American Journal of Physiology. Gastrointestinal and Liver Physiology

Epithelial metabolism in the intestine is increasingly known to be important for stem cell maintenance and activity while also affecting weight gain and diseases. This review compiles studies from recent years which describe major transcriptional factors controlling metabolic activity across the intestinal epithelium as well as transcriptional and epigenetic networks controlling the factors themselves. Recent studies show that transcriptional regulators serve as the link between signals from the microbiota and diet and epithelial metabolism...

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to be fed enterally. Clinically, infants are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Unfortunately, neonates experience extremely high rates of hepatic complications Adult rodent and piglet models of PN are well-established, but neonatal models capable of leveraging the considerable transgenic potential of the mouse remain underdeveloped...

Perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) has been shown to disrupt the development of serotonergic signaling pathways. Serotonin (5-hydroxytryptamine; 5-HT) signaling is critical for gastrointestinal homeostasis; changes in 5-HT expression and regulation have been associated with gastrointestinal diseases of motility and inflammation. We tested the hypothesis that perinatal exposure to the SSRI, fluoxetine, can influence the development of the gastrointestinal tract in exposed offspring...

Notch signaling regulates gastrointestinal stem cell proliferation and differentiation yet Notch-regulated transcriptional effectors of gastric epithelial cell differentiation are poorly understood. Here we tested the role of the bHLH transcription factor achaete-scute homolog 1 (ASCL1) in gastric epithelial cell differentiation, and its regulation by Notch. Newborn Ascl1 null mice showed a loss of expression of markers of neurogenin-3 dependent enteroendocrine cells, with normal expression of enterochromaffin-like cells, mucous cells, chief cells, and parietal cells...

The liver plays a significant role in regulating a wide range of metabolic, homeostatic, and host-defense functions. However, the impact of liver injury on the host's ability to control bacteremia and morbidity in sepsis is not well understood. Leukocyte recruitment and activation lead to cytokine and chemokine release, which in turn, trigger hepatocellular injury and elevate nucleotide levels in the extracellular milieu. P2Y2 purinergic receptors, G-protein coupled and activated by extracellular ATP/UTP, are expressed at the cell surface of hepatocytes and non-parenchymal cells...

BACKGROUND: Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The ACE2 receptor plays a key role in SARS-COV-2 pathogenesis, facilitating entry of the virus into epithelial cells, while also regulating mucosal inflammatory responses. Here, we investigated roles for the nuclear bile acid receptor, farnesoid x receptor (FXR), in regulating ACE2 expression and virally-mediated inflammatory responses in intestinal epithelia. METHODS: Human colonic or ileal enteroids and cultured T84 and Caco-2 monolayers were treated with the FXR agonists, obeticholic acid (OCA) or GW4064, or infected with live SARS-CoV-2 (2019-nCoV/USA_WA1/2020)...

Deep crypt secretory (DCS) cells are a population of epithelial cells located at the colonic crypt base that share some similarities to Paneth and goblet cells. They were initially defined as c-Kit expressing cells, though subsequent work showed that they are more specifically marked by Reg4 in the murine colon. The best-understood function of DCS cells at present is supporting the stem cell niche by generating Notch and EGF ligands. However, as these cells also express immunoregulatory (e.g. Ccl6 ) and host defense (e...

Mediator subunit MED1 mediates ligand-dependent binding of the Mediator coactivator complex to various nuclear receptors and plays critical role in embryonic development, lipid and glucose metabolism, liver regeneration and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice, and positively correlated with TGF-β signaling and pro-fibrotic factors...

The liver plays a crucial role in maintaining systemic iron homeostasis through iron storage, sensing of systemic iron needs, and production of the iron-regulatory hormone hepcidin. While mice are commonly used as models for studying human iron homeostasis, their liver structure differs significantly from humans. Since the mouse liver is structured in 6 separated lobes, often, the analysis of a single defined lobe is preferred due to concerns over data reproducibility between experimental cohorts. In this study, we compared iron-related parameters in distinct liver lobes of C57BL/6 wild-type mice across different ages...

