased body weight at baseline of their F1 offspring, and these F1 mice exhibited increased susceptibility to DSS-induced colitis compared to offspring from F0(Ctrl) males. This study hence demonstrates epigenetic transmissibility of metabolic and inflammatory traits resulting from experimental colitis.This study was carried out as part of the Research Training Group “Genes, Environment and Inflammation”, supported by the Deutsche Forschungsgemeinschaft (RTG 1743/1) of which A.F. is the spokesperson, the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant agreement no. 260961 (A.K.), the Austrian Science Fund and Ministry of Science P21530-B18 and START Y446-B18 (A.K.), the Wellcome Trust (investigator award 106260/Z/14/Z) to A.K., the Cambridge Biomedical Research Centre (A.K.), a fellowship from the European Crohn’s and Colitis Organisation (M.T. and T.E.A.) and a DOC fellowship from the Austrian Academy of Sciences (J.K.).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep3164

The microbiota: an underestimated actor in radiation-induced lesions?

International audienc

The Selective Autophagy Receptor Optineurin in Crohn’s Disease

Autophagy is a pathway that allows cells to target organelles, protein complexes, or invading microorganisms for lysosomal degradation. The specificity of autophagic processes is becoming increasingly recognized and is conferred by selective autophagy receptors such as Optineurin (OPTN). As an autophagy receptor, OPTN controls the clearance of Salmonella infection and mediates mitochondrial turnover. Recent studies demonstrated that OPTN is critically required for pathogen clearance and an appropriate cytokine response in macrophages. Moreover, OPTN emerges as a critical regulator of inflammation emanating from epithelial cells in the intestine. OPTN directly interacts with and promotes the removal of inositol-requiring enzyme 1α, a central inflammatory signaling hub of the stressed endoplasmic reticulum (ER). Perturbations of ER and autophagy functions have been linked to inflammatory bowel disease (IBD) and specifically Crohn’s disease. Collectively, these studies may explain how perturbations at the ER can be resolved by selective autophagy to restrain inflammatory processes in the intestine and turn the spotlight on OPTN as a key autophagy receptor. This review covers a timely perspective on the regulation and function of OPTN in health and IBD

Using Infodemiology Metrics to Assess Public Interest in Liver Transplantation: Google Trends Analysis (Preprint)

BACKGROUND Liver transplantation (LT) is the only curative treatment for end-stage liver disease. Less than 10% of global transplantation needs are met worldwide, and the need for LT is still increasing. The death rates on the waiting list remain too high. OBJECTIVE It is, therefore, critical to raise awareness among the public and health care providers and in turn increasingly acquire donors. METHODS We performed a Google Trends search using the search terms &lt;i&gt;liver transplantation&lt;/i&gt; and &lt;i&gt;liver transplant&lt;/i&gt; on October 15, 2020. On the basis of the resulting monthly data, the annual average Google Trends indices were calculated for the years 2004 to 2018. We not only investigated the trend worldwide but also used data from the United Network for Organ Sharing (UNOS), Spain, and Eurotransplant. Using pairwise Spearman correlations, Google Trends indices were examined over time and compared with the total number of liver transplants retrieved from the respective official websites of UNOS, the Organización Nacional de Trasplantes, and Eurotransplant. RESULTS From 2004 to 2018, there was a significant decrease in the worldwide Google Trends index from 78.2 in 2004 to 20.5 in 2018 (–71.2%). This trend was more evident in UNOS than in the Eurotransplant group. In the same period, the number of transplanted livers increased worldwide. The waiting list mortality rate was 31% for Eurotransplant and 29% for UNOS. However, in Spain, where there are excellent awareness programs, the Google Trends index remained stable over the years with comparable, increasing LT numbers but a significantly lower waiting list mortality (15%). CONCLUSIONS Public awareness in LT has decreased significantly over the past two decades. Therefore, novel awareness programs should be initialized. </sec

Adipose type I interferon signalling protects against metabolic dysfunction

ObjectiveLow-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD.DesignWe determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep), adipocytes (Ifnar1Δat), intestinal epithelial cells (Ifnar1ΔIEC) or myelocytes (Ifnar1Δmyel) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB).ResultsLong chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver.ConclusionsOur study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.</jats:sec

Using Infodemiology Metrics to Assess Public Interest in Liver Transplantation: Google Trends Analysis

