Cellular and Molecular Gastroenterology and Hepatology

Editor picks for Cellular and Molecular Gastroenterology and Hepatology

Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation We describe a novel porcine 3-dimensional culture model that reproduces esophageal submucosal gland proliferation in vivo associated with cancer and injury.
Oct. 22, 2017

Analysis of Hepatitis C Virus Particle Heterogeneity in Immunodeficient Human Liver Chimeric fah-/- Mice Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet.
Oct. 22, 2017

Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells.
Oct. 22, 2017

Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in Humans This study provides the first demonstration of S Typhi–specific responses in the human terminal ileum mucosa .
Oct. 22, 2017

Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis Lamin A/C absence leads to male-selective fatty liver disease and predisposes to nonalcoholic steatohepatitis and fibrosis.
Oct. 22, 2017

Setting up a Lab: The Early Years Dr Habtezion provides advice on successfully navigating the early years of an independent career as a physician-scientist.
Oct. 22, 2017

The Farnesoid X Receptor: Good for BAD Herein, we review current concepts of bile acid diarrhea pathogenesis and the potential role for the farnesoid X receptor in its treatment.
Oct. 22, 2017

The Gut Microbiota and Liver Disease A more detailed picture of the intestinal microbiota contributing to liver disease beyond increasing intestinal permeability has started to evolve.
Oct. 22, 2017

Antifibrogenic Effects of the Antimicrobial Peptide Cathelicidin in Murine Colitis-Associated Fibrosis Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.
Oct. 22, 2017

Maintaining a Vibrant and Productive Laboratory as a Senior Investigator Dr Boyer discusses his decision to maintain a research program at this stage of his career.
Sept. 1, 2017

Cellular and Molecular Gastroenterology and Hepatology RSS

  • Adipose-derived Stromal Cells: The Good Side of Fat?

    Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions of the gastrointestinal tract triggered by inappropriate immune responses to commensal microorganisms, environmental factors, and genetic susceptibility. The molecular pathomechanisms of IBD remain largely elusive. Further understanding of both pathogenic and protective factors for IBD is critical for the development of innovative treatment modalities.
  • Nod-like receptor pyrin-containing protein 6 (NLRP6) is upregulated in ileal Crohns disease and differentially expressed in goblet cells

  • Diagnosis of malignant potential in mucinous peritoneal neoplasms by characterization of mucin carbohydrate structure

  • Monoclonal antibodies reveal dynamic plasticity between Lgr5- and Bmi1-expressing intestinal cell populations

    Multiple stem cell populations coordinately support continued epithelial renewal and regeneration in the intestine. The hierarchical function of discrete stem and progenitor cell populations remains controversial. Using novel antibody tools to assess active- and slow-cycling cell populations, Wong et al. reveal a unique stem cell property of a slow-cycling epithelial cell and show that it has bi-directional plasticity with the Lgr5-expressing stem cell.
  • Neonatal colonic inflammation epigenetically aggravates epithelial inflammatory responses to injury in adult life

    This investigation demonstrates that neonatal inflammation increases susceptibility to IBD by epigenetically sensitizing the IL-1 promoter for exacerbated overexpression when exposed to another episode of inflammation later in life. Propranolol might mitigate against the IBD susceptibility by reversing epigenetic modifications.
  • Human Fetal Enterospheres: New Tools for the Study of Necrotizing Enterocolitis

    Necrotizing enterocolitis (NEC) is a serious and often life-threatening disorder that affects the gastrointestinal tract of premature infants. The disease develops in seemingly stable infants, who, after receiving formula feeds, suddenly develop abdominal distention and feeding intolerance, which often progresses to systemic sepsis and death. At laparotomy, which is required in approximately half of all babies with NEC, patchy regions of intestinal necrosis are encountered, necessitating intestinal resection in an attempt to save the infants life.
  • Cholecystokinin receptor-targeted polyplex nanoparticle inhibits growth and metastasis of pancreatic cancer

