Background & Aims Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis

Background & Aims Defining the genetic heterogeneity of intrahepatic biliary epithelial cells (BECs) is challenging and tools for identifying BEC subpopulations are limited. Here, we characterize the expression of a Sox9EGFP transgene in the liver and demonstrate that GFP expression levels are associated with distinct cell types. Methods Sox9EGFP BAC transgenic mice were assayed by immunofluorescence

Background & Aims Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Methods Propionibacterium acnes (P. acnes)-primed

Background and aims A coordinated stress and regenerative response is important following hepatocyte damage. Here, we investigate the phenotypes that result from genetic abrogation of individual components of the CHK2/p53/p21-pathway in a murine model of metabolic liver injury. Methods NTBC was reduced or withdrawn in Fah-/- mice lacking Chk2, p53 or p21, and survival, tumor development, liver injury

Background & Aims Cancer associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G protein-coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF pro-tumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models

Background & Aims Colonization by the gut microbiota in early life confers beneficial effects on immunity throughout the host lifespan. We sought to elucidate the mechanisms whereby neonatal supplementation with p40, a probiotic functional factor, reprograms intestinal epithelial cells (IECs) for protection against adult-onset intestinal inflammation. Methods p40 was used to treat young adult mouse

Background and Aims TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays

Background & Aims Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment. Methods ALF was induced in C5-knockout (KO, B10D2/oSn) mice

Background and aims Non-alcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and ALT, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma

Background and aims Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. Methods To identify subtype-specific genes, we performed single-nucleus RNA-seq

Background & Aims Noroviruses (NoVs) are the leading cause of acute gastroenteritis worldwide and are associated with significant morbidity and mortality. Moreover, an asymptomatic carrier state can persist following acute infection, promoting NoV spread and evolution. Thus, defining immune correlates of NoV protection and persistence is needed to guide the development of future vaccines and limit

Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors, such as an excess in oxidant molecules

Background & Aims Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy. Methods Cirrhosis

Background Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis/cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal versus cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using single-cell

BACKGROUND & AIMS Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung’s disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant

Background & Aims Inflammatory bowel disease is commonly treated by administration of glucocorticoids. While the importance of intestinal epithelial cells for the pathogenesis of this disorder is widely accepted, their role as target cells for glucocorticoids has not been explored. To address this issue, we induced colonic inflammation in GRvillin mice, which carry an inducible deletion of the glucocorticoid

BACKGROUND & AIMS Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1

Background and Aims Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential

Celiac disease (CD) is a common autoimmune disease triggered by the ingestion of gluten in genetically susceptible individuals. Although the mechanisms underlying gliadin-mediated activation of adaptive immunity in CD have been well characterized, regulation of innate immune responses and functional roles of different immune cell populations within the epithelium and lamina propria are not well understood

Background and aims Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration. Methods In

Background and aims Despite recent advances in antiviral therapy for HCV, a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens [1,2]. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals (DAAs). We previously reported that amino acid polymorphisms (A150V and K206E) in the polymerase

AIM Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS) - induced acute colitis has not been addressed. Method We investigated HDC+ MB-HSCs and myeloid cells by flow

Epithelial cells in the liver (known as hepatocytes) are high-performance engines of myriad metabolic functions and versatile responders to liver injury. As hepatocytes metabolize amino acids, alcohol, drugs, and other substrates, they produce and are exposed to a milieu of toxins and harmful byproducts that can damage themselves. In the healthy liver, hepatocytes generally divide slowly. However,

Background and Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis

Background and aims Patients with ulcerative colitis have low concentrations of the major membrane lipid phosphatidylcholine (PC) in gastrointestinal mucus, suggesting that defects in colonic PC metabolism might be involved in the development of colitis. To determine the precise role that PC plays in colonic barrier function, we examined mice with intestinal epithelial cell (IEC)-specific deletion

Background and Aims Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair. Methods Mouse small intestinal epithelial cells

Background & Aims Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ) are two co-activators downstream of Hippo tumor suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Methods Expression

Background&Aims PAK1 belongs to a family of serine-threonine kinases and contributes to cellular pathways like NFκB, MAPK, PI3K/AKT and Wnt/ β-catenin all of which are involved in intestinal homeostasis. Overexpression of PAK1 is linked to IBD as well as colitis-associated cancer (CAC) and similar was observed in IL-10 KO mice, a model of colitis and CAC. Here we tested the effects of PAK1 deletion

Background&Aims Acute liver failure (ALF) represents an unmet medical need in Western countries. While the link between intestinal dysbiosis and chronic liver disease is well established, there is little evidence for a functional role of gut-liver interaction during ALF. Here, we hypothesized that intestinal dysbiosis may affect ALF. Methods To test this hypothesis, we assessed the association of proton

