Intestinal Cell News Volume 3.02 | Jan 20 2017

TOP STORY

Orphan Gpr182 Suppresses ERK-Mediated Intestinal Proliferation during Regeneration and Adenoma Formation

Scientists used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. They observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body. [J Clin Invest] Full Article

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INTESTINAL CANCERS & DISEASES

Matriptase-Mediated Cleavage of EpCAM Destabilizes Claudins and Dysregulates Intestinal Epithelial Homeostasis

The authors hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 are functionally linked. They demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in intestinal epithelial cells led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. [J Clin Invest] Full Article

Tryptophan Metabolite Activation of the Aryl Hydrocarbon Receptor Regulates IL-10 Receptor Expression on Intestinal Epithelia

Guided by an unbiased metabolomics screen, researchers identified tryptophan (Trp) metabolism as a major modifying pathway in interferon-γ (IFNγ)-dominant murine colitis. In parallel, they demonstrated that IFNγ induction of indoleamine 2,3-dioxygenase 1, an enzyme that catalyzes the conversion of Trp to kynurenine, induces IL-10 receptor 1 expression. [Mucosal Immunol] Abstract

c-Jun N-Terminal Kinase 2 Promotes Enterocyte Survival and Goblet Cell Differentiation in the Inflamed Intestine

Using genetic mouse models, the authors characterized the role of c-Jun N-terminal kinase (JNK) 1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation, and barrier function were analyzed in intestinal epithelium-specific or complete JNK1 and bone marrow chimeric or complete JNK2 deficient mice as well as double-knockout animals during homeostasis and acute dextran sulfate sodium-induced colitis. [Mucosal Immunol] Abstract

Food-Grade TiO₂ Impairs Intestinal and Systemic Immune Homeostasis, Initiates Preneoplastic Lesions and Promotes Aberrant Crypt Development in the Rat Colon

In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer’s patches (PP) as observed with the titanium dioxide (TiO₂) containing a nanoscale particle fraction model NM-105. Dendritic cell frequency increased in PP regardless of the TiO₂ treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. [Sci Rep] Full Article

Protein Kinase C δ Signaling Is Required for Dietary Prebiotic-Induced Strengthening of Intestinal Epithelial Barrier Function

Scientists demonstrated that two commercial prebiotics, inulin and short-chain fructo-oligosaccharide, when applied onto intestinal epithelia in the absence of microbes, directly promote barrier integrity to prevent pathogen-induced barrier disruptions. They further showed that these effects involve the induction of select tight junction proteins through a protein kinase C δ-dependent mechanism. [Sci Rep] Full Article

Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells to Induce Mucosal Tolerogenic Dendritic Cells

Investigators demonstrated that dietary fiber and short chain fatty acids induced the expression of the vitamin A–converting enzyme RALDH1 in intestinal epithelial cells in vivo and in vitro, respectively. Their data showed that the expression levels of RALDH1 in small intestinal epithelial cells correlated with the activity of vitamin A–converting enzymes in mesenteric lymph node dendritic cells, along with increased numbers of intestinal regulatory T cells and a higher production of luminal IgA. [J Immunol] Abstract

O-GlcNAc Expression Levels Epigenetically Regulate Colon Cancer Tumorigenesis by Affecting the Cancer Stem Cell Compartment via Modulating Expression of Transcriptional Factor MYBL1

To study the regulation of colorectal adenocarcinoma progression by O-linked N-acetylglucosamine (O-GlcNAc), researchers focused on the O-GlcNAc-mediated epigenetic regulation of human colon cancer stem cells. Xenograft tumors from colon tumor cells with OGT knockdown grew significantly slower than those formed from control cells, indicating a reduced proliferation of tumor cells due to inhibition of OGT expression. [J Biol Chem] Abstract | Full Article

c-Jun Enhances Intestinal Epithelial Restitution after Wounding by Increasing Phospholipase C-_γ1 Transcription

Researchers reported that c-Jun up-regulates phospholipase C-_γ1 (PLC_γ1) expression and enhances PLC_γ1-induced Ca²⁺ signaling, thus promoting intestinal epithelial restitution after wounding. Ectopically expressed c-Jun increased PLC_γ1 expression at the transcription level and this stimulation is mediated by directly interacting with AP-1- and C/EBP-binding sites that are located at proximal region of the PLC_γ1 promoter. [Am J Physiol Cell Physiol] Abstract

Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers

Scientists demonstrated the ability of alpha-melanocyte-stimulating hormone (α-MSH) to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. [PLoS One] Full Article

Genome-Wide Immune Modulation of TLR3-Mediated Inflammation in Intestinal Epithelial Cells Differs between Single and Multi-Strain Probiotic Combination

Investigators used human expression microarray chips in an in vitro intestinal epithelial cell model to investigate the impact of three probiotic bacteria, Lactobacillus helveticus R0052, Bifidobacterium longum subsp. infantis R0033 and Bifidobacterium bifidum R0071 individually and in combination, and of a surface-layer protein purified from Lh-R0052, on HT-29 cells’ transcriptional profile to polyinosinic:polycytidylic acid-induced inflammation. [PLoS One] Full Article