    Here we report the development of a polyplex nanoparticle that selectively targets the CCK receptor on human pancreatic cancer and delivers small interfering RNAs specific to gastrin, to block cancer cell growth in vitro and in vivo. One remarkable finding in our investigation was that this therapeutic approach completely prevented metastasis the most common cause of death in this condition.
  • The role of ion transporters in the pathophysiology of infectious diarrhea

    Intestinal ion transporters ensure fluid and electrolyte homeostasis. Several are modulated during enteric infections, potentially contributing to diarrhea. This review surveys changes in the abundance and/or regulation of transporters that occur in these conditions, pointing to possible novel targets for therapy.
  • FXR-mediated cortical cholesterol accumulation contributes to the pathogenesis of Type A hepatic encephalopathy

    Concentrations of cholesterol are elevated in the brain during acute liver failure-induced hepatic encephalopathy in mice as a result of aberrant FXR-mediated signaling. Strategies aimed at reducing brain cholesterol levels improved neurological and neuromuscular deficiencies in mice with acute liver failure.
  • The Novel Role of Lgr5 as a Regulator of Cell Homeostasis and Disease of the Gastric Oxyntic Mucosa

    The stem cell compartment is crucial for driving the replenishment of the gastric epithelium. The leucine-rich, repeat-containing G-proteincoupled receptor 5 (Lgr5) was among the first genes identified to mark the stem cells within the gastric mucosa.1 It is accepted that Lgr5 is located in adult stem cells at the base on the antral glands of the stomach, and are capable of long-term renewal of the epithelium.1 Recently, using a nonvariegated Lgr5-2A-CreERT2 mouse model, investigators found that Lgr5 is expressed within the chief cells of the corpus and are recruited to function as stem cells to regulate epithelial renewal in response to injury.
  • Mutant KRAS Exosomes Influence the Metabolic State of the Colon Microenvironment

    KRAS is mutated in approximately 30% to 40% of colorectal cancers (CRC) and KRAS mutations lead to an adaptive metabolic shift in cancer cells with increased aerobic glycolysis (Warburg effect) in part owing to higher uptake of glucose. In mutant KRAS CRC cells, overexpression of the glucose transporter GLUT-1 (SLC2A1) is observed and contributes to increased glucose uptake, leading to acquisition of this metabolic change. However, the ability of KRAS to reach beyond the cancer cell and alter the metabolic state within the tumor microenvironment is not entirely clear.
  • Host-Gut Microbiota Cross-Talk in Intestinal Adaptation

    Short-bowel syndrome represents the most common cause of intestinal failure and occurs when the remaining intestine cannot support fluid and nutrient needs to sustain adequate physiology and development without the use of supplemental parenteral nutrition. After intestinal loss or damage, the remnant bowel undergoes multifactorial compensatory processes, termed adaptation, which are largely driven by intraluminal nutrient exposure. Previous studies have provided insight into the biological processes and mediators after resection, however, there still remains a gap in the knowledge of more comprehensive mechanisms that drive the adaptive responses in these patients.
  • Esophageal Adenocarcinomas: A Need for Speed Driven by Immune Pathways That Have Druggable Targets

    Despite advances in multimodality therapy and the development of agents that target tumor growthpromoting pathways, the 5-year survival of patients with esophageal adenocarcinoma (EAC) remains less than 20%. Most of these targeted agents have been directed at growth factor receptor tyrosine kinases, with clinical trials yielding woefully disappointing results. Genomic studies of EACs have shown amplification of multiple receptor tyrosine kinases and their downstream signaling pathways, showing a complex, diffuse, and redundant spider web of signaling networks that might elude inhibition even by combinations of several molecularly targeted agents.
  • Parietal Cell Death by Cytokines