Background Liver transplantation (LT) is the only curative treatment for end-stage liver disease. Less than 10% of global transplantation needs are met worldwide, and the need for LT is still increasing. The death rates on the waiting list remain too high. Objective It is, therefore, critical to raise awareness among the public and health care providers and in turn increasingly acquire donors. Methods We performed a Google Trends search using the search terms liver transplantation and liver transplant on October 15, 2020. On the basis of the resulting monthly data, the annual average Google Trends indices were calculated for the years 2004 to 2018. We not only investigated the trend worldwide but also used data from the United Network for Organ Sharing (UNOS), Spain, and Eurotransplant. Using pairwise Spearman correlations, Google Trends indices were examined over time and compared with the total number of liver transplants retrieved from the respective official websites of UNOS, the Organización Nacional de Trasplantes, and Eurotransplant. Results From 2004 to 2018, there was a significant decrease in the worldwide Google Trends index from 78.2 in 2004 to 20.5 in 2018 (–71.2%). This trend was more evident in UNOS than in the Eurotransplant group. In the same period, the number of transplanted livers increased worldwide. The waiting list mortality rate was 31% for Eurotransplant and 29% for UNOS. However, in Spain, where there are excellent awareness programs, the Google Trends index remained stable over the years with comparable, increasing LT numbers but a significantly lower waiting list mortality (15%). Conclusions Public awareness in LT has decreased significantly over the past two decades. Therefore, novel awareness programs should be initialized. </jats:sec

1950-P: Effects of Dietary Composition on Intestinal Glucocorticoid Receptor Signaling

Enhanced glucose transport capacity of the intestinal epithelium, specifically enterocytes, is known to significantly contribute to systemic glucocorticoid (GC) - induced hyperglycemia. This effect is mainly dependent on overexpression of sodium glucose transporter 1 (Sglt1) and its enhanced activation by serum and glucocorticoid-regulated kinase 1 (Sgk1). In this work we aimed to investigate whether dietary intake affects intestinal glucocorticoid receptor (Nr3c1) signaling. In male C57/BL6 mice short term feeding of a Western diet (WD) resulted in increased glucocorticoid receptor expression in the ileum which was accompanied by an upregulation of the effector genes Sgk1 and sodium-hydrogen exchanger 3 (Nhe3) and liver receptor homologe 1 (Lrh1). The latter is known as the key regulator of intestinal corticosterone synthesis. Histological analysis showed that glucocorticoid receptor expression was mainly located in enterocytes. Intestinal Sgk1 expression remained significantly, about 2-fold, increased in mice fed a Western diet for 10 weeks, while Nr3c1, Lrh1 and Nhe3 expression levels were not significantly altered after long-term feeding. Further regulatory mechanisms were investigated in immortalized murine small intestine enterocyte cell line Mode-K: Stimulation with palmitic acid resulted in a significant upregulation of Sgk1 expression, while no effect was seen when exposed to oleic acid, arachidonic acid or docosahexanoic acid. In contrast to Sgk1, Nr3c1 expression was downregulated in Mode-K cells exposed to palmitic acid. In conclusion, our data suggest that dietary fat intake might contribute to GC induced hyperglycemia by modulating intestinal Sgk1 expression in a glucocorticoid receptor-independent way. Disclosure B. Radlinger: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. S. Folie: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. J. Dobner: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. T. Adolph: None. C. Ress: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. F. Hornsteiner: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. S. Boentges: Research Support; Self; Boehringer Ingelheim International GmbH, Merck &amp; Co., Inc. K. Salzmann: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. H. Tilg: None. S. Kaser: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. Funding Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Merck Sharp &amp; Dohme Austria; Boehringer Ingelheim RCV </jats:sec

Liver stiffness by transient elastography accompanies illness severity in COVID-19

ObjectiveSevere liver damage is associated with worse outcome in COVID-19. Our aim was to explore the degree of liver damage, liver stiffness (LS) and severity of illness in patients with COVID-19.DesignWe investigated 32 patients with COVID-19 admitted to the University Hospital of Innsbruck in a prospective cross-sectional study. We performed laboratory testing, liver and spleen sonography and elastography to measure organ stiffness.Results12 patients (38%) showed elevated aminotransferases and gamma-glutamyltransferase levels. LS was positively correlated with elevated aminotransferase levels in patients with COVID-19 compared with those without elevated enzymes. Even mild liver damage raised LS significantly in COVID-19 as it was in patients with gastrointestinal symptoms. Furthermore, higher LS measurements were significantly associated with illness severity like pneumonia, need for mechanical ventilation, and even death.ConclusionTransient elastography is a useful and non-invasive tool to assess onset and severity of acute liver injury in patients with COVID-19 patients. Increased LS seems to be predictive for a more severe and complicated course of disease.</jats:sec