1. 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.

2. 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

3. 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.

13. 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.

14. 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.

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

16. 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.

17. 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.

18. 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

19. 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.

20. 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

21. 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?

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

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. The Role of Helicobacter pylori in Non-alcoholic Fatty Liver Disease
We have already conducted two randomized control clinical trials (ClinicalTrials.gov ID: NCT , NCT ) 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.