Increased Prevalence of Esophageal Eosinophilia in Patients with Inflammatory Bowel Disease.

BACKGROUND: The overlap between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) has not been extensively examined. We aimed to assess the prevalence of esophageal eosinophilia in patients with IBD. METHODS: We conducted a retrospective cohort study using diagnostic codes to identify adults with EoE and IBD between 2008 and 2016 at a tertiary care center. Electronic medical records were reviewed to extract clinical, endoscopic, and treatment data. Patients with esophageal eosinophilia and IBD were compared to EoE cases without IBD. RESULTS: Of 621 EoE patients and 4,814 IBD patients identified, 35 had a code for both diseases and 12 were confirmed to have overlapping IBD and esophageal eosinophilia. The prevalence of esophageal eosinophilia in IBD was 12/4814 (0.25%), and the prevalence of confirmed EoE in IBD was 5/4,814 (0.10%). There were no substantial clinical, endoscopic, or histologic differences between EoE patients with and without IBD. IBD was diagnosed before esophageal eosinophilia 92% of the time, with an average time between diagnoses of 9.6 years. Of the IBD patients, 71% were started on biologic anti-tumor necrosis factor-α therapy an average of 7.6 years prior to developing esophageal eosinophilia. CONCLUSIONS: The prevalence of esophageal eosinophilia in IBD is 5 times higher than expected in the general population (0.25 vs. 0.05%) and EoE in IBD is 2 times higher than expected (0.10 vs. 0.05%). Upper gastrointestinal (GI) symptoms in patients with IBD should merit evaluation not only for upper GI Crohn's disease, but also for esophageal eosinophilia.

Methionine adenosyltransferases in cancers: Mechanisms of dysregulation and implications for therapy.

Methionine adenosyltransferase genes encode enzymes responsible for the biosynthesis of S-adenosylmethionine, the principal biological methyl donor and precursor of polyamines and glutathione. Mammalian cells express three genes - MAT1A, MAT2A, and MAT2B - with distinct expression and functions. MAT1A is mainly expressed in the liver and maintains the differentiated states of both hepatocytes and bile duct epithelial cells. Conversely, MAT2A and MAT2B are widely distributed in non-parenchymal cells of the liver and extrahepatic tissues. Increasing evidence suggests that methionine adenosyltransferases play significant roles in the development of cancers. Liver cancers, namely hepatocellular carcinoma and cholangiocarcinoma, involve dysregulation of all three methionine adenosyltransferase genes. MAT1A reduction is associated with increased oxidative stress, progenitor cell expansion, genomic instability, and other mechanisms implicated in tumorigenesis. MAT2A/MAT2B induction confers growth and survival advantage to cancerous cells, enhancing tumor migration. Highlighted examples from colon, gastric, breast, pancreas and prostate cancer studies further underscore methionine adenosyltransferase genes' role beyond the liver in cancer development. In this subset of extra-hepatic cancers, MAT2A and MAT2B are induced via different regulatory mechanisms. Understanding the role of methionine adenosyltransferase genes in tumorigenesis helps identify attributes of these genes that may serve as valuable targets for therapy. While S-adenosylmethionine, and its metabolite, methylthioadenosine, have been largely explored as therapeutic interventions, targets aimed at regulation of MAT gene expression and methionine adenosyltransferase protein-protein interactions are now surfacing as potential effective strategies for treatment and chemoprevention of cancers. Impact statement This review examines the role of methionine adenosyltransferases (MATs) in human cancer development, with a particular focus on liver cancers in which all three MAT genes are implicated in tumorigenesis. An overview of MAT genes, isoenzymes and their regulation provide context for understanding consequences of dysregulation. Highlighting examples from liver, colon, gastric, breast, pancreas and prostate cancers underscore the importance of understanding MAT's tumorigenic role in identifying future targets for cancer therapy.

Environmental Factors Modify the Severity of Acute DSS Colitis in Caspase-11-Deficient Mice.

Background: Human and mouse studies implicate the inflammasome in the pathogenesis of inflammatory bowel diseases, though the effects in mice are variable. The noncanonical inflammasome activator caspase-11 (Casp11) reportedly attenuates acute dextran sodium sulfate (DSS) colitis in mice. However, the effects of Casp11 on chronic experimental colitis and factors that influence the impact of Casp11 on acute DSS colitis are unknown. Methods: We studied the role of Casp11 in Il10-/- mice and acute and chronic DSS colitis mouse models. We quantified colonic Casp11 mRNA using quantative polymerase chain reaction and colitis using weight loss, blinded histological scoring, IL-12/23p40 secretion by colonic explants, and fecal lipocalin-2. We determined fecal microbial composition using 16S amplicon sequencing. Results: We detected increased colonic Casp11 mRNA in Il10-/- mice with chronic colitis, but not in mice with DSS colitis. The presence of Casp11 did not alter the severity of chronic colitis in DSS-treated or Il10-/- mice. Contrary to prior reports, we initially observed that Casp11 exacerbates acute DSS colitis. Subsequent experiments in the same animal facility revealed no effect of Casp11 on acute DSS colitis. There were pronounced stochastic changes in the fecal microbiome over this time. The majority of bacterial taxa that changed over time in wild-type vs Casp11-/- mice belong to the Clostridiales. Conclusions: Casp11 does not impact chronic experimental colitis, and its effects on acute DSS colitis vary with environmental factors including the microbiota, particularly Clostridiales. Stochastic drifts in intestinal microbiota composition, even in mice in the same housing facility, should be considered when interpreting studies of acute DSS colitis models.

New therapeutic targets in alcoholic hepatitis.

Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic steatosis, steatohepatitis, fibrosis, cirrhosis and its related complications, and the acute-on-chronic state of alcoholic hepatitis. While multidisciplinary efforts continue to be aimed at curbing progression of this spectrum of disorders, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with severe AH is very high (20-50 % at 3 months). The current therapeutic regimens are limited. The development of new therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of human AH. This review article summarizes the clinical syndrome, pre-clinical translational tools, and pathogenesis of AH at a molecular and cellular level, with the aim of identifying new targets of potential therapeutic intervention.