    Parietal cell atrophy in the human stomach occurs along a continuum of gastric inflammation, atrophy, and then metaplasia, a preneoplastic lesion. In mice, and to a lesser extent in human beings, the best-characterized typeof metaplasia is spasmolytic polypeptide-expressing metaplasia. Inflammation in the stomach generally arises in response to autoimmune gastritis or an infection from Helicobacter pylori. Although relatively rare, autoimmune gastritis is known to occur in response to autoantibodies to parietal cell proteins, specifically the and subunits of the proton pump H+, K+-adenosine triphosphatase.
  • Proteomic Study Defines How Alcohol Alters ER Structure and Redox Proteome to Trigger ER Stress and Acinar Cell Pathology in Pancreatitis

    In a new study published in this issue of Cellular andMolecular Gastroenterology and Hepatology, Waldron etal1 used proteomic approaches to define how ethanol modifies the redox state of the pancreas ER proteome. These structural changes and ER dysfunction may contribute to ethanol-induced pathology associated with pancreatitis.
  • Estrogen-Mediated Effects Underlie Gender Bias in Inflammatory Bowel Disease

    The gastrointestinal tract is continuously exposed toa myriad of food antigens and symbiotic microflora, thus modulation of the inflammatory response is tightly regulated to prevent aberrant immune activation andchronic inflammation. However, in individuals with a genetic and environmental predisposition (eg, altered microbiota, viral or bacterial infection, chemical additives, or pollutants), regulation of intestinal inflammation is impaired. This condition leads to a chronic relapsing immune activation against luminal antigens, also known as inflammatory bowel disease (IBD).
  • Move Over Caco-2 Cells: Human-Induced Organoids Meet Gut-on-a-Chip

    The intestinal epithelium serves as both a crucial barrier and a critical site of interaction between the body and the environment. As such, it comprises a large surface area, and is implicated in a wide range of diseases including inflammatory bowel disease, celiac disease, infectious diarrheas, and intestinal cancers. Architecturally, the small intestine is notable for its proliferative crypts, where stem and transit-amplifying progenitor cells reside, and villi, which consist of multiple differentiated cell types from the absorptive and secretory lineages, including enterocytes, goblet cells, Paneth cells, tuft cells, M cells, and enteroendocrine cells.
  • Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems

    Function at the organ level manifests itself from a heterogeneous population of cell types. Cellular heterogeneity emerges from developmental processes by which multipotent progenitor cells make fate decisions and transitions to specific cell types through intermediate cell states. Although genetic experimental strategies such as lineage tracing have provided insights into cell lineages, recent developments in single-cell technologies have greatly increased our ability to interrogate distinct cell types, as well as transitional cell states in tissue systems.
  • OST-OST Guards the Ileal Enterocyte From the Accumulation of Toxic Levels of Bile Acids

    OST-OST (SLC51A and SLC51B) is a heteromeric organic solute transporter that was first isolated from the liver of a marine skate, Leukoraja erinacia, by Ballatori etal in a quest for a sodium-independent transporter of hepatic bile acid uptake.1 Subsequent studies identified SLC51A and B orthologues from mice and human beings. These 2 gene products are the only known members of this SLC family and are unique in requiring 2 subunits for function. Human SLC51A encodes for a 340amino acid protein with 7 membrane-spanning domains whereas SLC51B encodes for a 128amino acid single-membrane-spanning domain protein.
  • Molecular Basis and Differentiation-Associated Alterations of Anion Secretion in Human Duodenal Enteroid Monolayers

    Human enteroids present a novel toolto study human intestinal ion transport physiology and pathophysiology. The present study describes the contributions of Cl- and HCO3- secretion to total cyclic adenosine monophosphate (cAMP)-stimulated electrogenic anion secretion in human duodenal enteroid monolayers and the relevant changes after differentiation.
  • Cysteine Protease-Mediated Autocleavage of Clostridium difficile Toxins Regulates Their Proinflammatory Activity

    Clostridium difficile toxin A (TcdA) and C difficile toxin toxin B (TcdB), the major virulence factors of the bacterium, cause intestinal tissue damage and inflammation. Although the 2 toxins are homologous and share a similar domain structure, TcdA is generally more inflammatory whereas TcdB is more cytotoxic. The functional domain of the toxins that govern the proinflammatory activities of the 2 toxins is unknown.
  • Mesenteric Adipose-derived Stromal Cells From Crohns Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis

