title: Long-term cannabinoid type 2 receptor agonist therapy decreases bacterial translocation in rats with cirrhosis and ascites.
abstract: OBJECTIVE
  Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats.
  
  
  METHODS
  Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed.
  
  
  RESULTS
  Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFα receptor/NFκBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment.
  
  
  CONCLUSIONS
  Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor.
authors: Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Clinical Skill Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: yangyy@vghtpe.gov.tw.
authors: Ying-Ying
authors: YY
authors: Yang
authors: Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Infection and Immunology Center & Institute of Microbiology and Immunology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors: Shie-Liang
authors: SL
authors: Hsieh
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Pei-Chang
authors: PC
authors: Lee
authors: Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Yi-Chen
authors: YC
authors: Yeh
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Kuei-Chuan
authors: KC
authors: Lee
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Yun-Cheng
authors: YC
authors: Hsieh
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Ying-Wen
authors: YW
authors: Wang
authors: Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taipei, Taiwan.
authors: Tzung-Yan
authors: TY
authors: Lee
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Yi-Hsiang
authors: YH
authors: Huang
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Che-Chang
authors: CC
authors: Chan
authors: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: hclin@vghtpe.gov.tw.
authors: Han-Chieh
authors: HC
authors: Lin
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage; D001201:Ascites / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D001424:Bacterial Infections / Q000209:etiology / Q000517:prevention & control; D018988:Bacterial Translocation / Q000187:drug effects*; D002186:Cannabinoids / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology; D008102:Liver Circulation / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D010538:Peritonitis / Q000209:etiology / Q000517:prevention & control; D010587:Phagocytosis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D016207:Cytokines; D007211:Indoles; D018836:Inflammation Mediators; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119325:arachidonyl-2-chloroethylamide; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline
keywords: Bacterial translocation; Cannabinoid receptors; Intestinal hyperpermeability; Peritoneal macrophages; Spontaneous bacterial peritonitis