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.

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.

Inositol hexaphosphate promotes intestinal adaptation in short bowel syndrome via an HDAC3-mediated epigenetic pathway.

Background: Short bowel syndrome (SBS) has high morbidity and mortality rates, and promoting intestinal adaptation of the residual intestine is a critical treatment. Dietary inositol hexaphosphate (IP6) plays an important role in maintaining intestinal homeostasis, but its effect on SBS remains unclear. This study aimed at investigating the effect of IP6 on SBS and clarified its underlying mechanism. Methods: Forty male Sprague-Dawley rats (3-week-old) were randomly assigned into four groups (Sham, Sham + IP6, SBS, and SBS + IP6 groups). Rats were fed standard pelleted rat chow and underwent resection of 75% of the small intestine after 1 week of acclimation. They received 1 mL IP6 treatment (2 mg/g) or sterile water daily for 13 days by gavage. Intestinal length, levels of inositol 1,4,5-trisphosphate (IP3), histone deacetylase 3 (HDAC3) activity, and proliferation of intestinal epithelial cell-6 (IEC-6) were detected. Results: IP6 treatment increased the length of the residual intestine in rats with SBS. Furthermore, IP6 treatment caused an increase in body weight, intestinal mucosal weight, and IEC proliferation, and a decrease in intestinal permeability. IP6 treatment led to higher levels of IP3 in feces and serum, and higher HDAC3 activity of the intestine. Interestingly, HDAC3 activity was positively correlated with the levels of IP3 in feces (r = 0.49, P = 0.01) and serum (r = 0.44, P = 0.03). Consistently, IP3 treatment promoted the proliferation of IEC-6 cells by increasing HDAC3 activity in vitro. IP3 regulated the Forkhead box O3 (FOXO3)/Cyclin D1 (CCND1) signaling pathway. Conclusion: IP6 treatment promotes intestinal adaptation in rats with SBS. IP6 is metabolized to IP3 to increase HDAC3 activity to regulate the FOXO3/CCND1 signaling pathway and may represent a potential therapeutic approach for patients with SBS.

Selective depletion of CD11b-positive monocytes/macrophages potently suppresses bleomycin-induced pulmonary fibrosis.

The understanding of pathogenesis underlying idiopathic pulmonary fibrosis (IPF) is still limited presently. Monocytes or macrophages are involved in progression of the pulmonary injury and repair. The aim of this study is to investigate the roles of CD11b+ monocytes/macrophages in the progression of pulmonary fibrosis. In this study, the expression levels of CD11B gene and inflammatory genes in the IPF patients are evaluated using the available datasets. CD11b cells are conditionally depleted in a CD11b-diptheria toxin receptor (CD11b-DTR) mouse by administration of diptheria toxin (DT). Pulmonary fibrosis in mice is induced using intranasalbleomycin. The mRNAs and proteins expression in lung tissues are determined by quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence (IF) staining and Western-blot assays. It shows that the expression of CD11B mRNA is up-regulated in fibrotic lungs and alveolar macrophages of IPF patients and bleomycin-treated rodents. Selective depletion of CD11b+ monocytes/macrophages in CD11b-DTR mice potently halts bleomycin-induced pulmonary fibrosis progression. CD11b depletion inhibits the polarization of macrophages in the fibrotic lungs. Mechanically, CD11b deficiency represses the activation of sphingosine 1-phosphate receptor 2 (S1PR2)/sphingosine kinase 2 (SphK2) signaling during pulmonary fibrosis. In conclusion, our data suggest that CD11b+ monocytes/macrophages contribute to pulmonary fibrosis and represent a potential therapeutic target for IPF.

Metabolic regulation of cholestatic liver injury by D-2-hydroxyglutarate with the modulation of hepatic microenvironment and the mammalian target of rapamycin signaling.