    Mesenteric adipose tissue hyperplasia is a hallmark of Crohns disease (CD). Recently, we showed that mesenteric adipose-derived stromal cells (ADSCs) from CD, ulcerative colitis, and control patients synthesize and release adipokines in a disease-dependent manner. Here we examined the expression profiles of CD and control patient-derived mesenteric ADSCs and studied the effects of their extracellular mediators on colonocyte signaling invitro and experimental colitis invivo. ADSCs were isolated from mesenteric fat of control and CD patients.
  • Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC)

    Untreated necrotizing enterocolitis (NEC) can lead to massive inflammation resulting in intestinal necrosis with a high mortality rate in preterm infants. Limited access to human samples and relevant experimental models have hampered progress in NEC pathogenesis. Earlier evidence has suggested that bacterial colonization of an immature and developing intestine can lead to an abnormally high inflammatory response to bacterial bioproducts. The aim of our study was to use human fetal organoids to gain insights into NEC pathogenesis.
  • Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine

    The stratified squamous epithelium of the esophagus shows a proliferative basal layer of keratinocytes that undergo terminal differentiation in overlying suprabasal layers. Esophageal pathologies, including eosinophilic esophagitis, gastroesophageal reflux disease, Barrett's esophagus, squamous cell carcinoma, and adenocarcinoma, cause perturbations in the esophageal epithelial proliferation-differentiation gradient. Three-dimensional (3D) culture platforms mimicking invivo esophageal epithelial tissue architecture exvivo have emerged as powerful experimental tools for the investigation of esophageal biology in the context of homeostasis and pathology.
  • Obesity and Binge Drinking: Two Hits Driving Liver Fibrosis Progression?

    Alcoholic fatty liver disease and nonalcoholic fatty liver disease frequently are associated with alcohol consumption and obesity. Both diseases start with steatosis/steatohepatitis, and some patients can develop advanced liver injuries and subsequent permanent liver damage, including fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Epidemiologic evidence has shown that drinking alcohol synergistically increases the prevalence and severity of liver injury in obese individuals. Likewise, liver damage in alcohol abusers is greatly exacerbated by obesity.
  • A Sabbatical: The Gift That Keeps on Giving

    Scott Friedman is the Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai, a former president of the American Association for the Study of Liver Diseases, and a leader in liver fibrosis research. He speaks often of the transformative role his sabbatical played in his career, and this month encourages other researchers to consider similar academic experiences, providing advice on what to doand not doto make a sabbatical worthwhile.
  • CFTR and the Regulation of Crypt Cell Proliferation

    Gastrointestinal manifestations of cystic fibrosis (CF) may be quite severe and a cause of significant morbidity. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) result in meconium ileus, and, in later life, small-bowel bacterial overgrowth, bowel obstructions, and an increased incidence of intestinal cancers. A 2013 study of more than 40,000 patients from 250 US CF centers showed an increased risk of colon cancer (standardized incidence ratio, 6.2) and small-bowel cancer (standardized incidence ratio, 11.5).
  • siRNA Library Screening Identifies a Druggable Immune-Signature Driving Esophageal Adenocarcinoma Cell Growth

    Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barretts esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation.
  • Mutant KRAS Exosomes Alter the Metabolic State ofRecipient Colonic Epithelial Cells

    In colorectal cancer (CRC) cells, mutant KRAS cell-autonomously imparts Warburg-like1 metabolic changes through induction of GLUT-1 (SLC2A1).2,3 We previously reported that mutant KRAS has marked effects on the constituents of CRC exosomes, including proteins and enzymes involved in metabolism and glycolysis.4,5 The present studies were designed to test whether mutant KRAS exosomes can alter the metabolic state cell-nonautonomously in recipient colonic epithelial cells.
  • Translating Developmental Principles to Generate Human GastricOrganoids

