Abstract and Introduction
Abstract
Background The human intestinal microbiota is a key regulator of host metabolic and immune functions and alterations in the microbiome ('dysbiosis') have been implicated in several human diseases. Because of the anatomical links between the intestines and the liver, dysbiosis may also disrupt hepatic function and thereby contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD).
Aim To perform a comprehensive review of the medical literature investigating associations between intestinal dysbiosis and NAFLD, with a particular emphasis on studies that characterise the microbiome in NAFLD.
Methods We conducted a search of PubMed, Embase, and Web of Science using multiple search terms including: 'NAFLD, NASH, fatty liver, steatohepatitis' combined with 'metagenome, microbiom*, microbiota*, fecal flora, intestinal flora, gut bacteria'. Results were manually reviewed and studies selected based on relevance to intestinal microbiota and NAFLD. We also included studies that addressed potential mechanistic models of pathways linking the dysbiosis to NAFLD.
Results Nine studies (five human and four animal models) were identified in our search that assessed associations between specific intestinal microbiota composition and NAFLD. We reviewed and summarised the results of additional investigations that more broadly addressed the mechanisms by which the microbiome may impact NAFLD pathogenesis.
Conclusions Investigations in humans and animals demonstrate associations between intestinal dysbiosis and NAFLD; however, causality has not been proven and mechanistic links require further delineation. As the field of microbiome research matures in techniques and study design, more detailed insights into NAFLD pathogenesis and its associations with the intestinal microbiota will be elucidated.
Introduction
The relationship between hepatic and intestinal function in influencing the risk for human disease is a topic of active scientific investigation. The liver and intestines are anatomically linked from early embryology with the liver budding directly from the foregut. This link is maintained in later life with the liver receiving 75% of its blood flow directly from the intestinal portal circulation. All portal blood from the intestine first flows through the liver, which performs its essential metabolic, immunological and detoxifying processing before the blood reaches the systemic circulation. An estimated 10–100 trillion microorganisms from 500 to 1000 different species reside within the adult human intestine, the sum of which has been named the microbiome. As the majority of the microorganisms constituting the human microbiome are found within the intestines and there is an anatomical link between the intestines and the liver, the microbiota have been hypothesised to exert direct influence on hepatic pathology through multiple potential mechanisms.
Early experiments with mice raised in the absence of any colonising microbes (i.e. germ-free, or gnotobiotic conditions) found that gut microbiota play a beneficial role in numerous essential aspects of host growth and development. For example, germ-free mice fail to develop normal mucosal immune systems and thus are at a greater risk of infection compared with conventionally reared animals. These deficiencies in germ-free mice can, however, be corrected through reconstitution with conventional microbiota. To date, intestinal microbiota have been ascribed critical protective (i.e. pathogen displacement, production of anti-microbial factors), structural (i.e. immune system development, induction of IgA), and metabolic (i.e. synthesis of vitamins, iron absorption, energy salvage) functions. 'Dysbiosis' is the concept that compositional alterations away from the conventional symbiotic gut microbiota may be associated with pathology within the host. For instance, Clostridium difficile infection arising from antibiotic-induced disruption of the gut microbiota is one such example of how dysbiosis can lead to substantial morbidity. Although many studies have implicated dysbiosis in a variety of human diseases, including obesity and nonalcoholic fatty liver disease (NAFLD), establishing a causal relationship remains challenging.
Nonalcoholic fatty liver disease has become the most common cause of chronic liver disease in the Western world with up to 40% of the general population affected. NAFLD is tightly associated with obesity, diabetes, and insulin resistance, along with other features of the metabolic syndrome. NAFLD is characterised by pathologic fat accumulation within the liver, which can lead to the more clinically concerning entity of nonalcoholic steatohepatitis (NASH). NASH is defined histologically by fat with inflammation and ballooning degeneration, and poses a risk for evolution to hepatic fibrosis and progression to cirrhosis with risk for hepatocellular carcinoma and other complications of portal hypertension. The pathogenesis of NAFLD is incompletely understood, but several different pathways may link an altered intestinal microbiome with NAFLD, along with the related pathologies of obesity and metabolic syndrome.
In this review, we will explore the relationships between NAFLD and intestinal dysbiosis. We will begin by presenting important background concepts with respect to dysbiosis, followed by a summary of the original research investigations in humans and in animal models that have directly characterised the microbiome in the setting of NAFLD. We will then put this original research into context by summarising the currently hypothesised mechanistic links between the microbiome and NAFLD.