Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Non-alcoholic fatty liver disease is considered one of the major troubling diseases worldwide since we are moving towards a gradual reduction of viral hepatitis and a progressive increase in obesity and type-2 diabetes mellitus. Moreover, gut microbiota is a crucial factor in pathogenesis of simple steatosis (SS) and non-alcoholic steatohepatitis (NASH).Therefore, targeting the gut{u2013}liver axis might be a novel therapeutic approach to treat SS and NASH.This study aimed to investigate the therapeutic effects of using a probiotic (Lactobacillus reuteri) and metronidazole (MTZ) (an antibiotic against Bacteroidetes) either alone or in combination with metformin (MTF) in experimentally-induced SS and NASH. SS and NASH were induced by feeding rats with high fat diet (HFD) for 6 or 12 weeks, respectively. MTF (150 mg/kg/day) or L. reuteri (2x109 colony forming unit/day) were given orally for either 6 or 8 weeks to treat either SS or NASH, respectively; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Treatment with L. reuteri and MTZ in combination with MTF showed additional benefit compared to MTF alone concerning liver function, oxidative stress, lipid profile, inflammatory and autophagy markers. Furthermore, the combined regimen succeeded to modulate acetate: propionate: butyrate ratios as well as Firmicutes and Bacteroidetes fecal content with improvement of insulin resistance. Yet, the administration of MTF alone failed to normalize Bacteriodetes and acetate contents which could be the reason of its moderate effect. In conclusion, gut microbiota modulation may be an attractive therapeutic avenue against NASH. In conclusion, more attention should be paid deciphering the crosstalk mechanisms linking gut microbiota to non-alcoholic fatty liver disease to identify new therapeutic targets for this disease

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