Reg4 deficiency aggravates pancreatitis by increasing mitochondrial cell death and fibrosis.

Regenerating gene family member 4 (Reg4) has been implicated in acute pancreatitis, but its precise functions and involved mechanisms have remained unclear. Herein, we sought to investigate the contribution of Reg4 to the pathogenesis of pancreatitis and evaluate its therapeutic effects in experimental pancreatitis. In acute pancreatitis, Reg4 deletion increases inflammatory infiltrates and mitochondrial cell death and decreases autophagy recovery, which are rescued by the administration of recombinant Reg4 (rReg4) protein. In chronic pancreatitis, Reg4 deficiency aggravates inflammation and fibrosis and inhibits compensatory cell proliferation. Moreover, C-X-C motif ligand 12 (CXCL12)/C-X-C motif receptor 4 (CXCR4) axis is sustained and activated in Reg4-deficient pancreas. The detrimental effects of Reg4 deletion are attenuated by the administration of the approved CXCR4 antagonist plerixafor (AMD3100). Mechanistically, Reg4 mediates its function in pancreatitis potentially via binding its receptor exostosin-like glycosyltransferase 3 (Extl3). In conclusion, our findings suggest that Reg4 exerts a therapeutic effect during pancreatitis by limiting inflammation and fibrosis and improving cellular regeneration.

Neurotensin contributes to cholestatic liver disease potentially modulating matrix metalloprotease-7.

The diagnosis and treatment of biliary atresia pose challenges due to the absence of reliable biomarkers and limited understanding of its etiology. The plasma and liver of patients with biliary atresia exhibit elevated levels of neurotensin. To investigate the specific role of neurotensin in the progression of biliary atresia, the patient's liver pathological section was employed. Biliary organoids, cultured biliary cells, and a mouse model were employed to elucidate both the potential diagnostic significance of neurotensin and its underlying mechanistic pathway. In patients' blood, the levels of neurotensin were positively correlated with matrix metalloprotease-7, interleukin-8, and liver function enzymes. Neurotensin and neurotensin receptors were mainly expressed in the intrahepatic biliary cells and were stimulated by bile acids. Neurotensin suppressed the growth and increased expression of matrix metalloprotease-7 in biliary organoids. Neurotensin inhibited mitochondrial respiration, oxidative phosphorylation, and attenuated the activation of calmodulin-dependent kinase kinase 2-adenosine monophosphate-activated protein kinase (CaMKK2-AMPK) signaling in cultured biliary cells. The stimulation of neurotensin in mice and cultured cholangiocytes resulted in the upregulation of matrix metalloprotease-7 expression through binding to its receptors, namely neurotensin receptors 1/3, thereby attenuating the activation of the CaMKK2-AMPK pathway. In conclusion, these findings revealed the changes of neurotensin in patients with cholestatic liver disease and its mechanism in the progression of the disease, providing a new understanding of the complex mechanism of hepatobiliary injury in children with biliary atresia.

Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the glutamine metabolism and urea cycles in cholestatic livers.

Hyperammonemia refers to elevated levels of ammonia in the blood, which is an important pathological feature of liver cirrhosis and hepatic failure. Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia significantly elevated in patients with biliary atresia (BA) and was positively correlated with liver injury. Targeted metabolomics and immunblotting showed glutamine metabolism and urea cycles were impaired in BA patients. Next, we observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries in liver and brain with improving the glutamine metabolism and urea cycles. Within the liver, TXR enhances glutamine metabolism and urea cycles by up-regulation of key regulatory enzymes, including glutamine synthetase (GS), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers.

Loss of Mptx2 alters bacteria composition and intestinal homeostasis potentially by impairing autophagy.

A recent single-cell survey of the small-intestinal epithelium suggests that mucosal pentraxin 2 (Mptx2) is a new Paneth cell marker, but its function and involved mechanism in the Paneth cell are still unknown. Therefore, we create Mptx2 knockout (Mptx2-/-) mice to investigate its precise effects on intestinal homeostasis using models of lipopolysaccharide (LPS), methicillin-resistant Staphylococcus aureus (MRSA) peritoneal infection, and dextran sulfate sodium (DSS)-induced intestinal injury and inflammation. We here find that Mptx2 is selectively expressed in Paneth cells in the small intestines of mice. Mptx2-/- mice have increased susceptibility to intestinal inflammation and injured. Mptx2 deficiency reduces Paneth cell count and expression of antimicrobial factors, leading to altered intestinal bacteria composition. Loss of Mptx2 aggravates MRSA infection-induced damage in the intestine while decreasing autophagy in Paneth cells. Mptx2-/- mice are more vulnerable to LPS-induced intestinal possibly due to inhibition of the autophagy/endoplasmic reticulum (ER) stress pathway. Mptx2-/- mice are susceptible to DSS-induced colitis that could be ameliorated by treatment with gentamicin or vancomycin antibiotics. In conclusion, Mptx2 is essential to maintain intestinal homeostasis potentially via regulation of autophagy in Paneth cells.

Intestinal Reg4 deficiency confers susceptibility to high-fat diet-induced liver steatosis by increasing intestinal fat absorption in mice.

Background & Aims: Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved. Methods: Mice with intestinal-specific Reg4 deficiency (Reg4 ΔIEC ) and Reg4-floxed alleles (Reg4 fl/fl ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA. Results: Reg4 ΔIEC mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, Reg4 ΔIEC mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis (p <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides. Conclusions: Our findings directly link Reg4 deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children. Impact and Implications: Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.

A systematic evaluation of methodological and reporting quality of meta-analysis published in the field of gastrointestinal endoscopy.

