Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic consequence of metabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. The connection between gut microbiota (GM) and NAFLD has attracted significant attention in recent years. Data has shown that GM affects hepatic lipid metabolism and influences the balance between pro/anti-inflammatory effectors in the liver. Although studies reveal the association between GM dysbiosis and NAFLD, decoding the mechanisms of gut dysbiosis resulting in NAFLD remains challenging. The potential pathophysiology that links GM dysbiosis to NAFLD can be summarized as: (1) disrupting the balance between energy harvest and expenditure, (2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing), and (3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol). Due to the hypothesis that probiotics/synbiotics could normalize GM and reverse dysbiosis, there have been efforts to investigate the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Recent randomized clinical trials suggest that probiotics/synbiotics could improve transaminases, hepatic steatosis, and reduce hepatic inflammation. Despite these promising results, future studies are necessary to understand the full role GM plays in NAFLD development and progression. Additionally, further data is needed to unravel probiotics/synbiotics efficacy, safety, and sustainability as a novel pharmacologic approaches to NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined by an excessive accumulation of fat in the liver tissue, when other causes of secondary hepatic fat accumulation disorders, including significant alcohol consumption, hereditary disorders, and steatogenic medication, have been ruled out [1].NAFLD is characterized by a large spectrum of liver disease, from isolated steatosis to steatohepatitis, and can progress to cause hepatic fibrosis formation and cirrhosis
Once the intestinal barrier is disrupted and endotoxemia circulates via the liver-gut through the gut-liver axis resulting in increased levels of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) that bind with toll-like receptors (TLRs) (TLR2, TLR4, TLR5, TLR9, etc.), the inflammatory cascade of releasing inflammatory cytokines (TNF-α, IL-8, IL1β) could be initiated, and lipid accumulation and cell death in hepatocytes could be stimulated leading to NAFLD, nonalcoholic steatohepatitis (NASH), and cirrhosis [34,35,36,37,38]
Hoyles et al found that plasma phenylacetic acid (PAA) levels are positively associated with steatosis severity in a morbidly obese women cohort (n = 56) and mice treated with PAA for 2 weeks had significantly increased triglyceride accumulation
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined by an excessive accumulation of fat in the liver tissue, when other causes of secondary hepatic fat accumulation disorders, including significant alcohol consumption, hereditary disorders, and steatogenic medication, have been ruled out [1]. It is widely accepted that the onset and progression of NAFLD are linked to inflammation, oxidative stress, insulin resistance, dyslipidemia, and obesity [9,10] This process is driven by the interaction of environmental, diet, and genetic factors via biochemical and immunological alterations in lipid and glucose metabolism [11]. Through multivariate analysis Boursier et al concluded that Bacteroides is independently associated with NASH and Ruminococcus is linked to fibrosis [26]. Despite these studies revealing an association between GM dysbiosis and NAFLD, whether gut dysbiosis is a causative factor that results in NAFLD remains unclear. Further clarification is necessary to investigate the causative relationship and potential pathogenesis links between NAFLD and dysbiosis
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