American Journal of Physiology. Gastrointestinal and Liver Physiology

Clostridioides difficile is an important nosocomial pathogen that produces toxins to cause life-threatening diarrhea and colitis. Toxins bind to epithelial receptors and promote the collapse of the actin cytoskeleton. C. difficile toxin activity is commonly studied in cancer-derived and immortalized cell lines. However, the biological relevance of these models are limited. Moreover, no model is available for examining C. difficile-induced enteritis, an understudied health problem. We hypothesized human intestinal enteroids (HIEs) express toxin receptors and provide a new model to dissect C...

Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 months. In particular, a subset of toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the current study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies...

Helicobacter pylori infection always induces gastritis, which may progress to ulcer disease or cancer. The mechanisms underlying mucosal injury by the bacteria are incompletely understood. Here we identify a novel pathway for H. pylori-induced gastric injury, the impairment of maturation of the essential transport enzyme and cell adhesion molecule, Na,K-ATPase. The Na,K-ATPase is comprised of α and β subunits that assemble in the ER prior to trafficking to the plasma membrane. Attachment of H. pylori to gastric epithelial cells increased Na,K-ATPase ubiquitylation, decreased its surface and total levels, and impaired ion balance...

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There is increasing evidence that microRNA (miRNA) abnormity is involved in the occurrence and the development of various malignancies, including colon cancer. MiRNA-524-5p has been reported to possess anti-cancer activity in various tumors, which function is seldom investigated in colon cancer cells. The aim of this study was to explore the effect of miRNA-524-5p/with-nolysine kinases 1 (WNK1) system on angiogenesis in colon cancer cell line (HT-29 and COLO205 cells) and further investigate the potential mechanisms...

Glucagon regulates hepatic amino acid metabolism and increases ureagenesis. Ureagenesis is activated by N-acetylglutamate (NAG), formed via activation of N-acetylglutamate synthase (NAGS). Aiming to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we investigated whether glucagon receptor mediated activation of ureagenesis is required in a situation where NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle in vivo. Female C57Bl/6JRj mice, treated with a glucagon receptor antagonist (GRA), glucagon receptor knockout (Gcgr-/- ) mice, and wild-type (Gcgr+/+ ) littermates received an intraperitoneal injection of N-carbamoyl glutamate (a stable variant of NAG) (Car), L-citrulline (Cit), Car and Cit (Car+Cit), or PBS...

Each individual is endowed with a unique gut microbiota (GM) footprint, which mediates numerous host-related physiological functions such as nutrient metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against microbial pathogens. The rapid scientific interest in GM has recognized its central role in the pathophysiology of many intestinal and extra-intestinal conditions. Given the close relationship between the gastro-intestinal tract and the liver, many pathological processes have been investigated in the light of a microbial-centered hypothesis of hepatic damage...

BACKGROUND/PURPOSE: Colorectal cancer (CRC) is one of the most common malignant tumours and is associated with a high mortality rate due to the lack of specific biomarkers available for early diagnosis, targeted therapies and prognostic surveillance. In the present study, we investigated the function of Numb and its underlying mechanism in colorectal cancer. METHODS: Immunohistochemical staining and clinicopathological analysis were used to assess the expression of Numb and its clinical significance in patients with colorectal cancer...

The gastrointestinal tract houses a reservoir of bacterial-derived enzymes which can directly catalyze the metabolism of drugs, dietary elements, and endogenous molecules. Both host and environmental factors may influence this enzymatic activity, with the potential to dictate the availability of the biologically-active form of endogenous molecules in the gut and influence inter-individual variation in drug metabolism. We aimed to investigate the influence of the microbiota, and the modulation of its composition, on fecal enzymatic activity...

INTRODUCTION: DRA (down regulated in adenoma, SLC26A3) and NHE3 (Na+/H+ exchanger 3, SLC9A3) together mediate intestinal electroneutral NaCl absorption. Both transporters contain PDZ binding motifs and interact with PDZ adaptor proteins regulating their activity and recycling. Sorting nexin 27 (SNX27) contains a PDZ domain and is involved in the recycling of cargo proteins including NHE3. The interaction of SNX27 with DRA and its potential role for the activity and recycling of DRA have been evaluated in this study...

Alcoholic pancreatitis is a multi-factorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression...