Neuroimmune Regulation During Intestinal Development and Homeostasis

Evidence suggests that enteric neurons and intestinal immune cells share common regulatory mechanisms and can coordinate their responses to developmental challenges and environmental aggressions. These discoveries shed light on the physiology of system interactions and open novel perspectives for therapy designs that target underappreciated neurological–immunological commonalities. The authors highlight findings that address the importance of neuroimmune cell units in intestinal development, homeostasis and disease. [Nat Immunol] Abstract

The Mucosal Immune System: Master Regulator of Bidirectional Gut–Brain Communications

The authors consider the role of the immune system as the gatekeeper and master regulator of brain–gut and gut–brain communications. Although adaptive immunity participates in this process, there is an emerging role for cells of the innate immune compartment. They also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis. [Nat Rev Gastroenterol Hepatol] Abstract

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Synergy Pharmaceuticals’ Trulance^™ (Plecanatide) Receives U.S. FDA Approval for the Treatment of Adults with Chronic Idiopathic Constipation

Synergy Pharmaceuticals Inc. announced that the U.S. Food and Drug Administration (FDA) has approved TRULANCE^™ for the treatment of adults with chronic idiopathic constipation. TRULANCE is the first drug designed to replicate the function of uroguanylin, a naturally occurring and endogenous human gastrointestinal peptide that is thought to stimulate fluid secretion which results in a stool consistency associated with more regular bowel function. [Synergy Pharmaceuticals Inc.] Press Release

Opdivo (Nivolumab) Demonstrated Efficacy and Improved Survival in Patients with Previously Treated Advanced Gastric Cancer in a Randomized Phase III Study

Bristol-Myers Squibb Company announced the results of ONO-4538-12 demonstrating Opdivo significantly reduced the risk of death by 37% in patients with previously treated advanced gastric cancer refractory to or intolerant of standard therapy, a condition without current standard-of-care treatments. ONO-4538-12 is a Phase III, randomized, double-blind, placebo-controlled clinical trial evaluating Opdivo’s efficacy and safety in such patients. [Bristol-Myers Squibb Company] Press Release

Protagonist Therapeutics Initiates Phase IIb Study of Oral Drug Candidate PTG-100 in Ulcerative Colitis

Protagonist Therapeutics, Inc. announced that it has initiated a global Phase IIb induction study in ulcerative colitis with PTG-100, an oral peptide that targets alpha4beta7 integrin. The aim of this randomized, double-blind, placebo-controlled, adaptive design study is to evaluate the safety/tolerability and efficacy of PTG-100 in approximately 240 adult ulcerative colitis patients with moderate to severe active disease. [Protagonist Therapeutics, Inc.] Press Release

Synthetic Biologics Confirms Key Features of Pivotal Phase IIb/III Trial of SYN-010 Pursuant to Consultations with FDA

Synthetic Biologics, Inc. confirmed plans to initiate a Phase IIb/III adaptive pivotal trial for SYN-010, the company’s modified-release reformulation of lovastatin lactone designed to reduce methane production by certain microorganisms in the gut to treat the underlying cause of irritable bowel syndrome with constipation. The company anticipates initiating this trial by the end of the first quarter of 2017. [Synthetic Biologics, Inc.] Press Release

NIH Director Francis Collins Staying on — For Now

President-elect Donald Trump has decided to retain Francis Collins as director of the US National Institutes of Health (NIH) — at least temporarily. It is not clear whether Trump will formally reappoint Collins, or whether Collins will stay in his job only until Trump appoints a permanent director. [Nature News] Editorial

NEW Gordon Research Conferences: Physical Science of Cancer
February 5-10, 2017
Galveston, United States

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NEW Postdoctoral Fellowship – Dendritic Cell Function in Gut Mucosa (Technical University of Denmark)

NEW Postdoctoral Fellowship – Neuro-Immune Regulation of Mucosal Barrier Function (Linköping University)

Postdoctoral Research Fellow – Intestinal Disease (Children’s Hospital Los Angeles)

Research Fellow – Cross Talk between Immune Cells, Microbes and the Intestinal Barrier (University of Michigan Ann Arbor)

Project Scientist – Early Life Microbiota Interaction with the Host (Institute of Food Research)

Assistant Professor – Gastrointestinal Health/Physiology Tenure-Track Faculty Position (University of Maryland)

Scientific Writing Associate – Literature Review/Analysis and Relevant Scientific and Medical Material (Genfit SA)

Tenure-Track Position – Various Projects (University Medical Center Utrecht)

Assistant Professor – Molecular Therapeutics of Cancer (Dartmouth College)

Assistant or Associate Member – Stem Cell/Gene Therapy (Fred Hutchinson Cancer Research Center)

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