Biliary atresia (BA) is a cholestatic liver disease in neonates with devastating obstructive intrahepatic and extrahepatic biliary ducts. Owing to the lack of an early diagnostic marker and limited understanding of its pathogenesis, BA often leads to death within 2 years. Therefore, this study aimed to develop early diagnostic methods and investigate the underlying pathogenesis of liver injury in BA using metabolomics. Metabolomics and organoid combined energy metabolism analysis was used to obtain new insights into BA diagnosis and pathobiology using patient samples, mice liver organoids, and a zebrafish model. Metabolomics revealed that D-2-hydroxyglutarate (D-2-HG) levels were significantly elevated in the plasma and liver of patients with BA and closely correlated with liver injuries and impaired liver regeneration. D-2-HG suppressed the growth and expansion of liver organoids derived from the intrahepatic biliary ducts. The energy metabolism analysis demonstrated that D-2-HG inhibited mitochondrial respiration and ATP synthase; however, it increased aerobic glycolysis in organoids. In addition, D-2-HG exposure caused liver degeneration in zebrafish larvae. Mechanistically, D-2-HG inhibited the activation of protein kinase B and the mammalian target of rapamycin signaling. These findings reveal that D-2-HG may represent a novel noninvasive diagnostic biomarker and a potential therapeutic target for infants with BA.

Reg4 protects against Salmonella infection-associated intestinal inflammation via adopting a calcium-dependent lectin-like domain.

Salmonella Typhimurium (S. Tm) is Gram-negative flagellated bacteria that can cause food-borne gastroenteritis and diarrhea in human. Developing efficacious methods against Salmonella infection is still challenged. Herein, we report that regenerating islet-derived family member 4 (Reg4) has potent bactericidal activity against S. Tm. For the S. Tm-infected mice, Reg4 significantly inhibits colonization of S. Tm in the intestine and subsequently ameliorates intestinal inflammation. In vitro experiments, the addition of Reg4 significantly suppresses the growth and proliferation of Salmonella. Moreover, both human and mice Reg4 proteins restrain the Salmonella to invade the intestinal epithelia. Mechanistically, Reg4 performs bactericidal action against Salmonella via a motif (HDPQK) homologous to a calcium-dependent (C-type) lectin-like domain. Reg4 can specifically bind to the flagella of Salmonella to restrain bacterial motility and suppress the host inflammatory response. In conclusion, our findings identify that Reg4 acts as a new antimicrobial protein against Salmonella, which suggests Reg4 may have a great significance for developing novel agents against Salmonella infection-associated intestinal inflammation.

Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.

INTRODUCTION: Biliary atresia (BA) is a devastating obstructive bile duct disease found in newborns. This study aims to investigate the roles and involved mechanisms of beta-amyloid (Aß) in the pathogenesis of BA. METHODS: We examined the distribution of Aß protein and its precursor in the livers of patients with BA. A murine liver organoid and a zebrafish model were established to investigate the exact roles of Aß in liver regeneration for BA. RESULTS: Both Aß mRNA and protein significantly increased in livers of infants with BA and deposited around the central vein. In the plasma, Aß elevated significantly in patients with BA and positively correlated with liver injury progression. In vitro , Aß treatment induced abnormal morphology and caused impaired growth in liver organoids. Energy metabolism analysis demonstrated Aß increased aerobic glycolysis and reduced ATP synthase in organoids, in which the mammalian target of rapamycin signaling was suppressed. In vivo , Aß42 exposure caused liver degeneration in zebrafish larvae. DISCUSSION: Aß depositing in livers of infants with BA reduced the liver regeneration through attenuating mitochondrial respiration and mammalian target of rapamycin signaling.

Diagnostic values of plasma matrix metalloproteinase-7, interleukin-8, and gamma-glutamyl transferase in biliary atresia.

Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and liver fibrosis. The early diagnosis of BA is still challenging. This study aimed to evaluate the diagnostic values of matrix metalloprotease-7 (MMP-7), interleukin-8 (IL-8), and gamma-glutamyl transferase (GGT) in BA. Infants diagnosed with BA and non-BA between 2013 and 2018 were retrospectively analyzed. Plasma levels of MMP-7, IL-8, and GGT were measured in these infants. The receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were used to assess the diagnostic values of MMP-7, IL-8, and GGT. The expression of MMP-7 and IL-8 in the livers was detected by immunofluorescence staining. A total of 229 infants were enrolled in this study: 156 BA infants and 73 non-BA infants including 16 ones with infantile hepatitis syndrome. The plasma levels of MMP-7, IL-8, and GGT in BA infants had a median of 11.8 ng/mL (interquartile range, IQR: 5.3-57.5), 1.5 ng/mL (IQR: 1.0-2.8), and 381.0 U/L (IQR: 197.0-749.0), respectively, which were higher than non-BA subjects [MMP-7, 4.4 ng/mL (IQR: 3.3-6.1); IL-8, 0.7 ng/mL (IQR: 0.5-1.0); GGT, 59.0 U/L (IQR: 26.0-124.0)]. The AUC values of MMP-7, IL-8, and GGT for the diagnosis of BA were 0.8035, 0.8083, and 0.9126, respectively. The AUC values of MMP-7 + IL-8, MMP-7 + GGT, IL-8 + GGT, and MMP-7 + IL-8 + GGT for the diagnosis of BA were 0.8248, 0.9382, 0.9168, and 0.9392, respectively. The AUC values of MMP-7, IL-8, and GGT for differentiating BA infants with cholic stool from non-BA infants with cholic stool were 0.8006, 0.8258, and 0.9141, respectively. The expression of MMP-7 and IL-8 was increased in the cholangiocytes in BA livers.   Conclusion: Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA and may be reliable biomarkers for BA. What is Known: • Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and progressive liver fibrosis. • Although early diagnosis of BA is crucial for good outcomes, it remains a clinical challenge. What is New: • Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA. • Plasma MMP-7, IL-8, and GGT have good accuracy for differentiating BA infants with cholic stool from non-BA infants with cholic stool.

Upregulation of cadherin-11 contributes to cholestatic liver fibrosis.

Importance: Cadherin-11 (CDH11), a cell-to-cell adhesion molecule, is implicated in the fibrotic process of several organs. Biliary atresia (BA) is a common cholestatic liver disease featuring cholestasis and progressive liver fibrosis in children. Cholestatic liver fibrosis may progress to liver cirrhosis and lacks effective therapeutic strategies. Currently, the role of CDH11 in cholestatic liver fibrosis remains unclear. Objective: This study aimed to explore the functions of CDH11 in cholestatic liver fibrosis. Methods: The expression of CDH11 in BA livers was evaluated by database analysis and immunostaining. Seven BA liver samples were used for immunostaining. The wild type (Wt) and CDH11 knockout (CDH11-/- ) mice were subjected to bile duct ligation (BDL) to induce cholestatic liver fibrosis. The serum biochemical analysis, liver histology, and western blotting were used to assess the extent of liver injury and fibrosis as well as activation of transforming growth factor-ß (TGF-ß)/Smad pathway. The effect of CDH11 on the activation of hepatic stellate cell line LX-2 cells was investigated. Results: Analysis of public RNA-seq datasets showed that CDH11 expression levels were significantly increased in livers of BA, and CDH11 was correlated with liver fibrosis in BA. BDL-induced liver injury and liver fibrosis were attenuated in CDH11-/- mice compared to Wt mice. The protein expression levels of phosphorylated Smad2/3 were decreased in livers of CDH11-/- BDL mice compared to Wt BDL mice. CDH11 knockdown inhibited the activation of LX-2 cells. Interpretation: CDH11 plays an important role in cholestatic liver fibrosis and may represent a potential therapeutic target for cholestatic liver disease, such as BA.

Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition-fed piglets.