Liver Sinusoidal Endothelial Cells (LSECs) are the first liver cells encountering waste macromolecules, pathogens and toxins in blood. LSECs are highly specialized to mediate the clearance of these substances via endocytic scavenger receptors and are equipped with fenestrae that mediate the passage of macromolecules towards hepatocytes.Although some transcription factors (TFs) are known to play a role in LSEC specialization, information about the specialized LSEC signature and its transcriptional determinants remains incomplete...

Mitochondria exist in a complex network that is constantly remodeling via the processes of fission and fusion in response to intracellular conditions and extracellular stimuli. Excessive fragmentation of the mitochondrial network, as a consequence of an imbalance between fission and fusion, reduces the cells' capacity to generate ATP and can be a forerunner of cytotoxicity and subsequent cell death. Given the critical roles mitochondria play in cellular homeostasis and innate immunity, it is not surprising that many bacterial pathogens can disrupt mitochondrial activity...

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of newborns. Although incompletely understood, NEC is associated with intestinal barrier dysfunction. E-cadherin, an adherens junction, is a protein complex integral in maintaining normal barrier homeostasis. ROCK1 is a kinase that regulates the E-cadherin complex and p120-catenin is a subunit of the E-cadherin complex that has been implicated in stabilizing the cadherin complex at the plasma membrane. We hypothesized that E-cadherin is decreased in NEC and that inhibition of ROCK1 would protect against adherens junction disruption...

BACKGROUND: Anemia is a frequent diagnosis in critically-ill infants, but the clinical implications of severe anemia in these patients remain unclear. In this study, we examined pre-weaned mice to investigate the effects of severe anemia during early infancy on gut mucosal permeability. METHODS: C57BL/6 mice were subjected to timed phlebotomy between postnatal days (P) 2-10 to induce severe anemia (hematocrits 20-24%), and intestinal permeability was tracked longitudinally between P10-20 as intestine-to-plasma translocation of enteral macromolecules and bacterial translocation...

Aging is a risk factor in the development of many diseases including liver-related diseases. The two aims of the present study were (1) to determine how aging affects liver health in mice in the absence of any interventions and (2) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance and apoptosis as well as the toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3 and 24 months old male C57BL/6J mice...

TMEM16A is a Ca2+ -activated Cl- channel in the apical membrane of biliary epithelial cells, known as cholangiocytes, which contributes importantly to ductular bile formation. While cholangiocyte TMEM16A activity is regulated by extracellular ATP binding membrane purinergic receptors, channel expression is regulated by interleukin-4 (IL-4) through an unknown mechanism. The aim of the present study therefore was to identify the signaling pathways involved in TMEM16A expression and cholangiocyte secretion. Studies were performed in polarized normal rat cholangiocyte monolayers, human Mz-Cha-1 biliary cells, and cholangiocytes isolated from murine liver tissue...

Characterization of High-Amplitude Propagating Pressure Waves (HAPWs or HAPCs) plays a key role in diagnosis of colon dysmotility using any type of colonic manometry. With the introduction of high-resolution manometry, more insight is gained into this most prominent propulsive motor pattern. Here we employ a water-perfused catheter with 84 sensors with intervals between measuring points of 1 cm throughout the colon, for 6-8 hours, in 19 healthy subjects. The catheter contained a balloon to evoke distention...

BACKGROUND & AIMS: Sacral nerve stimulation (SNS) was reported to improve TNBS-induced colitis in rats. The aim of this study was to investigate whether the SNS anti-inflammatory effect is mediated via the local sacral splanchnic nerve or the spinal afferent-vagal efferent-colon pathway. METHODS: Under general anesthesia, rats were administrated with TNBS intra-rectally and bipolar SNS electrodes were implanted unilaterally at S3. The sacral and vagal nerves were severed at different locations for the assessment of the neural pathway...

Recently peripheral lymphatic vessels were found to transport HDL from interstitial tissues to the blood circulation during reverse cholesterol transport. This function is critical to the clearance of cholesterol from atherosclerotic plaques. The role of organ-specific lymphatics in modulating HDL transport and composition is, however, incompletely understood. This study aimed to 1) determine the contribution of the lymphatics draining the intestine and liver (which are major sites of HDL synthesis) to total (thoracic) lymph HDL transport, and 2) verify whether the HDLs in lymph are derived from specific organs and are modified during trafficking in lymph...