American Journal of Physiology. Gastrointestinal and Liver Physiology

The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterised impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells and the neurons themselves...

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. AIM: To characterize and determine the mechanisms of the EECR. METHODS: Cats (N=35) were decerebrated and electrodes placed on pharynx and cervical esophagus, and esophageal motility recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCL, vagus nerve or pharyngo-esophageal nerve (PEN) transection, or hexamethonium administration (Hex; 5 mg/kg, IV) were determined...

Mechanical distension beyond a particular threshold evokes visceral pain from distal colon and rectum (colorectum) and thus biomechanics plays a central role in visceral nociception. In this study we focused on the layered structure of the colorectum through the wall thickness and determined the biomechanical properties of layer-separated colorectal tissue. We harvested the distal 30 mm of mouse colorectum and dissected into inner and outer composite layers. The inner composite consists of the mucosa and submucosa while the outer composite includes the muscular layers and serosa...

The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes, CMMCs, 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns is unclear. Using transgenic animals expressing the genetically-encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively...

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1a and HIF-2a (Endothelial PAS Domain Protein 1, EPAS1) play important but opposing roles in its pathogenesis. While activation of HIF-1a decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2a exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2a in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2a led to massive intestinal inflammation and decreased survival...

Organic cation transporters (OCT) are responsible for the intracellular uptake and detoxification of a broad spectrum of substrates. OCT are downregulated in cholestasis, fibrosis and hepatocellular carcinoma, but the underlying molecular mechanisms are unknown.Oct3-knockout ( Oct3-/- ; FVB.Slc22a3tm10pb ) and wild type (WT; FVB ) mice were subject to escalating doses of carbon tetrachloride (CCl4 ) or thioacetamide (TAA) for 6 weeks to induce liver fibrosis. Secondary biliary fibrosis was generated by bile duct ligation (BDL)...

Symptoms of functional gastrointestinal disorders (FGID), including fullness, bloating, abdominal pain, and altered gastrointestinal (GI) motility, present a significant clinical problem, with a reported prevalence of 25-40% within the general population. More than 60% of those affected seek and require health care, and affected individuals report a significantly decreased quality of life. FGID are highly correlated with episodes of acute and chronic stress, and are increased in prevalence and reported severity in women compared to men...

BACKGROUND AND AIMS: The temporal relationship between cirrhotic cardiomyopathy, progression of liver disease, and survival remains unknown. Our aim was to investigate the development of structural and functional cardiac changes over time with the progression of cirrhosis and outcome. METHODS: Sixty-three cirrhotic outpatients (Child class: A=9, B=46, C=8) and 14 healthy controls were included in this 2-year longitudinal study. Advanced cardiac characteristics such as cardiac MRI with extracellular volume (ECV) quantification, speckle tracking echocardiography, and biomarkers were assessed at 0/6/12/18/24 months...

Increasedbile acids in the colon can evoke increased epithelial secretion resulting in diarrhea but little is known whether colonic bile acids contribute to abdominal pain. This study aimed to investigate the mechanisms underlying activation of colonic extrinsic afferent nerves and their neuronal cell bodies by a major secondary bile acid, deoxycholic acid (DCA). All experiments were performed on male C57BL/6 mice. Afferent sensitivity was evaluated using in vitro extracellular recordings from mesenteric nerves in the proximal colon (innervated by vagal and spinal afferents) and distal colon (spinal afferents only)...

Extended liver resection results in the loss of a large fraction of the hepatic vascular bed and thereby abrupt alterations in the perfusion of the remnant liver. Mechanisms of hemodynamic adaptation and associated changes in oxygen metabolism after liver resection and the effect of mechanical portal blood flow reduction were assessed. A pig model (n=16) of extended partial hepatectomy that included continuous observation for 24 hours under general anesthesia was established. Pigs were randomly separated into 2 groups, one group with a portal flow reduction of 70% compared to the preoperative values, and the other group as a control (n=8, each)...

Recent advances in the fields of electronics and microfabrication techniques have led to the development of implantable medical devices for use within the field of precision medicine. Monitoring visceral surface tissue O2 tension (ptO2 ) by means of an implantable sensor is potentially useful in many clinical situations including the peri-operative management of patients undergoing intestinal resection and anastomosis. This concept could provide a means by which treatment could be tailored to individual patients...

The prevalence of celiac disease has increased in the last decades suggesting a role for environmental factors in addition to gluten. Several cohort studies have shown that different gastrointestinal infections increase CeD risk. However, the mechanisms by which microbes participate in CeD have been remained elusive. Recently, using animal models, both viral and bacterial opportunistic pathogens were shown to induce immune activation relevant for CeD. The hypothesis that viral and or bacterial infections can contribute to immune activation and breakdown of tolerance towards gluten in genetically susceptible individuals, is thus reinforced...

Background. Metabolic and alcoholic liver injuries result in non-alcoholic (NAFLD) or alcoholic fatty liver disease (ALD), respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. Carbon-tetrachloride (CCl4 ) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Methods.Ethanol in drinking water (16%) or Western diet(WD) were administered for seven weeks in mice either alone or in combination with CCl4 intoxications...

The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord respectively. Whilst the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill-defined. Using dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labelling with phosphorylated MAP Kinase (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input...

ATP is both an important mediator of physiological gut functions such as motility and epithelial function, and a key danger signal that mediates cell death and tissue damage. The actions of extracellular ATP are regulated through the catalytic functions extracellular nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3 and -8 that ultimately generate nucleosides. Ectonucleotidases have distinct cellular associations, but the specific locations and functional roles of individual NTPDases in the intestine are still poorly understood...

Inorganic phosphate (Pi ) is crucial for many biological functions such as energy metabolism, signal transduction and pH buffering. Efficient systems must exist to ensure sufficient supply of the body with Pi from diet. Previous experiments in humans and rodents suggest that two pathways for the absorption of Pi exist, an active transcellular Pi transport and a second paracellular pathway. Whereas the identity, role and regulation of active Pi transport has been extensively studied, much less is known about the properties of the paracellular pathway...

Post-surgical gastric dysfunction is common, but the mechanisms are varied and poorly understood. The pylorus normally acts as an electrical barrier isolating gastric and intestinal slow waves. In this report, we present an aberrant electrical conduction pathway arising between the stomach and small intestine, following pyloric excision and surgical anastomosis, as a novel disease mechanism. A patient was referred with post-surgical gastroparesis following antrectomy, gastroduodenostomy and vagotomy for peptic ulceration...

HBV-infection and alcoholism are major public health problems worldwide, contributing to development of end-stage liver disease. Alcohol intake affects HBV-infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T-lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-MHC class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs...

Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective pro-resolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide...

Prenatal inflammation is a risk factor for necrotizing enterocolitis (NEC) and it increases intestinal injury in a rat NEC model. We previously showed that maldevelopment of the intestinal microvasculature and lack of VEGFR2 signaling play a role in experimental NEC. However, whether prenatal inflammation affects the intestinal microvasculature remains unknown. In this study, mouse dams were injected intraperitoneally with lipopolysaccharide (LPS) or saline at E17. Neonatal intestinal microvasculature density, endothelial cell proliferation and intestinal VEGF-A (VEGF) and VEGFR2 proteins were assessed in vivo ...