Gut-liver axis, nutrition, and non-alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to fibrosis and cirrhosis over time. NAFLD is often associated with obesity, insulin resistance, and diabetes. The interactions between the liver and the gut, the so-called "gut-liver axis", play a critical role in NAFLD onset and progression. Compelling evidence links the gut microbiome, intestinal barrier integrity, and NAFLD. The dietary factors may alter the gut microbiota and intestinal barrier function, favoring the occurrence of metabolic endotoxemia and low grade inflammation, thereby contributing to the development of obesity and obesity-associated fatty liver disease. Therapeutic manipulations with prebiotics and probiotics to modulate the gut microbiota and maintain intestinal barrier integrity are potential agents for NAFLD management. This review summarizes the current knowledge regarding the complex interplay between the gut microbiota, intestinal barrier, and dietary factors in NAFLD pathogenesis. The concepts addressed in this review have important clinical implications, although more work needs to be done to understand how dietary factors affect the gut barrier and microbiota, and to comprehend how microbe-derived components may interfere with the host's metabolism contributing to NAFLD development.

Keywords: Dietary factors; Gut microbiome; Intestinal barrier; Metabolic endotoxemia; Nonalcoholic fatty liver disease.

Figure 1

Concepts of obesity and NAFLD pathogenesis are: classical (A) and (B) innovative gut-liver-axis-mediated. Classically, obesity is considered to be due to a surplus of energy intake over energy expenditure, resulting in storage of excess energy as a fat. Genetic, physiological, and environmental factors (e.g., high fat diet [HFD] and sedentary lifestyle) also play a significant role in the etiology of obesity and obesity-associated metabolic disorders. The gut-liver-axis-mediated concept suggests that the increased consumption of obesogenic foods (particularly those enriched in fat and fructose) may alter the gut microbiota and intestinal barrier function favoring the occurrence of metabolic endotoxemia and low-grade inflammation thereby contributing to the development of obesity and obesity-associated fatty liver disease.

Figure 2

Diet is a major factor driving the composition and metabolic activity of the gut microbiota. Dietary factors and altered gut microbiota may affect intestinal barrier function resulting in metabolic endotoxemia; gut-derived products/toxins activate hepatic toll-like receptors with a subsequent production of pro-inflammatory mediators and low-grade systemic inflammation contributing to the development of obesity and obesity-associated fatty liver disease. Abbreviations: LPS, lipopolysaccharides; TLR - Toll-like receptors

Figure 3

The intact (A) and disrupted (B) gut barrier. The gut barrier is a complex structure, consisting of epithelial cells sealed with the so-called intestinal tight junctions’, the mucus layer which coats the intestinal epithelial surface (mucins, the major components of mucus layer, are mainly produced by Goblet cells), and the antimicrobial defense system consisting of numerous anti-bacterial peptides produced by Paneth cells. The gut barrier prevents translocation of luminal bacteria and bacteria-derived products into the blood. Numerous factors, including dietary factors, can alter one or more components of the gut barrier structure resulting in the condition known as endotoxemia. Abbreviations: LPS, lipopolysaccharides; TJs, tight junctions.

Figure 4

The interplay between dietary factors, gut microbiota, and gut barrier integrity in the development of NAFLD. Both high fat or high fructose diets may cause dysbiosis and bacterial overgrowth. Intestinal bacteria alterations result in disruption of gut barrier integrity with the subsequent increase in gut permeability to bacteria-derived pathogens, including LPS. The altered gut microbiota may change its metabolic activity, including an increase in fermentation of dietary polysaccharides to SCFAs, and production of endogenous EtOH. The produced metabolites are absorbed and transported to the liver where SCFAs may stimulate de novo synthesis of triglycerides and EtOH may elevate ROS production. The presence of LPS in the systemic circulation results in the activation of the innate immune system and a massive secretion of pro-inflammatory cytokines, particularly TNF-α. Low-grade systemic inflammation involves a complex network of signals interconnecting several organs, including the liver, adipose tissue, and skeletal muscles. In the liver, LPS causes hepatocellular inflammation by stimulating distinct cell types to release pro-inflammatory cytokines via TLR-4-mediated mechanisms leading to liver injury. Abbreviations: EtOH, ethanol; LPS, lipopolysaccharides; ROS, reactive oxygen species; SCFAs, short chain fatty acids; TJs, tight junctions; TLR, Toll like receptor; TNF-α, tumor-necrosis factor alpha