    Gastric diseases, including peptic ulcer disease and gastric cancer, are highly prevalent in human beings. Despite this, the cellular biology of the stomach remains poorly understood relative to other gastrointestinal organs such as the liver, intestine, and colon. In particular, little is known about the molecular basis of stomach development and the differentiation of gastric lineages. Although animal models are useful for studying gastric development, function, and disease, there are major structural and physiological differences in human stomachs that render these models insufficient.
  • TRPing Up Fibrosis: A Novel Role for TRPA1 in Intestinal Myofibroblasts

    Intestinal fibrosis is a common complication of theinflammatory bowel diseases (IBDs), affecting 30%50% of patients with Crohns disease (CD). It is thought to be a consequence of chronic inflammation, andintestinal fibrosis is characterized by myofibroblast accumulation, excessive deposition of extracellular matrix (ECM), and in some cases smooth muscle hypertrophy. The most severe phenotype, in which tissue remodeling leads to luminal narrowing, occurs in more than 30% of CD patients within 10 years of disease diagnosis,1 with many of these patients requiring surgery and, ultimately, experiencing stricture recurrence.
  • Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

    Gastric Lgr5 cells exert important functions during injury and homeostasis. Bone morphogenetic protein (BMP) signaling regulates gastric inflammation and epithelial homeostasis. We investigated if BMP signaling controls the fate of Lgr5+ve cells during inflammation.
  • NAFLD Phenotype in Patients With V-ATPase Proton Pump Assembly Defects

    Nonalcoholic fatty liver disease (NAFLD) is a very common chronic liver disease marked by hepatic fat accumulation. This might trigger inflammation and liver cell injury, a condition known as nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis may promote fibrogenesis and evolve toward cirrhosis and hepatocellular carcinoma, and is considered the phenotypic extension of NAFLD.
  • Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche

    The relationship between intestinal stem cells (ISCs) and the surrounding niche environment is complex and dynamic. Key factors localized at the base of the crypt are necessary to promote ISC self-renewal and proliferation, to ultimately provide a constant stream of differentiated cells to maintain the epithelial barrier. These factors diminish as epithelial cells divide, migrate away from the crypt base, differentiate into the postmitotic lineages, and end their life span in approximately 7 days when they are sloughed into the intestinal lumen.
  • Organic Solute Transporter - Protects Ileal Enterocytes From Bile AcidInduced Injury

    Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter - (OST-OST). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in Ost-/- mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids.
  • NRF2 Induction for NASH Treatment: A New Hope Rises

    Nonalcoholic fatty liver disease (NAFLD) is a complex disease characterized by excessive fat storage in the liver. NAFLD ranges from simple steatosis (fat accumulation) to nonalcoholic steatohepatitis (NASH), which in addition to steatosis involves liver inflammation (hepatitis) and fibrosis, and can progress into cirrhosis or liver cancer. Coupled with a worldwide increase in obesity, type 2 diabetes, metabolic syndrome, and hypertension, the incidence of NAFLD/NASH is also steadily increasing.
  • Ferroportin Expression in Adipocytes Does Not Contribute to Iron Homeostasis or Metabolic Responses to a High Calorie Diet

    Iron has an increasingly recognized role in the regulation of adipose tissue function, including the expression of adipokines involved in the pathogenesis of nonalcoholic fatty liver disease. The cellular iron exporter, ferroportin, has been proposed as being a key determinant of adipocyte iron homeostasis.
  • NeutrophilHepatic Stellate Cell Interactions Promote Fibrosis inExperimental Steatohepatitis

    Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown.
  • Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model

    Heavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk.Mice fed ethanol long term show no pancreas damage unlessadaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ERproteins.
  • Stinging Tight Junctions With WASPs

    Extracellular bacterial pathogens can hijack the N-WASPbased machinery to promote actin nucleation and polymerization in their hosts. One well-studied example is the family of attaching and effacing (A/E) bacterial pathogens, which includes the human diarrheagenic enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E coli, and the mouse pathogen Citrobacter rodentium. These bacteria, which infect the intestinal epithelium, activate a syringe-like machinery, termed the type III secretion system, through which they translocate a battery of protein effectors from their own cytoplasm into the infected host.
  • The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive EpithelialChanges

