The Role of Intestinal Microbiota, Endotoxemia and Systemic Inflammation in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Introduction. Currently there are few and contradictory data concerning the influence of intestinal microbiota (IM) disturbances on the nature and severity of inflammatory processes in the liver tissue, the role of microbial metabolites in the activation of steatosis and fibrosis processes in patients with non-alcoholic fatty liver disease (NAFLD).

The aim of the study. To clarify the role of intestinal microbiota, endotoxemia and systemic inflammation in the development and progression of nonalcoholic fatty liver disease.

Materials and methods. 108 patients with NAFLD were examined, control group included 30 people. Detection of CRP and TNF-alpha levels, endotoxin in blood serum was carried out by the immunoenzymatic method. Determination of IM composition at the level of the main phylotypes was carried out by the method of quantitative polymerase chain reaction in real time.

Results. A weak direct correlation between TNF-alpha, CRP and endotoxin with Firmicutes content (F), and an inverse correlation between CRP with Bacteroidetes content (B) was revealed.

The dependence of the ratio of main intestinal phyla (F/B) on markers of systemic inflammation in NAFLD patients with different levels of endotoxin was evaluated. In patients with NAFLD, as endotoxin concentration increased, a deeper imbalance of IM was observed. In the group of patients with NAFLD with a high level of endotoxin, the maximum values of the F/B index were observed. Also, the increase in the intestinal permeability of the mucous barrier depended not only on changes in the IM, but also on systemic inflammation. The highest levels of endotoxemia were observed in patients with a high F/B index and increased activity of pro-inflammatory markers.

In patients with NAFLD with varying degrees of fatty infiltration of the liver, an imbalance of IM was detected in comparison with the control group. As the degree of steatosis increased in NAFLD patients, an increase in Firmicutes content was observed. The maximum shift in the balance of the main phyla towards a decrease in the relative content of Bacteroidetes and an increase in Firmicutes was determined in patients with 3rd degree of steatosis (p < 0.05). In the group of patients with a low and moderate degree of steatosis, a similar trend of IM disorders was observed, but these changes were insignificant. The relative number of Actinobacteria exposed no differences between the examined patients.

The analysis of changes in IM in patients with NAFLD depending on the stage of liver fibrosis revealed no significant differences both from the control group and between groups with different degrees of fibrosis. The obtained data indicate that the imbalance of IM makes a significant contribution to the development of liver steatosis, while other important factors are involved in the formation of fibrosis processes, in particular, inflammation, the activity of intestinal metabolites and regulatory molecules.

Conclusions.The imbalance of the intestinal microbiota towards an increase in Firmicutes leads to an increase in the production of intestinal metabolites with subsequent initiation of systemic inflammation, which stimulates the accumulation of fat in hepatocytes, affecting the progression of steatosis and the processes of fibrosis in the liver.