BACKGROUND: To evaluate the methodological and reporting quality of published meta-analyses (MAs) in four major gastrointestinal endoscopic journals, and identify the predicted factors for high quality. METHODS: A systematic search was performed in PubMed to identify MAs from 1, January, 2016 to 31, December, 2020 in four major gastrointestinal endoscopic journals (including Digestive Endoscopy, Gastrointestinal Endoscopy, Surgical Endoscopy, and Endoscopy). We collected the characteristics of MAs after filtering unqualified articles, and assessed methodological and reporting qualities for eligible articles by AMSTAR tool and PRISMA checklist, respectively. Logistic regression was used for identifying predictive factors for high quality. RESULTS: A total of 289 MAs were identified after screening by predefined inclusion and exclusion criteria. The scores (mean ± SD) of AMSTAR and PRISMA were 7.73 ± 1.11 and 22.90 ± 1.85, respectively. In PRISMA checklist, some items had less than 50% complete adherence, including item 2 (structured summary), items 5 (protocol and registration), items 12 and 19 (risk of bias in studies), item 27 (funding support). Item 1 (a priori design), item 4 (gray literature research), item 5 (list of included and excluded) were inferior to 50% adherence in AMSTAR tool. We found the predictive factors for high quality through logistic regression analysis: a priori design and funding support were associated with methodological quality. Protocol and registration influenced the methodological and reporting quality closely. CONCLUSION: In general, qualities on the methodology and the reporting of MAs published in the gastrointestinal endoscopic journals are good, but both of which still potentially need further improvement.

The role of polyglycolic acid sheets in the management of post-endoscopic submucosal dissection gastrointestinal bleeding and esophageal stricture: A PRISMA compliant systematic review and meta-analysis.

BACKGROUND: As a relatively minimally invasive technique, endoscopic submucosal dissection (ESD) is widely used for the treatment of gastrointestinal lesions. However, it is associated with complications, such as postoperative bleeding, stricture, and perforation. A covering method using polyglycolic acid (PGA) sheets for ESD-induced ulcers has been reported to be effective in reducing the risk of post-ESD bleeding and esophageal stricture. Herein, we conducted a systematic review and meta-analysis to evaluate the role of PGA sheets in the prevention of gastrointestinal bleeding and esophageal stricture after ESD. METHODS: We searched PubMed, Web of Science, and the Cochrane Library databases on October 15, 2019. All eligible articles were selected based on the predefined inclusion and exclusion criteria. The main outcomes were the rates of post-ESD gastrointestinal bleeding and esophageal stricture. Cochrane's Q statistic and I2 test were used to identify heterogeneity between the studies. When there was no obvious heterogeneity (I2 < 50%, P > .1), a fixed-effect model was used. When there was obvious heterogeneity (I2 > 50%, P < .1), a random effect model was used. Funnel plots and the Egger regression test were used to assess publication bias. RESULTS: Fifteen articles were included in the meta-analysis, of which 7 were exclusively about the use of PGA sheets to prevent postoperative gastrointestinal bleeding, and the remaining reported the use of PGA sheets to prevent postoperative esophageal stenosis. Our analysis showed that preventive therapy with PGA sheets decreased the rates of post-ESD gastrointestinal bleeding (risk ratio [RR] = 0.35, 95% confidential interval [CI]: 0.19-0.64, P < .001) and esophageal stricture (RR = 0.46, 95% CI: 0.27-0.79, P = .005), and the gastrointestinal bleeding and esophageal stricture rates after preventive treatment with PGA sheets were 5.7% (95% CI: 3.6%-8.8%) and 20.6% (95% CI: 14.5%-28.4%), respectively. CONCLUSION: The utilization of PGA sheets after ESD has an excellent outcome in reducing the risk of postoperative gastrointestinal bleeding and esophageal stricture.

Supplementary education can improve the rate of adequate bowel preparation in outpatients: A systematic review and meta-analysis based on randomized controlled trials.

BACKGROUND: Colonoscopy is widely used for the screening, diagnosis and treatment of intestinal diseases. Adequate bowel preparation is a prerequisite for high-quality colonoscopy. However, the rate of adequate bowel preparation in outpatients is low. Several studies on supplementary education methods have been conducted to improve the rate of adequate bowel preparation in outpatients. However, the controversial results presented encourage us to perform this meta-analysis. METHOD: According to the PRISMA statement (2020), the meta-analysis was registered on PROSPERO. We searched all studies up to August 28, 2021, in the three major electronic databases of PubMed, Web of Science and Cochrane Library. The primary outcome was adequate bowel preparation rate, and the secondary outcomes included bowel preparation quality score, polyp detection rate, adenoma detection rate, cecal intubation time, withdrawal time, nonattendance rate and willingness to repeat rate. If there was obvious heterogeneity, the funnel plot combined with Egger's test, meta-regression analysis, sensitivity analysis and subgroup analysis were used to detect the source of heterogeneity. RevMan 5.3 and Stata 17.0 software were used for statistical analysis. RESULTS: A total of 2061 records were retrieved, and 21 full texts were ultimately included in the analysis. Our meta-analysis shows that supplementary education can increase the rate of adequate bowel preparation for outpatients (79.9% vs 72.9%, RR = 1.14, 95% CI: 1.08-1.20, I2 = 87%, p<0.00001). Supplementary education shortened the withdrawal time (MD: -0.80, 95% CI: -1.54 to -0.05, p = 0.04) of outpatients, increased the Boston Bowel Preparation Scale (MD: 0.40, 95% CI: 0.36 to 0.44, p<0.00001), reduced the Ottawa Bowel Preparation Scale (MD: -1.26, 95% CI: -1.66 to -0.86, p<0.00001) and increased the willingness to repeat (91.9% vs 81.4%, RR:1.14, 95% CI: 1.04 to 1.25, p = 0.004). CONCLUSION: Supplementary education for outpatients based on the standard of care can significantly improve the quality of bowel preparation.