    Aberrations in the esophageal proliferation-differentiation gradient are histologic hallmarks in eosinophilic esophagitis (EoE) and gastroesophageal reflux disease. A reliable protocol to grow 3-dimensional (3D) esophageal organoids is needed to study esophageal epithelial homeostasis under physiological and pathologic conditions.
  • Interleukin 17A Promotes Parietal Cell Atrophy by Inducing Apoptosis

    Atrophic gastritis caused by chronic inflammation in the gastric mucosa leads to the loss of gastric glandular cells, including acid-secreting parietal cells. Parietal cell atrophy in a setting of chronic inflammation induces spasmolytic polypeptide expressing metaplasia, a critical step in gastric carcinogenesis. However, the mechanisms by which inflammation causes parietal cell atrophy and spasmolytic polypeptide expressing metaplasia are not well defined. We investigated the role of interleukin 17A (IL17A) in causing parietal cell atrophy.
  • Enhanced Utilization of Induced Pluripotent Stem CellDerived Human Intestinal Organoids Using Microengineered Chips

    Human intestinal organoids derived from induced pluripotent stem cells have tremendous potential to elucidate the intestinal epitheliums role inhealth and disease, but it is difficult to directly assay thesecomplex structures. This study sought to make this technology more amenable for study by obtaining epithelial cells from induced pluripotent stem cellderived human intestinal organoids and incorporating them into small microengineered Chips. We then investigated if these cells within the Chip were polarized, had the 4 major intestinal epithelial subtypes, and were biologically responsive to exogenous stimuli.
  • Is the Lower Esophageal Sphincter Tone Related to a Gas?

    Sphincters are placed at critical locations in the gastrointestinal tract, where they separate adjoining regions with distinct functions (eg, the lower esophageal sphincter [LES] between the esophagus and stomach). Sphincters are generally 2-way valves and control the direction of movement of luminal contents. Under resting conditions, sphincters maintain tonic closure for compartmentalization, as in the case of the LES, which prevents movement of gastric contents into the esophagus (reflux). With swallowing, the LES opens briefly for esophageal emptying into the stomach.
  • Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease

    The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinallamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling.
  • Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer

    Pancreatic ductal adenocarcinoma is one of the most aggressive forms of cancer, and the third leading cause of cancer-related mortality in the United States. Although important advances have been made in the last decade, themortality rate of pancreatic ductal adenocarcinoma has not changed appreciably. This review summarizes a rapidly emerging model of pancreatic cancer research, focusing on 3-dimensional organoids as a powerful toolforseveral applications, but above all, representing astep toward personalized medicine.
  • Estrogen Receptor Loss-of-Function Protects Female Mice From DSS-Induced Experimental Colitis

    Males are at greater risk than femalesfor developing ulcerative colitis (UC) and experiencing worse clinical disease13; the molecular basis for this sex bias remains unclear. An important regulatory mechanism of colonic homeostasis is via noncanonical estrogen receptor (ER) signaling. Very low levels of circulating estrogen are required to bind transmembrane and cytosolic ERs, such that immune responses in both sexes are subject toregulation by estrogen. Estrogen receptor (ER) is expressed abundantly in the human colon,4,5 where it has a critical role in maintaining barrier function and colonic architecture.
  • Attaching-and-Effacing Pathogens Exploit Junction Regulatory Activities of N-WASP and SNX9 to Disrupt the Intestinal Barrier

    Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9).
  • Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis AreAmeliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)

    Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis.
  • Antibiotic Treatment Leads to Fecal Escherichia coli and Coliphage Expansion in Severely Malnourished Diarrhea Patients