Background & Aims RING Finger Protein 43 (RNF43) is a tumor suppressor that is frequently mutated in gastric tumors. The link between RNF43 and modulation of WNT signaling has not been clearly demonstrated in the stomach. As mutations in RNF43 are highly enriched in microsatellite-instable gastric tumors, which show defects in DDR, we investigated whether RNF43 is involved in DDR in the stomach. Methods

Background and aims The COVID-19 pandemic has spread worldwide and poses a severe health risk. While most patients present mild symptoms, descending pneumonia can lead to severe respiratory insufficiency. Up to 50% of patients show gastrointestinal symptoms like diarrhea or nausea, intriguingly associating with prolonged symptoms and increased severity. Thus, models to understand and validate drug

The incidence of esophageal adenocarcinoma (EAC) and other gastrointestinal (GI) cancers have risen dramatically, thus defining the oncogenic drivers to develop effective therapies are necessary. Patients with Barrett’s Esophagus (BE), have an elevated risk of developing EAC. Around 70-80% of BE cases that progress to dysplasia and cancer have detectable TP53 mutations. Similarly, in other GI cancers

Background & Aims The functions of the liver and the intestine are closely tied in both physiological and pathological conditions. The gut microbiota (GM) often causes deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here, we investigated the effect of hepatic autophagy

Cell fusion, whereby two cells merge to create one, has been widely described in development, but the role of cell fusion in tissue regeneration and homeostasis remains an open debate. We propose that the regenerative capacity of the gut can be fully attributed to extensive plasticity of the intestinal epithelium.

Background & Aims The Fragile X Mental Retardation Protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated. Methods FMRP transcripts and proteins expression were analyzed in human colon samples derived from patients with sporadic CRC and healthy subjects

Background & aims Tight junctions form a barrier to the paracellular passage of luminal antigens. Although most tight junction proteins reside within the apical tight junction complex, claudin-18 localizes mainly to the basolateral membrane where its contribution to paracellular ion transport is undefined. Claudin-18 loss in mice results in gastric neoplasia development and tumorigenesis that may or

Background & Aims Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD has heretofore remained uncharted. Methods To decipher the role of hepatic sEH

Background and aims Acid hypersensitivity is claimed to be a symptomatic trigger in functional dyspepsia (FD); however, the neuroimmune pathway(s) and the mediators involved in this process have not been systematically investigated. Palmitoylethanolamide (PEA) is an endogenous compound, able to modulate nociception and inflammation, but its role in FD has never been assessed. Methods Duodenal biopsies

Background And Aims Besides prominent respiratory involvement, gastrointestinal manifestations are commonly reported in Coronavirus Disease 2019 (COVID-19) patients. We compared infection of ex vivo human intestinal tissues by SARS-CoV-2 and SARS-CoV with respect to their replication kinetics and immune activation profile. Methods Human intestinal tissues were obtained from patients while undergoing

Background & Aims Adherent-invasive E. coli (AIEC) are implicated in inflammatory bowel disease (IBD), and mitochondrial dysfunction has been observed in IBD-patient biopsies. As a novel aspect of AIEC-epithelial interaction we hypothesized that E. coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function. Methods Monolayers of human colon-derived epithelial

Background and Aims Liver injury due to COVID-19 is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients. Methods: The current report details the clinical courses of two patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light

Background & Aims YAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has revealed their critical importance for embryonic development of the heart, vasculature and gastrointestinal mesenchyme. The aim of this study was to determine the functional

Background & Aims Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular

Background & aims Aspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we

Background & Aims The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance DSS-induced colitis in mice. The primary objectives of the current study were to elucidate the mechanism(s) underlying the pro-colitic effects of

Background and Aims As the incidence of nonalcoholic steatohepatitis (NASH) continues to rise, understanding how normal liver functions are affected during disease is required before developing novel therapeutics which could reduce morbidity and mortality. However, very little is understood about how the transport of proteins and cells from the liver by the lymphatic vasculature is affected by inflammatory

BACKGROUND AND AIMS The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and certain populations exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ∼100 diverse inbred strains of mice, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these, liver pyruvate

Background & Aims Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and

Background & Aims Cancer associated fibroblasts (CAFs) play a key role in cancer process, but the research progress is hampered by the paucity of preclinical models essential for mechanistic dissection of cancer cell-CAF interactions. Here, we aim to establish a 3D organotypic co-cultures of primary liver tumor-derived organoids with CAFs, and to understand their interactions and the response to treatment

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