The Influence of the Microbiome on NAFLD and NASH

Abstract

Watch a video presentation of this article Watch an interview with the author The microbiota is an extensively diverse community of intestinal habitats that maintains a symbiotic relationship physiologically. There are an estimated 10 trillion to 100 trillion microorganisms in each gram of stool, with approximately 500 to 1000 highly prevalent species that contribute to various functions, such as digestion, resistance to pathogen colonization, and synthesis of vitamins,1 in addition to boosting the metabolic capabilities and genetic composition of its host.1 The microbiota plays important immunological roles to maintain intestinal homeostasis and protect the host. The intestinal cells have a system of receptors, namely, the membranous Toll-like receptors (TLRs) and intracellular nucleotide-binding oligomerization domain–like receptors, that recognize bacterial lipopolysaccharides (LPSs), bacterial DNA, and peptidoglycans,2 which involves interactions between the gut microbiota and host immune response through TLRs 2, 4, and 9 (Fig. 1). Given that most of the information and technology has focused on the study of bacteria, we focus on gut bacteria. The gut microbiota are collectively an intense biochemical reactor, generating by-products that can cross the intestinal mucosa to the portal circulation and directly to the liver. Some microbial metabolites are suspected to stimulate inflammation or cause hepatocellular injury. Most notable in this regard is LPS, which has been reportedly detected in serum of obese patients and correlated with the degree of liver injury, suggesting a link between microbiota-derived LPS and progression to nonalcoholic steatohepatitis (NASH).3 Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum that ranges from simple steatosis to NASH and cirrhosis. It is commonly associated with obesity, metabolic syndrome, insulin resistance, and dyslipidemia. Alterations to the intestinal microbiota (known as dysbiosis) are thought to be associated with progression to NASH by affecting digestion, development of obesity, the immune response, and production of gut hormones (Table 1). Other metabolic pathways that are affected by microbiota and believed to contribute to NASH include short-chain fatty acids, ethanol, and bile acids. Furthermore, animal models reveal that antibiotic treatment, probiotics, and prebiotics can delay disease progression.4, 5 In spite of the data on dysbiosis in NAFLD, there is currently no evidence of a direct, causative link between alterations in intestinal microbiota composition or function and NAFLD development. It is also not clear whether the dysbiosis precedes the development of NAFLD or results from it.6 Patients with NAFLD have lower proportions of Bacteroidetes and higher proportions of Prevotella and Porphyromonas spp. compared with healthy controls (HCs).7 Studies showed a reduced microbial diversity that correlated with obesity and NAFLD compared with HCs.7 Patients with NASH have an increased abundance of ethanol-producing microbiota (such as Escherichia) and increased blood concentrations of ethanol, indicating a role for this family in the pathogenesis of NASH.7 Fecal samples from patients with NASH have decreased proportions of Bacteroidetes and increased proportions of Clostridium coccoides.7 It has been reported that children with NASH had increases in Bacteroidetes and decreases in Firmicutes. Proportions of Proteobacteria were significantly greater in children with NASH than in control subjects. However, proportions of Lachnospiraceae,Ruminococcaceae, and Firmicutes decreased, and there was an even greater reduction in Blautia and Faecalibacterium genera in children with NASH compared with controls. The increase in Proteobacteria correlated with an increased proportion of Enterobacteriaceae, especially Escherichia.7 Studies found that patients with higher-stage fibrosis or NASH with cirrhosis have significantly greater proportions of Bacteroides and Ruminococcus.7 Patients with type 2 diabetes also have higher proportions of Bacteroides and Ruminococcus than patients without.8 Due to its key role in the development and pathogenesis of NAFLD and NASH, intense study has focused on the gut microbiota as a target for therapeutic and preventative interventions. These include treatments with probiotics and prebiotics, symbiotic supplements, antidiabetic drugs, and fecal microbiota transplantation. For example, several studies have shown that glucagon-like peptide-1 (GLP-1) agonists induce weight loss in obese patients and can improve lipid profiles. Compared with controls, mice given GLP-1 agonists had reduced hepatic triglyceride content and a change in the overall abundance of weight-relevant phylotypes, such as decreased Proteobacteria.9 A randomized clinical trial in children showed that administration of the probiotic VSL#3 for 4 months significantly reduced NASH by increasing levels of GLP-1. The probiotic VSL#3 was also found to reduce hepatic fat deposits and oxidative and inflammatory liver damage in mice with steatosis.10 The butyrate-producing probiotic MIYAIRI 588 reduced hepatic oxidative stress in a rat model of NASH. Furthermore, supplementation of butyrate reduced liver injury in mice with steatosis. Obeticholic acid (OCA) is a potent activator of the farnesoid X receptor (FXR) that reduces liver fat content and fibrosis in animal models of NAFLD and has been studied specifically for the treatment of NASH.11 It has been shown to increase gram-positive facultative anaerobic bacteria in the stool of healthy people, likely as a result of an FXR-dependent reduction in small-intestinal bile acid levels.12 In addition, OCA reduces bacterial translocation, improves dysbiosis, and ameliorates the intestinal immune cell infiltration in rats with cirrhosis.13 Nonetheless, further studies about its long-term benefits are awaited. Although there is increasing evidence that dysbiosis of gut microbiota contributes to the development of NAFLD, a number of unresolved issues and questions remain. The intestinal metabolome is complex; therefore, further advances in analytical technologies and chemical structure identification methods are needed to obtain a more comprehensive understanding of microbiota-derived gut-liver signaling molecules. NASH phenotypes are variable among different ethnicities, so multiethnic studies are needed to compare differences in microbiomes and other factors that might contribute to these differences. Larger multicenter studies over longer time periods are essential to determine the interplay between the gut microbiota and liver disease. It is important to remember that NAFLD is a multisystem disease that involves metabolic syndrome; thus, the microbiota composition varies widely among individuals with NAFLD, and its effects on liver disease would involve additional environmental, genetic, and psychosocial factors.

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