OBJECTIVE: Long-term parenteral nutrition (PN) causes PN-associated liver disease, for which therapeutic approaches are limited. This study aimed to investigate the effects of Lactobacillus plantarum CGMCC 1258 (LP) on liver and intestinal injury in PN-fed neonatal piglets. METHODS: The piglets received PN with or without oral LP for 14 days. The levels of liver enzymes and inflammatory markers were measured using biochemical kits and quantitative real-time polymerase chain reaction. Serum fibroblast growth factor 19 (FGF19) was detected using an enzyme-linked immunosorbent assay. The bile acid (BA) profiles in the liver, serum, and intestinal contents were determined using ultraperformance liquid chromatography coupled with mass spectrometry. The composition of intestinal bacteria was analyzed with 16S rRNA gene amplicon sequencing. RESULTS: LP supplementation was associated with improved markers of liver disease, inflammation, and oxidative stress in PN-fed piglets. Moreover, markers of intestinal injury and inflammation were alleviated by LP in PN-fed piglets. Mechanistically, LP increased the abundance of Lactobacillus in ileal contents and stimulated FGF19 expression in ileal mucosa. Subsequently, it increased the expression of small heterodimer partner (SHP) and inhibited cholesterol 7α-hydroxylase (CYP7A1) expression in the liver. Additionally, LP altered the systemic composition and metabolism of BAs. CONCLUSIONS: LP alleviated liver and intestinal injury in PN-fed neonatal piglets by altering the composition of intestinal bacteria and BAs.

Fish oil-based lipid emulsion alleviates parenteral nutrition-associated liver diseases and intestinal injury in piglets.

BACKGROUND: Thisstudy aimed to investigate the impact of fish oil-based lipid emulsion (FO) on enterohepatic injuries and intestinal microbiota in piglets of parenteral nutrition (PN). METHODS: Newborn piglets were divided into three groups, including enteral diet (the controls), PN with 100% FO and PN with medium-chain triglyceride/long-chain triglyceride-based lipid emulsion (MCT/LCT) for 14 days. Serum biochemical indicators, hepatic and intestinal histology, and expression of genes associated with inflammation, oxidative stress, and lipid metabolism were measured. The bile acid (BA) profiles in serum and the taxonomic composition of the gut microbiome in different intestinal segments were analyzed. RESULTS: Compared with MCT/LCT-piglets, FO reduced inflammation, promoted fatty acid oxidation, and decreased oxidative stress in the liver. In the intestine, FO decreased intestinal inflammation and intestinal permeability, leading to reduced lipopolysaccharide entry into the blood circulation relative to MCT/LCT-piglets. PN groups have dominant contents of Proteobacteria and Bacteroides, whereas the control group have Firmicutes at the phylum level. FO altered the taxonomic compositions of the gut microbiome in different segments, increased the relative abundance of Bacteroidaceae in ileum, and Rikenellaceae and Ruminococcaceae in the colon. FO treatment shifted BA composition ratio in serum and had a lower ratio of secondary BAs to primary BAs. CONCLUSION: FO alleviates PNLAD and intestinal injury by regulating the homeostasis of BAs' enterohepatic circulation and altering microbiota composition in different intestinal segments.

Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects.

BACKGROUND: The breakpoint cluster region (BCR) is a protein that originally forms a fusion protein with c-Abl tyrosine kinase and induces leukemia. Researchers have shown that BCR is enriched in the central nervous system and may contribute to neurological disorders. We aimed to investigate the physiological function of BCR in neural development in the gastrointestinal (GI) tract and brain. METHODS: Whole-exome sequencing was used to screen for mutations in the BCR. Bcr knockout mice (Bcr-/- , ΔExon 2-22) were generated using the CRISPR/Cas9 system. Transit of carmine red dye and glass bead expulsion assays were used to record total and proximal GI transit and distal colonic transit. KEY RESULTS: In an infant with pediatric intestinal pseudo-obstruction, we found a heterozygous de novo mutation (NM_004327.3:c.3072+1G>A) in BCR. Bcr deficiency mice (Bcr-/- ) exhibited growth retardation and impaired gastrointestinal motility. Bcr-/- mice had a prolonged average total GI transit time with increased distal colonic transit and proximal GI transit in isolation. Morphology analysis indicated that Bcr-/- mice had a less number of neurons in the submucosal plexus and myenteric plexus. Bcr-/- mice exhibited apparent structural defects in the brain, particularly in the cortex. Additionally, Bcr- depletion in the mouse cortex altered the expression of Ras homologous (Rho) family small GTPases. CONCLUSIONS AND INFERENCES: BCR mutations are associated with intestinal obstruction in children. Loss of Bcr can cause intestinal dysmotility and brain developmental defects may via regulation of Rho GTPases.

Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19.

Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19-/-) and conditional deletion of H19 in macrophage (H19ΔCD11B) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.

A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

BACKGROUND & AIMS: Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL). METHODS: The piglets received BDL and TXR for 2 wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7α-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL. CONCLUSION: TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.

The Farnesoid X Receptor Agonist Tropifexor Prevents Liver Damage in Parenteral Nutrition-fed Neonatal Piglets.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) is a life-threatening complication for patients with intestinal failure who receive long-term parenteral nutrition (PN). We evaluated the effects of the farnesoid X receptor agonist tropifexor on a neonatal piglet model of IFALD fed with PN. METHODS: The piglets received PN and tropifexor for 14 days, then levels of liver enzymes, bile acid metabolism, inflammation, and intestinal barrier markers were assessed using quantitative real-time PCR. Fibroblast growth factor (FGF) 19 serum levels were determined using enzyme-linked immunosorbent assays. Bile acids were determined in liver, serum, and intestinal contents, and the microbiome was sequenced in different intestinal segments. RESULTS: The PN model was established in newborn piglets. The levels of serum liver enzymes, pro-inflammatory factors, and oxidative stress increased in the livers of piglets fed with PN, but not in those fed with PN and tropifexor. Tropifexor stimulated FGF19 expression in ileal epithelial cells, increased portal FGF19 levels, then inhibited cholesterol 7α-hydroxylase expression in the liver. Tropifexor increased the relative abundance of bacteria associated with bile salt hydrolase and 7α-dehydrogenation in the contents of ileum and altered the composition of bile acids in serum, liver, and intestinal contents. Tropifexor also inhibited intestinal inflammation, alleviated intestinal mucosal atrophy, and improved the intestinal barrier. CONCLUSIONS: Tropifexor might prevent liver damage in neonatal piglets receiving PN by altering the composition of intestinal microbiota and bile acids. Tropifexor also alleviates intestinal inflammation and preserves the intestinal barrier.

Long non-coding RNA H19 deficiency ameliorates bleomycin-induced pulmonary inflammation and fibrosis.

BACKGROUND: The poor understanding of pathogenesis in idiopathic pulmonary fibrosis (IPF) impaired development of effective therapeutic strategies. The aim of the current study is to investigate the roles of long non-coding RNA H19 (lncRNA H19) in the pulmonary inflammation and fibrosis of IPF. METHODS: Bleomycin was used to induce pulmonary inflammation and fibrosis in mice. The mRNAs and proteins expression in lung tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. H19 knockout (H19-/-) mice were generated by CRISPR/Cas9. RESULTS: The expression of H19 mRNA was up-regulated in fibrotic lungs patients with IPF as well as in lungs tissues that obtained from bleomycin-treated mice. H19-/- mice suppressed bleomycin-mediated pulmonary inflammation and inhibited the Il6/Stat3 signaling. H19 deficiency ameliorated bleomycin-induced pulmonary fibrosis and repressed the activation of TGF-ß/Smad and S1pr2/Sphk2 in the lungs of bleomycin-treated mice. CONCLUSIONS: Our data suggests that H19 is a profibrotic lncRNA and a potential therapeutic target for IPF.