Short-chain fatty acids and SCFA-producing bacteria in NAFLD patients are associated with an increased Th17/rTreg ratio and hepatic disease progression
09 May 2017 (online)
The intestinal microbiome and bacterial metabolites (e.g. short-chain fatty acids (SCFA)) influences chronic liver disease. The composition of microbiota impacts on weight gain and body fat, but conflicting results for microbial diversity are reported in non-alcoholic fatty liver disease (NAFLD). Changes of SCFA levels are thought to be important in NAFLD pathogenesis, but no data on their impact on immunology and liver histology exist in NAFLD patients. To analyse changes of intestinal microbiome together with fecal SCFA concentrations and immune cell changes in blood of histology-proven NAFLD patients.
Prospective study including 14 NAFL, 18 NASH patients and 29 healthy controls (HC). Stool samples were collected to analyse intestinal microbiome. Bacterial communities in feces were profiled by 16S rRNA genome sequencing. SCFA levels were analysed by HPLC.
32 NAFLD patients with significantly higher BMI compared to HC partly underwent bariatric surgery. Higher acetate and propionate concentrations in feces of NAFL and NASH patients were found compared to HC. A slight increase in butyrate was detected in NASH. No significant difference in the main phyla of Firmicutes or Bacteroidetes was seen in NAFLD compared to HC. NASH patients were characterized by an increase in Proteobacteria mainly in E. coli and Enterobacteriacae. In line with fecal SCFA levels, higher abundance of acetate- and propionate-producing bacteria (e.g. Proteobacteria, Veillonella and Fusobacteria) was observed in NASH compared to NAFL and HC. No significant changes were found for butyrate-producing bacteria. Higher fecal propionate and acetate levels were associated with lower resting Tregs (rTregs, CD4+CD45RA+CD25++) as well as higher Th17/rTreg ratio in PBMC of our study cohort. 22 NAFLD patients had F0-F1 fibrosis and 10 patients had higher fibrosis (≥F2). F0-F1 patients had higher fecal concentrations of acetate and propionate compared to ≥F2 patients and HC. In line with this finding lower abundance of Roseburia as SCFA-producing bacteria was detected in ≥F2 patients.
In NASH patients, higher abundance of fecal SCFA was observed together with changes in SCFA-producing bacteria. These changes were associated with an increased peripheral Th17/rTreg ratio and were reversed during disease progression with fibrosis. Our data further elucidate a mechanistic role of the intestinal microbiome and immunomodulatory bacterial metabolites in human NAFLD.