The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease Raika Jamali M.D., Gastroenterologist and hepatologist, Assistant Professor of Medicine, Research Development Center, Sina Hospital, Tehran University of Medical Sciences.

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease (NAFLD) Summary: Overview of gut mucosal barrier The effect of “leaky gut syndrome” on liver Tolerance of liver to translocated bacteria Possible roles of probiotics in liver cell damage Helicobacter pylori and NAFLD

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease The effect of gut microbiota on the development and progression of liver cell damage has come to interest. Non-alcoholic Fatty Liver Disease (NAFLD) is a common cause of chronic liver cell damage.

Concept of gut–liver axis in liver diseases The liver constantly encounters food-derived antigens bacterial components (PAMP) damage associated molecular patterns (DAMP) translocated from the gut into the portal vein. TLR: Toll-like receptors; T reg: regulatory T cells.

Concept of gut–liver axis in liver diseases PAMP and DAMP stimulate Toll-like receptors (TLR), TLR are expressed on Kupffer cells, biliary epithelial cells, hepatocytes, hepatic stellate cells, endothelial cells dendritic cells T reg: regulatory T cells.

Relation of Toll-like receptors and inflammasomes DAMP: Damage-associated molecular patterns PAMP: Pathogen-associated molecular patterns TLR: Toll-like receptors

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease The signaling of TLR triggers inflammation. In order to protect against hyperactivation of the immune system and to prevent organ failure by persistent inflammation, TLR tolerance to repeated stimuli is induced. In CLD a breakdown in TLR tolerance occurs.

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease Activation of inflammasome was revealed to control the secretion of proinflammatory cytokines (interleukin-1b) in response to PAMP and DAMP.

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease Kupffer cells, hepatic stellate cells and natural killer T cells are key components of innate immunity. Impaired ability of innate immunity Failures in immune tolerance Persistent inflammation

Intrahepatic condition of liver cells, TLR, cytokines and causative microbes in the chronic liver diseases HSC, hepatic stellate cells; IFN, interferon; IL, interleukin; NASH, non-alcoholic steatohepatitis; ND, no data; NKT, natural killer T cells; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; TLR, Toll-like receptors; TNF, tumor necrosis factor; Treg, regulatory T cells.

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease Probiotics affect various liver diseases via Shifts in gut microbiota The stability of intestinal permeability Producing antimicrobial factors (SCFA) Decrease in bacterial translocation

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease Many unresolved questions remain: Why TLR tolerance is disrupted in various liver diseases? Which factors control the protective or detrimental roles of NKT cells and Kupffer cells? Which probiotic will be most effective for treating which liver disease?

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease Recently the role of helicobacter pylori (HP) in extragastric diseases has come to interest.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease Probiotics might improve liver function tests (LFT) in NAFLD. They protect gut epithelial cells from the adhesion and invasion of HP.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease There are proposed mechanisms for the development of NAFLD in HP infected patients. Taylor et al expressed the earlier theory, that HP species would produce a liver specific toxin that cause liver cell damage. Then it was developed that HP invasion to intestinal mucosa might increase gut permeability and facilitates bacterial endotoxin passage via portal vein to the liver.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease HP DNA was detected in liver samples from patients with various etiologies of chronic liver disease (CLD). However, no bacteria could be cultured. Meanwhile a study in patients with CLD, reported no association between the presence of HP DNA in the liver biopsy samples and LFT.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease There is a large body of evidence that shows the association between HP and CLD. The prevalence of HP DNA in the liver tissue samples of patients with CLD was significantly higher than the patients with metastatic adenocarcinoma. The prevalence of HP antibody (IgG) was higher in males with HCV associated cirrhosis compared to age-matched male blood donors. In this study, the genomic sequences corresponding to HP were determined in the liver tissues of cirrhotic HCC patients. It was proposed that HP might be implicated in the progression of cirrhosis in HCV infected patients.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease Specific studies with regard to HP and NAFLD are increasing. The presence of HP DNA in one sample of liver tissue from a NAFLD patient was a novel finding. The anti HP antibody (IgG) was higher in NAFLD than in matched healthy controls. It was reported that HP infection was one of the risk factors for the development of NAFLD. This study suggested that eradication of HP infection might have therapeutic perspectives in NAFLD treatment.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease It was proposed that gut microbiota might play a role in the development of IR. HP seropositivity was higher in those with metabolic syndrome than the controls. On the other hand, there are reports that showed the enhanced risk of obesity following HP cure. These studies proposed that the increase of gerlin following HP treatment improves the appetite and leads to weight gain. We believe the controversial results of the above studies could be due to the difference in the duration of HP infection in the studied populations.

The Role of Gut Microbiota in Non-alcoholic Fatty Liver Disease There is still paucity of literature and controversial results with regard to the influence of HP infection on the course of NAFLD and IR. Since HP treatment is not difficult, the discovery of its role in diseases causing trouble outside the stomach would be a major concern to the public health.

The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease We have already conducted two randomized control clinical trials (ClinicalTrials.gov ID: NCT01654549, NCT01712711) that showed HP eradication in dyspeptic NAFLD patients did not provide any additional improvement in LFT compared with subjects who managed with lifestyle modification alone. Further studies are needed to define the exact role of gut microbiota in hepatocellular damage.