American Journal of Physiology. Gastrointestinal and Liver Physiology

Background Polycystic liver disease (PLD) is hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and a poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats...

Despite the availability of various diagnostic tests for inflammatory bowel diseases (IBD), misdiagnosis of IBD occurs frequently, and thus there is a clinical need to further improve the diagnosis of IBD. As gut dysbiosis is reported in IBD patients, we hypothesized that supervised machine learning (ML) could be used to analyze gut microbiome data for predictive diagnostics of IBD. To test our hypothesis, fecal 16S metagenomic data of 729 IBD and 700 non-IBD subjects from the American Gut Project were analyzed using five different ML algorithms...

Advances in metagenomics have allowed a detailed study of the gut microbiome, and its role in human health and disease. Infants born prematurely possess a fragile gut microbial ecosystem that is vulnerable to perturbation. Alterations in the developing gut microbiome in preterm infants are linked to life-threatening diseases such as necrotizing enterocolitis (NEC) and late onset sepsis; and may impact future risk of asthma, atopy, obesity, and psychosocial disease. In this mini review, we summarize recent literature on the origins and patterns of development of the preterm gut microbiome in the perinatal period...

Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis when absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with high concentration of hydrogen in our study named hydrogen rich water (HRW) on mice with non-alcoholic fatty liver disease to elucidate the mechanism underlying the molecular hydrogen therapeutic action. The choline-supplemented, L-amino acid-defined (CSAA) or choline-deficient, L-amino acid-defined (CDAA) diet for 20 weeks were used to induce NASH and fibrosis in the mice model and simultaneously treated with HRW for different periods of time...

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4 -induced liver fibrosis in mice...

Tumour stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation and AMPK activation...

BACKGROUND AND AIMS: Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations...

Butyrate is a short-chain fatty acid produced by colonic gut bacteria as a result of fermentation of dietary fibers. In the colon, butyrate is a major energy substrate and contributes to the nutritional support and proliferation of a healthy mucosa. It also promotes the intestinal barrier function by enhancing mucus production and tight junctions. In addition to its pro-proliferative effect in healthy colonocytes, butyrate inhibits the proliferation of cancer cells. The antineoplastic effect of butyrate is associated with the inhibitory effect of butyrate on histone deacetylase (HDAC) enzymes, which promote carcinogenesis...

INTRODUCTION: Poor translatability of animal disease models has hampered development of new inflammatory bowel disorders (IBD) therapeutics. We describe a preclinical, ex vivo system using freshly obtained and well-characterized human colorectal tissue from ulcerative colitis (UC) and healthy control (HC) participants to test potential therapeutics for efficacy and target engagement, using the JAK/STAT inhibitor Tofacitinib (TOFA) as a model therapeutic. METHODS: Colorectal biopsies from HC and UC were cultured and stimulated with multiple mitogens +/-TOFA...

Mast cells and eosinophils are the key effector cells of allergic disorders. Although most studies on eosinophilic esophagitis (EoE), an allergic disorder of the esophagus, have focused on the role of eosinophils, recent studies suggest a major role for mast cells in causing the clinical manifestations of this disease. Cellular and animal studies have demonstrated that mast cells can cause esophageal muscle cells to proliferate and differentiate into a more contractile phenotype, and that mediators released by degranulating mast cells such as tryptase and histamine can activate smooth muscle contraction pathways...

Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were i.v. injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced non-alcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice...

The purpose of this study was to evaluate the mechanisms of intestinal motility in a rat model of short bowel syndrome (SBS). Rats were divided into three groups: Sham rats underwent bowel transection; SBS-NSI rats underwent a 75% bowel resection and presented with normal intestinal size (NSI) at sacrifice and hypermotility patterns; SBS-DYS showed dysmotile (DYS) enlarged intestine and inhibited motility patterns. Animals were sacrificed after 2 weeks. Illumina's Digital Gene Expression (DGE) analysis was used to determine the intestinal motility-related gene expression profiling in mucosal samples...

Extracellular matrix rigidity has important effects on cell behaviors and is increased sharply during liver fibrosis and cirrhosis. Hepatic blood flow is essential in maintaining hepatocytes (HC) functions. However, it is still unclear how matrix stiffness and shear stresses orchestrate HC phenotype in concert. A fibrotic 3D liver sinusoidal model is constructed using a porous membrane sandwiched between two PDMS layers with respective flow channels. The HC are cultured in collagen gels of various stiffness in the lower channel, while the upper channel is pre-seeded with liver sinusoidal endothelial cells (LSEC) and accessible to shear flow...

Mucosal damage is a key feature of inflammatory bowel diseases (IBD) and healing of the mucosa is an endpoint of IBD treatment that is often difficult to achieve. Autonomic neurons of the parasympathetic and sympathetic nervous system may influence intestinal epithelial cell growth and modulating epithelial innervation could for that reason serve as an interesting therapeutic option to improve mucosal healing. Understanding of the biological processes triggered by nonspecific and specific epithelial adrenergic and cholinergic receptor activation is of key importance...

The extensive investigation of the human microbiome and the accumulating evidence regarding its critical relationship to human health and disease has advanced recognition of its potential as the next frontier of drug development. The rapid development of technologies, directed at understanding the compositional and functional dynamics of the human microbiome, and the ability to mine for novel therapeutic targets and biomarkers is leading innovative efforts to develop microbe-derived drugs that can prevent and treat autoimmune, metabolic, and infectious diseases...

Bowel resection accelerates enterocyte proliferation in the remaining gut that may have suboptimal absorptive and digestive capacity because of proliferation-associated decrease in functional differentiation markers. We hypothesized that although Slfn3 is an important regulator of murine enterocytic differentiation, Slfn3 would have less impact on the bowel resection adaptation where accelerated proliferation takes priority over differentiation. We assessed proliferation, cell shedding, and enterocyte differentiation markers of mucosa from resected and postoperative bowel of wild type (WT) and Slfn3 knockout (Slfn3KO) mice...

Sarcopenia, a condition of low muscle mass, quality and strength, is commonly found in cirrhotic patients and is associated with adverse clinical outcomes including: reduction in quality of life, increased mortality and post-transplant complications. In chronic liver disease (CLD) it is most commonly defined through the measurement of the skeletal muscle index of the third lumbar spine. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover, which likely occurs due to a decrease in muscle protein synthesis and an elevation in muscle protein breakdown...

Upregulating the expression of long non-coding RNA LINC00982 controlled cell proliferation in gastric cancer, but the regulatory molecular mechanisms are yet to be expounded. We here aimed to elaborate how LINC00982 regulated the malignancy of gastric cancer cells. RT-qPCR and Western blot analysis were used to detect the expression of LINC00982 and CTSF in gastric cancer tissues and cells. Modulatory effect of LINC00982 on gastric cancer cells was assessed by CCK-8, colony formation, Transwell migration and invasion assays...

BACKGROUND: Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development...

Gastric vagal afferents (GVAs) sense food related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early-, mid-, and late- stages of pregnancy in mice...