Review Article

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

Saumya Jayakumar; Rohit Loomba


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

In This Article

Gut Microbiome and Metabolic Syndrome

Metabolic syndrome is defined as the presence of any three of the following conditions: central obesity, hypertension, impaired glucose tolerance (or overt diabetes mellitus), hypertriglyceridemia and low levels of high-density lipoproteinemia (HDL).[58] Given the close association between NAFLD and obesity, insulin resistance and TG levels,[59] NAFLD is often considered the hepatic manifestation of metabolic syndrome.[60] Because gut microbiota play a key role in metabolism and energy production from dietary intake,[61] it stands to reason that they are closely related to components of metabolic syndrome (eg, obesity and diabetes).

One of the main factors in the development of obesity, diabetes and NAFLD is diet. Diet affects the composition of GI bacteria, which then influences host metabolism and inflammation.[62] Turnbaugh and colleagues demonstrated the effect of diet on the gut microbiota in a mouse model.[63] They humanised the gut microbiota of these mice by transplanting them with human faeces, and then they fed the mice either a high-fat, high-sugar diet ("Western diet") or a plant-based, low-fat diet.[63] The group that was fed a high-fat diet had a lower percentage of Bacteroidetes spp in its gut microbiota and a higher percentage of Firmicutes compared with mice fed a plant-based diet. Studies in humans and mice have shown an increased Firmicutes/Bacteroidetes ratio in individuals who are overweight or obese,[64,65] and a reduction in the Firmicutes/Bacteroidetes ratio with weight loss.[32]

In addition, higher colonic levels of SCFAs have been observed in obese individuals compared with their nonobese counterparts.[64,66,67] The higher production of SCFAs may result in energy accumulation and subsequent weight gain.[68] In a comparison between individuals who were morbidly obese and individuals of normal weight, increased numbers of both the H2-producing bacteria Prevotellaceae and H2-oxidising Archaea microorganisms were observed in the morbidly obese participants.[69] The authors hypothesised that interspecies H2 transfer accelerated carbohydrate fermentation and the production of acetate, with an ensuing increased energy uptake by the host. An increase in SCFA levels may also alter other metabolic pathways (eg, lipid and glucose metabolism via activation of peroxisome proliferator-activated receptor gamma[70] and glucagon-like peptide-1 [GLP-1]).[71]

The gut microbiota can also directly affect factors that control adiposity. For example, alterations in the gut microbiota affect the epithelial cell product, fasting-induced adipocyte factor (FIAF, also known as angiopoietin-like protein 4), which inhibits lipoprotein lipase. Preclinical models have demonstrated that microbial suppression of the FIAF gene increases lipogenesis,[72] whereas administration of the bacterial strain Lactobacillus paracasei ssp paracasei F19 both induced FIAF gene expression and reduced body fat.[73] The gut microbiota may also inhibit activity of the enzyme, adenosine monophosphate-activated protein kinase, in muscle and liver, resulting in reduction of fatty acid oxidation and increased fat storage.[74,75]

The gut microbiome also has a role in type 2 diabetes mellitus (T2DM). For example, a correlation between the Firmicutes/Bacteroidetes ratio and plasma glucose concentrations was reported in patients with T2DM.[76] In addition, as stated above, the gut microbiota affect the production and release of GLP-1, which affects pancreatic β-cell function. SCFAs also appear to be closely interrelated with insulin resistance. Compared with patients without insulin resistance, patients with T2DM have a decrease in butyrate-producing bacteria.[77] SCFAs bind to G-protein (GPR)-coupled receptors (eg, GPR41 and GPR43),[78] which may lead to the secretion of factors such as protein YY that affect satiety, gastric motility and pancreatic function.[79–81]

SCFAs also regulate various aspects of GI inflammation, such as neutrophil migration, T-cell differentiation and macrophage expression of proinflammatory cytokines.[82] Insulin resistance is often accompanied by low-grade inflammation.[83,84] The movement of the GI bacterial product lipopolysaccharides [LPS] into intestinal capillaries may contribute to inflammation and insulin resistance.[84] TLRs are a type of innate immune receptor that are thought to recognise LPS and other products of invading pathogenic bacteria.[83] TLR knockout studies in mice are helping to elucidate the role of the gut microbiota in metabolic syndrome and insulin resistance. For example, mice deficient in TLR-5 developed features of metabolic syndrome, including insulin resistance.[85] The authors of this report suggested that changes in the composition of gut microbiota, resulting from loss of TLR-5, induced the low-grade inflammation that contributed to the symptoms of metabolic syndrome. Another report described mice with elimination of TLR-4 specifically in hepatocytes.[86] When these mice received a high-fat diet, they became obese, but compared with control mice, these mice displayed enhanced insulin sensitivity and reduced hepatic steatosis. Thus, hepatocytes are centrally involved in the effects of inflammation on metabolic control, with the gut microbiota making up a significant part of that inflammatory signal.[86]