    Malnutrition predisposes to diarrhea and diarrhea adversely affects the nutritional status creating a vicious cycle.1 The role of the gut microbiome in malnutrition is an active research area.2 Parenteral antibiotics are recommended by the World Health Organization in hospitalized pediatric patients with severe acute malnutrition (SAM) presenting signs of infections.3 Stool microbiota data for such patients are, however, lacking. To fill this gap, we studied the stool microbiota in 19 SAM patients from Bangladesh hospitalized with acute diarrhea (AD) and compared it with that of matched 20 healthy control subjects (HC) (Supplementary Table1).
  • Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases

    New models to study the intestine are key to understanding intestinal diseases and developing novel treatments. Intestinal organ-like culture systems (organoids and enteroids) have substantially advanced the study of the human gastrointestinal tract. Stem cellderived cultures produce self-organizing structures that contain the multiple differentiated intestinal epithelial cell types including enterocytes, goblet, Paneth, and enteroendocrine cells. Understanding hostmicrobial interactions is one area in which these cultures are expediting major advancements.
  • Cftr Modulates Wnt/-Catenin Signaling and Stem Cell Proliferation in Murine Intestine

    Cystic fibrosis (CF) patients and CF mouse models have increased risk for gastrointestinal tumors. CF mice show augmented intestinal proliferation of unknown etiology and an altered intestinal environment. We examined the role of the cystic fibrosis transmembrane conductance regulator (Cftr) in Wnt/-catenin signaling, stem cell proliferation,and its functional expression in the active intestinal stem cell (ISC) population. Dysregulation of intracellular pH (pHi) in CF ISCs was investigated for facilitation of Wnt/-catenin signaling.
  • Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies

    Invitro models of the human liver are important for the following: (1) mitigating the risk of drug-induced liver injury to human beings, (2) modeling human liver diseases, (3) elucidating the role of single and combinatorial microenvironmental cues on liver cell function, and(4) enabling cell-based therapies in the clinic. Methods to isolate and culture primary human hepatocytes (PHHs), the gold standard for building human livermodels, were developed several decades ago; however, PHHs show a precipitous decline in phenotypic functions in 2-dimensional extracellular matrixcoated conventional culture formats, which does not allow chronic treatment with drugs and other stimuli.
  • Intestinal Farnesoid X Receptor Activation by Pharmacologic Inhibition of the Organic Solute Transporter -

    The organic solute transporter - (OST-OST) mainly facilitates transport of bile acids across the basolateral membrane of ileal enterocytes. Therefore, inhibition of OST-OST might have similar beneficial metabolic effects as intestine-specific agonists of the major nuclear receptor for bile acids, the farnesoid X receptor (FXR). However, no OST-OST inhibitors have yet been identified.
  • A Cell Culture Platform to Maintain Long-term Phenotype ofPrimary Human Hepatocytes and Endothelial Cells

    Modeling interactions between primary human hepatocytes (PHHs) and primary human liver sinusoidal endothelial cells (LSECs) invitro can help elucidate human-specific mechanisms underlying liver physiology/diseaseand drug responses; however, existing hepatocyte/endothelial coculture models are suboptimal because of theiruse of rodent cells, cancerous cell lines, and/or nonliver endothelial cells. Hence, we sought to develop a platform thatcould maintain the long-term phenotype of PHHs and primary human LSECs.
  • Epigenetic Reprogramming of Human Hepatoma Cells: A Low-Cost Option for Drug Metabolism Assessment

    Primary cultures of hepatocytes are widely considered the gold standard for evaluating the hepatic metabolism of pharmacologic molecules.1 However, limited access to human hepatocytes has led to the development of various alternative models.25 The procedures used to generate these cells remain complex and time-consuming. In addition, the resulting hepatocytes frequently display heterogeneous hepatic gene expression, rapidly dedifferentiate, and lose their metabolic functions, which are essential for biological, pharmacologic, and toxicologic studies.
  • Endogenous Hydrogen Sulfide Contributes to Tone Generation in Porcine Lower Esophageal Sphincter Via Na+/Ca2+ Exchanger

    Hydrogen sulfide (H2S) is a major physiologic gastrotransmitter. Its role in the regulation of the lower esophageal sphincter (LES) function remains unknown. The present study addresses this question.
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