American Journal of Physiology. Gastrointestinal and Liver Physiology

BACKGROUND: Intestinal fibrosis is a common complication of the inflammatory bowel diseases(IBD), contributing to tissue stiffening and luminal narrowing. NR4A1 was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function...

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiologic and pathophysiological processes that are unable to be studied using other model systems. Increases in the understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling...

Iron accumulation is frequently associated with chronic liver diseases. However, our knowledge on how iron contributes to the liver injury is limited. Aberrant Wnt/β-catenin signaling is a hallmark of several hepatic pathologies. We recently reported that peroxisome proliferator activated receptor alpha (PPARα) agonist, fenofibrate prevents iron induced oxidative stress and β-catenin signaling by chelating the iron. Sirtuin3 (Sirt3), a type of NAD+ -dependent deacetylase that plays a critical role in metabolic regulation was found to prevent ischemia reperfusion injury by normalizing the Wnt/β-catenin pathway...

BACKGROUND: As a major complication of hematopoietic stem cell transplantation, the incidence of hepatic sinusoidal obstruction syndrome (HSOS) is as high as 70%. Previous evidence has demonstrated that miR-511-3p was involved in HSOS, but the mechanism remains unclear. This study aims to examine the mechanism underlying miR-511-3p regulating HSOS. METHODS: Monocrotaline (MCT) was used to create an HSOS rat model and to treat liver sinusoidal endothelial cells (LSECs)...

Background Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. Aims To investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Methods Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study...

Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells...

Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used anti-arrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver, but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue...

The gallbladder is considered an important organ in maintaining digestive and metabolic homeostasis. Given that therapeutic options for gallbladder diseases are often limited to cholecystectomy, understanding gallbladder pathophysiology is essential in developing novel therapeutic strategies.Since Liver X Receptor β (LXRβ), an oxysterol-activated transcription factor, is strongly expressed in gallbladder cholangiocytes, the aim was to investigate LXRβ physiological function in the gallbladder. Thus, we studied the gallbladders of WT and LXRβ-/- male mice using immunohistochemistry, electron-microscopy, qRT-PCR, bile duct cannulation, bile and blood biochemistry and duodenal pH measurements...

Short chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fiber exert myriad of beneficial effects including the amelioration of inflammation. SCFAs exist as anions at luminal pH, their entry into the cells depends on the expression and function of monocarboxylate transporters. In this regard, sodium-coupled monocarboxylate transporter-1 (SMCT-1) is one of the major proteins involved in the absorption of SCFA in the mammalian colon. However, very little is known about the mechanisms of regulation of SMCT-1 expression in health and disease...

Advances in -omics analyses have tremendously enhanced our understanding of the role of the microbiome in human health and disease. Most research is focused on the bacteriome, but scientists have now realized the significance of the virome and microbial dysbiosis as well, particularly in noninfectious diseases such as cancer. In this review, we summarize the role of mycobiome in tumorigenesis, with a dismal prognosis, and attention to pancreatic ductal adenocarcinoma (PDAC). We also discuss bacterial and mycobial interactions to the host's immune response that is prevalently responsible for resistance to cancer therapy, including immunotherapy...

Bisacodyl is a stimulant laxative often used in manometric studies of pediatric constipation to determine if it can initiate propulsive high amplitude propagating contractions. While the effects of bisacodyl infusion on colonic motility are well described, the effects of the drug on other regions of the gut after colonic infusion are not known. The aim of the present study was to characterize the effects of bisacodyl on both colonic and small bowel motility. METHODS: Twenty seven children (9...

Until recently, gastric motility measurements in Humans were mostly limited to accommodation (using barostat or 3-dimensional imaging studies of gastric volume) and gastric emptying tests, the latter being the only one performed in routine clinical care. Accurate and easy to use techniques were lacking to assess pyloric function in health and disease. Recently, pyloric distensibility has been developed and validated to assess pyloric opening. Several studies confirmed that pyloric distensibility was decreased in gastroparesis and correlated with gastric emptying as well as gastroparesis symptoms...

Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording...

Vitamin D deficiency is an environmental factor involved in the pathogenesis of inflammatory bowel disease (IBD), however, the mechanisms surrounding its role remain unclear. Previous studies conducted in an intestinal epithelial-specific vitamin D receptor (VDR) knockout model suggest that a lack of vitamin D signaling causes a reduction in intestinal autophagy. A potential link between vitamin D deficiency and dysregulated autophagy is microRNA (miR)-142-3p, which suppresses autophagy. In this study, we found that wildtype C57BL/6 mice fed a vitamin D deficient diet for 5 weeks had increased miR-142-3p expression in ileal tissues compared to mice fed a matched control diet...

The western diet has been suggested to contribute to the rising incidence of Inflammatory Bowel Diseases. This has led to the hypothesis that fructose, a component of the western diet, could play a role in the pathogenesis of Inflammatory Bowel Diseases. A high fructose diet is known to exacerbate experimental colitis. This study tested whether the expression of GLUT5, the fructose transporter, is a determinant of the severity of experimental colitis during elevated fructose consumption and whether ileal inflammation is associated with altered GLUT5 expression in Crohn's Disease...

The role of leptin in the development of intestinal inflammation remains controversial, since proinflammatory and anti-inflammatory effects have been described. This study describes the effect of the absence of leptin signaling in intestinal inflammation. Experimental colitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to lean and obese Zucker rats (n=10). Effects on inflammation and mucosal barrier were studied. Bacterial translocation and LPS concentration were evaluated together with colonic permeability to 4 kDa FITC-dextran...

BACKGROUND: Untreated NAFLD may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver related but also cardiovascular mortality. However, almost nothing is known about co-existing NAFLD in patients with coronary artery disease (CAD). AIMS: We investigated the impact of surrogates scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography...

Recent studies in our lab have shown that the KV 7 channel activator, flupirtine, inhibits colonic epithelial Cl- secretion through effects on submucosal neurons of the enteric nervous system (ENS). We hypothesized that flupirtine would also stimulate Na+ absorption as a result of reduced secretory ENS input to the epithelium. To test this hypothesis, unidirectional 22 Na+ fluxes were measured under voltage-clamped conditions. Pharmacological approaches using an Ussing-style recording chamber, combined immunofluorescence microscopy techniques were used to determine the effect of flupirtine on active Na+ transport in the rat colon...

Hepato-splanchnic and pulmonary vasculatures constitute synapomorphic, highly comparable networks integrated with the external environment. Given functionality related to obligatory requirements of "feeding and breathing", these organs are subject to constant environmental challenges entailing infectious risk, antigenic and xenobiotic exposures. Host responses to these stimuli need to be both protective and tightly regulated. These functions are facilitated by dualistic, high-low pressure blood supply of the liver and lungs, as well as tolerogenic characteristics of resident immune cells and signaling pathways...

Swallowing is a critical function for survival and development in human neonates, and requires cross-system coordination between neurologic, airway, and digestive motility systems. Development of pharyngo-esophageal motility is influenced by intra- and extra-uterine development, pregnancy complications, and neonatal comorbidities. Primary role of these motility reflex mechanisms is to maintain aerodigestive homeostasis under basal and adaptive biologic conditions including oral feeding, gastroesophageal reflux, and sleep...