Long-term cannabinoid type 2 receptor agonist therapy decreases bacterial translocation in rats with cirrhosis and ascites.
BACKGROUND & AIMS
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.
['Yang|Ying-Ying|YY|', 'Hsieh|Shie-Liang|SL|', 'Lee|Pei-Chang|PC|', 'Yeh|Yi-Chen|YC|', 'Lee|Kuei-Chuan|KC|', 'Hsieh|Yun-Cheng|YC|', 'Wang|Ying-Wen|YW|', 'Lee|Tzung-Yan|TY|', 'Huang|Yi-Hsiang|YH|', 'Chan|Che-Chang|CC|', 'Lin|Han-Chieh|HC|']
D000818:Animals D001095:Arachidonic Acids D001201:Ascites D001424:Bacterial Infections D018988:Bacterial Translocation D002186:Cannabinoids D016207:Cytokines D056945:Hep G2 Cells D006801:Humans D007211:Indoles D018836:Inflammation Mediators D007413:Intestinal Mucosa D008102:Liver Circulation D008106:Liver Cirrhosis, Experimental D017737:Macrophages, Peritoneal D018384:Oxidative Stress D010538:Peritonitis D010587:Phagocytosis D012333:RNA, Messenger D051381:Rats D043884:Receptor, Cannabinoid, CB1 D043885:Receptor, Cannabinoid, CB2
Bacterial translocation Intestinal hyperpermeability Peritoneal macrophages Spontaneous bacterial peritonitis Cannabinoid receptors