Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction

AIM To investigate whether fecal microbiota transplantation(FMT) prevents hepatic encephalopathy(HE) in rats with carbon tetrachloride(CCl4)-induced acute hepatic dysfunction.METHODS A rat model of HE was established with CCl4. Rat behaviors and spatial learning capability were observed, and hepatic necrosis, intestinal mucosal barrier, serum ammonia levels and intestinal permeability were determined in HE rats receiving FMT treatment. Furthermore, the expression of tight junction proteins(Claudin-1, Claudin-6 and Occludin), Toll-like receptor(TLR) 4/TLR9, interleukin(IL)-1β, IL-6 and tumor necrosis factor(TNF)-α was examined.RESULTS FMT improved rat behaviors, HE grade and spatial learning capability. Moreover, FMT prevented hepaticnecrosis and intestinal mucosal barrier damage, leading to hepatic clearance of serum ammonia levels and reduced intestinal permeability. The expression of TLR4 and TLR9, two potent mediators of inflammatory response, was significantly downregulated in the liver of rats treated with FMT. Consistently, circulating proinflammatory factors such as interleukin(IL)-1β, IL-6 and tumor necrosis factor-α were remarkably decreased, indicating that FMT is able to limit systemic inflammation by decreasing the expression of TLR4 and TLR9. Importantly, HE-induced loss of tight junction proteins(Claudin-1, Claudin-6 and Occludin) was restored in intestinal tissues of rats receiving FMT treatment. CONCLUSION FMT enables protective effects in HE rats, and it improves the cognitive function and reduces the liver function indexes. FMT may cure HE by altering the intestinal permeability and improving the TLR response of the liver.

Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease

The use of non-steroidal anti-inflammatory drugs(NSAIDs) is widespread worldwide thanks to their analgesic, anti-inflammatory and antipyretic effects. However, even more attention is placed upon the recurrence of digestive system complications in the course of their use. Recent data suggests that the complications of the lower gastro-intestinal tract may be as frequent and severe as those of the upper tract. NSAIDs enteropathy is due to enterohepatic recycling of the drugs resulting in a prolonged and repeated exposure of the intestinal mucosa to the compound and its metabolites. Thus leading to so-called topical effects, which, in turn, lead to an impairment of the intestinal barrier. This process determines bacterial translocation and toxic substances of intestinal origin in the portal circulation, leading to an endotoxaemia. This condition could determine a liver inflammatory response and might promote the development of nonalcoholic steatohepatitis, mostly in patients with risk factors such as obesity, metabolic syndrome and a high fat diet, which may induce a small intestinal bacterial overgrowth and dysbiosis. This alteration of gut microbiota may contribute to nonalcoholic fatty liver disease and its related disorders in two ways: firstly causing a malfunction of the tight junctions that play a critical role in the increase of intestinal permeability, and then secondly leading to the development of insulin resistance, body weight gain, lipogenesis, fibrogenesis and hepatic oxidative stress.

Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test

AIM:To study intestinal permeability(IP) and its relationship to the disease activity in patients with inflammatory bowel diseases(IBD)-Crohn's disease(CD) and ulcerative colitis(UC).METHODS:Fifty-eight patients with active IBD(32 with CD and 26 with UC) and 25 healthy controls consented to participate in the study.The clinical activity of CD was estimated using the Crohn's Disease Activity Index(CDAI),and the endoscopic activity of UC using the Mayo scoring system.IP was assessed by the rise in levels of iohexol,which was administered orally(25 mL,350 mg/mL) 2 h after breakfast.Three and six hours later serum(SIC mg/L) and urine(UIC g/mol) iohexol concentrations were determined by a validated HPLC-UV technique.RESULTS:In the CD group,SIC values at 3 h(2.95 ± 2.11 mg/L) and at 6 h after ingestion(2.63 ± 2.18 mg/L) were significantly higher compared to those of healthy subjects(1.25 ± 1.40 mg/L and 1.11 ± 1.10 mg/L,respectively,P < 0.05).UIC(g/mol) values were also higher in patients,but the differences were significant only for UIC at 6 h.Significant positive correlation(P < 0.05) was found between the CDAI and IP,assessed by SIC at 3 h(r = 0.60) and 6 h(r = 0.74) after the ingestion.In comparison to controls,SIC and UIC of UC patients were higher in the two studied periods,but the differences were significant at 6 h only.Significantly higher values of SIC(P < 0.05) were found in patients with severe endoscopic activity of UC compared to those of patients with mild and moderate activity(3.68 ± 3.18 vs 0.92 ± 0.69 mg/L).CONCLUSION:Serum levels of iohexol at 3 h and 6 h after its ingestion reflect increased IP,which is related to the disease activity in patients with IBD.

Role of pregnane X-receptor in regulating bacterial translocation in chronic liver diseases

Bacterial translocation(BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases(CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor(PXR) is a ligandactivated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT. The importance of PXR as the mechanistic linker molecule in the gutliver axis and its role in regulating bacterial interactions with the host in CLD has not been explored. Pub Med was used to perform an extensive literature search using the keywords PXR and bacterial translocation, PXR and chronic liver disease including cirrhosis. In an adequate expression state, PXR acts as a sensor for bile acid dysregulation and bacterial derived metabolites, and in response shapes the immune profile beneficial to the host. Activation of PXR could be therapeutic in CLD as it counter-regulates endotoxin mediated inflammation and maintains the integrity of intestinal epithelium. This review mainly focuses PXR function and its regulation in BT in the context of chronic liver diseases.