Background Aims It is well established that chronic inflammation promotes gastric cancer-associated metaplasia, but little is known regarding the mechanisms by which immune cells and cytokines regulate metaplastic cellular changes. The goals of this study were to identify interleukin 13 (IL-13)-producing immune cells, determine the gastric epithelial cell response(s) to IL-13, and establish the role(s)

Background & Aims Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A in PDAC development. Methods We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed Bru-seq analysis to elucidate the

Background and Aims Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) is a major inhibitor of Toll-like Receptor (TLR) signaling. Our laboratory identified a novel SIGIRR stop mutation (p.Y168X) in an infant who succumbed to severe NEC. Herein, we investigated the mechanisms by which SIGIRR mutations induce TLR hyper-responsiveness in the neonatal gut disrupting postnatal intestinal adaptation

Background & Aims Intestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function. Methods Lgr5-EGFP, NT wild

The stomach is a complex and physiologically necessary organ, yet large differences in physiology between mouse and human stomachs have impeded translation of physiological discoveries and drug screens performed using murine gastric tissues. Gastric cancer (GC) is a global health threat, with a high mortality rate and limited treatment options. The heterogeneous nature of gastric cancer makes it poorly

BACKGROUND & AIMS Progression of chronic liver disease (CLD) to liver cirrhosis and liver cancer is a major global cause of morbidity and mortality. Treatment options capable of inhibiting progression of liver fibrosis when aetiological treatment of CLD is not available or fails, have yet to be established. We investigated the role of serine/threonine kinase p70S6K (p70 ribosomal protein S6 kinase)

Background and aims C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI). Methods The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in vitro and in

Background & Aims Activation of the Keap1-Nrf2 pathway has been associated with metabolic reprogramming in many tumors, including hepatocellular carcinoma (HCC). However, the contribution of Nrf2 mutations in this process remains elusive. Here, we investigated the occurrence of Nrf2 mutations in distinct models of mouse hepatocarcinogenesis. Methods HCCs were generated by experimental protocols consisting

Background and Aims Colonic motor patterns have been described by a number of different groups but the neural connectivity and ganglion architecture supporting patterned motor activity have not been elucidated. Our goals were to describe quantitatively, by region, the structural architecture of the mouse ENS and use functional calcium imaging, pharmacology and electrical stimulation to demonstrate

Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their

Background & Aims Hepatic immune microenvironment plays a pivotal role in the development of non-alcoholic steatohepatitis (NASH). However, the role of natural killer cells (NK cells), accounting for 10-20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods NASH was induced in mice fed methionine- and

The gastrointestinal (GI) tract is home to a complex and dynamic community of microorganisms, comprising bacteria, archaea, viruses, yeast and fungi. It is widely accepted that human health is shaped by these microbes and their collective microbial genome. This so-called “second genome” plays an important role in normal functioning of the host, contributing to processes involved in metabolism and immune

Background and Aims Mucosal-associated invariant T (MAIT) cells are innate-like T cells restricted by major histocompatibility complex-related molecule 1 (MR1) and express a semi-invariant T cell receptor. Previously, we reported the activation status of circulating MAIT cells in patients with ulcerative colitis (UC) was associated with disease activity and that these cells had infiltrated the inflamed

BACKGROUND & AIMS Metaplasia in the stomach is highly associated with development of intestinal-type gastric cancer. Two types of metaplasias, spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) are considered precancerous lesions. However, it remains unclear how SPEM and IM are related. Here, we investigated a new lineage-specific marker for SPEM cells, aquaporin 5

The intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication

Background & Aims The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR) can sense xenobiotics, dietary, microbial and metabolic cues. Roles of Ahr in intestinal epithelial cells (IECs) have been much less elucidated compared with those in intestinal innate immune cells. Here we aim to explore whether the intestinal epithelial cells (IECs)-intrinsic Ahr could modulate the development

Background & Aims Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand responsible for regulating stem cell proliferation in the distal mouse stomach. Methods

Background & Aims Maternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a gene encoding a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half

Background & Aims One of the features of ulcerative colitis (UC) is a defect in the protective mucus layer. This has been attributed to a reduced number of goblet cells (GC). However, it is not known whether abnormal GC mucus secretion also contributes to the reduced mucus layer. Our aims were to investigate whether GC secretion was abnormal in UC and exists as a long-term effect of chronic inflammation

BACKGROUND AND AIMS Microbiota dysbiosis and mucosa-associated bacteria are involved in colorectal cancer (CRC) progression. We hypothesize that an interaction between virulent pathobionts and epithelial defense promotes tumorigenesis. METHODS AND RESULTS Our study demonstrated that antibiotic treatment at mid-phase but not early- or late-phase reduced mouse tumor burden, suggesting a time-specific

BACKGROUND & AIMS TP53 mutations underlie Barrett’s (BE) progression to dysplasia and cancer. During BE progression, the ubiquitin ligase (E3) RNF128/GRAIL switches expression from isoform 2 (Iso2) to Iso1 stabilizing mutant p53. However, the ubiquitin conjugating enzyme (E2) that partners with Iso1 to stabilize mutant p53 is unknown. METHODS Single-cell RNA sequencing of paired normal esophagus and

