Review Article

Emerging Role of the Gut Microbiome in the Progression of Nonalcoholic Fatty Liver Disease and Potential Therapeutic Implications

Saumya Jayakumar; Rohit Loomba

Disclosures

Aliment Pharmacol Ther. 2019;50(2):144-158. 

In This Article

Abstract and Introduction

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is a prevalent disorder associated with obesity and diabetes. Few treatment options are effective for patients with NAFLD, but connections between the gut microbiome and NAFLD and NAFLD-associated conditions suggest that modulation of the gut microbiota could be a novel therapeutic option.

Aim: To examine the effect of the gut microbiota on pathophysiologic causes of NAFLD and assess the potential of microbiota-targeting therapies for NAFLD.

Methods: A PubMed search of the literature was performed; relevant articles were included.

Results: The composition of bacteria in the gastrointestinal tract can enhance fat deposition, modulate energy metabolism and alter inflammatory processes. Emerging evidence suggests a role for the gut microbiome in obesity and metabolic syndrome. NAFLD is often considered the hepatic manifestation of metabolic syndrome, and there has been tremendous progress in understanding the association of gut microbiome composition with NAFLD disease severity. We discuss the role of the gut microbiome in NAFLD pathophysiology and whether the microbiome composition can differentiate the two categories of NAFLD: nonalcoholic fatty liver (NAFL, the non-progressive form) vs nonalcoholic steatohepatitis (NASH, the progressive form). The association between gut microbiome and fibrosis progression in NAFLD is also discussed. Finally, we review whether modulation of the gut microbiome plays a role in improving treatment outcomes for patients with NAFLD.

Conclusions: Multiple pathophysiologic pathways connect the gut microbiome with the pathophysiology of NAFLD. Therefore, therapeutics that effectively target the gut microbiome may be beneficial for the treatment of patients with NAFLD.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is characterised by fat accumulation (or steatosis) in >5% of hepatocytes in individuals who either consume little alcohol or have no other secondary causes of steatosis such as viral hepatitis, lipodystrophy or medications associated with the development of steatosis.[1,2] The increasing prevalence of NAFLD parallels rises in the incidence of obesity and insulin resistance.[3,4] NAFLD is among the most common causes of liver disease and liver transplantation in the Western hemisphere.[4,5] NAFLD can be sub-classified into two categories: the non-progressive form, nonalcoholic fatty liver (NAFL) and the progressive form, nonalcoholic steatohepatitis (NASH).[1,6] NASH is a clinic-pathologic entity that is typically characterised by the presence of zone 3 steatosis, ballooning and lobular inflammation; perisinusoidal fibrosis may or may not be also present.[1,7] Fibrosis progression rate is estimated to be higher in NASH than in NAFL and progression to cirrhosis may take up to 30 years; however, rapid progression to cirrhosis may occur in a small subset of patients.[8] In addition, NASH is associated with increased risk of hepatocellular carcinoma (HCC) and all-cause (cardiovascular and liver-related) mortality.[9–11]

NAFLD pathogenesis is related to multiple insults that occur simultaneously and may act synergistically,[12,13] including accumulation of triglycerides (TGs),[12] mitochondrial dysfunction and increased oxidative stress,[12–14] altered mechanisms of apoptosis and autophagy,[15,16] increased levels of toxic lipid-related factors (eg, free fatty acids)[12] and liver inflammation.[12] Genetics (eg, mutations in the patatin-like phospholipase domain-containing 3 gene)[17] and adverse consequences of dietary habits and sedentary lifestyle (eg, insulin resistance, central obesity, dyslipidaemia and hypertriglyceridemia) likely contribute to overall NAFLD pathophysiology and augment the underlying mechanisms of liver insult.[12]

Accumulating evidence also implicates the gut microbiota in the development and progression of NAFLD[18,19] and suggests that therapeutic agents that target the gut microbiota may be beneficial. This review examines the pathophysiologic implications of altered gut microbiota in NAFLD and highlights recent progress in the development of microbiota-targeting therapies for patients with liver disease.

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