In numerous subtypes of central and peripheral neurons, small and intermediate conductance Ca2+ -activated K+ (SK and IK, respectively) channels are important regulators of neuronal excitability. Transcripts encoding SK channel subunits, as well as the closely related IK subunit, are co-expressed in the soma of colonic afferent neurons with receptors for the algogenic mediators adenosine triphosphate (ATP) and bradykinin, P2X3 and B2 , highlighting the potential utility of these channels as drug targets for the treatment of abdominal pain in gastrointestinal diseases such as irritable bowel syndrome...

Synthesis of plasma proteins is an important function of the liver that has sparsely been investigated by modern techniques in patients with advanced chronic liver disease (CLD). Twenty-eight well-characterized patients with CLD under evaluation for liver transplantation were included. Albumin and fibrinogen synthesis rates were measured by the flooding dose technique using stable isotope-labeled phenylalanine. Transcapillary escape rate of albumin and plasma volume were assessed by radioiodinated human serum albumin...

During acute pancreatitis (AP), free fatty acids (FFAs) are liberated from circulating triglycerides (TG) and injured adipocytes by pancreatic lipase. Circulating FFAs have been suspected as a source of systemic lipotoxicity in AP. However, assessment of FFAs is difficult and time-consuming, and little is known about relative levels of FFAs between patients with different severities of AP and controls. This study's aims were to assess early circulating levels of FFAs, (both saturated and unsaturated) in patients with AP vs...

Maternal influenza A virus (IAV) infection during pregnancy can affect offspring immune programming and development. Offspring born from influenza-infected mothers are at increased risk of neurodevelopmental disorders and have impaired respiratory mucosal immunity against pathogens. The gut-associated lymphoid tissue (GALT) represents a large proportion of the immune system in the body and plays an important role in gastrointestinal (GI) homeostasis. This includes immune modulation to antigens derived from food or microbes, gut microbiota composition, and gut-brain axis signaling...

Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model)...

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously, we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model...

Gut-brain axis and inflammation are two hot topics in Parkinson's disease. In this setting, the Leucine-rich repeat kinase 2 ( LRRK2 ) gene, which encodes the eponym protein has attracted much attention. LRRK2 is not only the gene most commonly associated with Parkinson's disease but also a susceptibility gene for Crohn's disease, thereby suggesting that it may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. In contrast to the accumulated data on LRRK2 in the CNS, research on LRRK2 in the digestive tract is still in its infancy and the scope of the present review article is therefore to review existing studies on LRRK2 in the gastrointestinal tract in both physiological and pathological conditions...

The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and co-immunolabeling protocol optimized for the tissue size and the processing time for 3D visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species...

Swallow related axial shortening of the esophagus results in the formation of phrenic ampulla in normal subjects. Whether above is the case in achalasia esophagus is not known. <u>Goal:</u> To study axial shortening of the esophagus and relative movement between the lower esophageal sphincter (LES) and crural diaphragm (CD) in normals and achalasia patients. <u>Methods:</u> A novel method, iso-impedance contour excursion at the lower edger of LES, as a marker of axial esophageal shortening was validated using X-ray fluoroscopy (n=5) and used to study axial shortening and separation between the LES and CD during peristalsis in normal subjects (n=15) and achalasia type 2 esophagus (n=15)...

INTRODUCTION: It is believed that whole liver grafts adjust their size to fit the body size of the recipient after transplantation, despite lack of evidence. The aim of this study was to test this hypothesis. METHODS: This was a retrospective cohort study of 113 liver transplantations performed at Karolinska University Hospital. The cohort was divided based on graft volume-to-standard liver volume ratio (GV/SLV) into quartiles of small, mid and large grafts. Serial volumetric assessment was performed on the day of transplantation and at post-transplant check-ups early (<2 months) and late (9-13 months) after transplantation using computed tomography (CT) volumetry...

INTRODUCTION: Gastric emptying scintigraphy (GES) measures total gastric retention after a solid meal, and can assess intragastric meal distribution (IMD). Water load satiety test (WLST) measures gastric capacity. Both IMD immediately after meal ingestion (ratio of proximal gastric counts after meal ingestion to total gastric counts at time 0 [IMD0 ]) and WLST (volume of water ingested over 5 min) are indirect measures of gastric accommodation. In this study, IMD0 and WLST were compared to each other and to symptoms of gastroparesis to gauge their clinical utility for assessing patients with symptoms of gastroparesis...