Background & aims SYK signaling pathway regulates critical processes in innate immunity but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate 3BP2 in both myeloid cells and hepatocytes in the onset of metabolic steatohepatitis. Methods Hepatic SYK-3BP2 pathway was evaluated in mouse models of MAFLD and in obese

Background and Aims Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH is also associated with adipose tissue (AT) inflammation, but the role of AT inflammation in NASH pathogenesis remains obscure. The aim of this study is to investigate the interplay between neutrophil recruitment in AT and

Background & Aims Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain

BACKGROUND & AIMS To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this

The pancreas consists of several specialized cell types which display a remarkable ability to alter cellular identity in injury, regeneration, and repair. The abundant cellular plasticity within the pancreas appears to be exploited in tumorigenesis, with metaplastic, dedifferentiation, and transdifferentiation processes central to the development of pancreatic intraepithelial neoplasia (PanIN) and

The human gut microbiota harbors a heterogenous and dynamic community of microorganisms which coexist with the host to exert a marked influence on human physiology and health. Throughout the lifespan, diet can shape the composition and diversity of the members of the gut microbiota by determining the microorganisms that will colonize, persist, or become extinct. This is no more pronounced than during

Background & Aims ARPKD is caused by mutations in PKHD1, encoding FPC [1-4]. Severe disease occurs in perinates[5]. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here is to uncover therapeutic strategies for ARPKD. Methods We used wild-type and an FPC-mutant cholangiocyte cell line in

Background & Aims Sustained JNK activation plays a major role in drug-induced liver injury (DILI). Stress-responsive microRNA-31 (miR-31) has been implicated in regulating different cellular damage, and JNK activation could induce miR-31 expression. However, the regulatory role of miR-31 in DILI has not been previously studied. We aimed to investigate whether miR-31 could ameliorate DILI and ascertain

Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly-universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Myeloid cells in the tumor microenvironment (TME) inhibit cytotoxic T cell responses promoting carcinogenesis

Background & Aims Although nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity, the role of adipose tissue in NAFLD is not well understood. As autophagy has been reported to be involved in the degradation of lipid droplets, we investigated the role of adipose tissue autophagy in the liver pathogenesis of NAFLD. Methods C57BL/6J mice and adipocyte-specific Atg7-knockout mice

Background & Aims The limited availability of organoid systems that mimic the molecular signatures and architecture of human intestinal epithelium has been an impediment to allowing them to be harnessed for the development of therapeutics as well as physiological insights. We developed a microphysiological Organ-on-Chip platform designed to mimic properties of human intestinal epithelium leading to

Background & Aims Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and triglyceride (TG)-enriched lipid droplets and cell death. The present study aimed to investigate how FFA or TG induce hepatocyte injury, thereby contributing to the development of ALD. Methods Hepatocyte-specific DGAT1 knockout (DGAT1Δhep) mice and lysosome-associated membrane

The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange

Background and aims The presence of tertiary lymphoid structures (TLS) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the precise role in PDAC has not been elucidated. Here we aim to investigate the structure and role of TLS in human and murine pancreatic cancer. Methods Multicolor immunofluorescence and

Background & Aims Epigenetic regulation of gene expression plays a critical role in the development of liver cancer; however, the molecular mechanisms of epigenetic-driven liver cancers are not well-understood. The aims of this study were to examine molecular mechanisms which cause the de-differentiation of hepatocytes into cancer cells in aggressive hepatoblastoma and test if the inhibition of these

Background and aims Neuroinflammation in the gut is associated with many gastrointestinal (GI) diseases, including inflammatory bowel disease. In the brain, neuroinflammatory conditions are associated with blood-brain barrier (BBB) disruption and subsequent neuronal injury. We sought to determine whether the enteric nervous system (ENS) is similarly protected by a physical barrier and whether that

Background & Aims The inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis, are caused in part by aberrant immune responses to resident intestinal bacteria. Certain dietary components, including carbohydrates, are associated with IBDs and alter intestinal bacterial composition. However, the effects of luminal carbohydrates on the composition and colitogenic potential of intestinal

BACKGROUND S AND AIM: The gastrointestinal epithelium plays a crucial role in maintaining homeostasis with the gut microbiome. Mucins are essential for intestinal barrier function and serve as a scaffold for antimicrobial factors. MUC2 is the major intestinal gel-forming mucin produced predominantly by goblet cells. Goblet cells express AGR2, a protein disulfide isomerase (PDI) that is crucial for

Background & Aims CD4+ T cells are regulated by activating and inhibitory cues and dysregulation of these proper regulatory inputs predisposes to aberrant inflammation and exacerbation of disease. We investigated the role of the inhibitory receptor, paired immunoglobulin-like receptor B (PIR-B) in the regulation of the CD4+ T-cell inflammatory response and exacerbation of the colitic phenotype. Methods

BACKGROUND & AIMS Gut microbiota have been reported to be sensitive to circadian rhythms and host lipometabolism, respectively. While melatonin-mediated beneficial efforts on many physiological sites have been revealed, the regulatory actions of oral melatonin on the communication between gut microbiota and host are still not clearly. Moreover, angiopoietin-like 4 (ANGPTL4) has been showed to be strongly

Background & Aims Tissue-resident memory T cells (Trm), both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data is conflicting regarding the profile of human CD8+ Trm, with studies suggesting both pro-inflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic