Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease

Abstract

Background & AimsNon-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied by an altered bile acid (BA) homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data.MethodsThis was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH) and healthy controls (HC). Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) and intestinal BA signalling, as well as IM composition were assessed.Results53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA), chenodeoxycholic acid (CDCA) and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons). The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004), but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively). C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA) (r = 0.526, p = 0.003) and inversely with unconjugated CA (r = -0.669, p<0.0001) and unconjugated CDCA (r = - 0.630, p<0.0001). FGF19 levels were not different between the groups (p = 0.114).ConclusionsIn adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury.

Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD

“…Elevated serum total bile acids in NASH were first reported by Ferslew et al 37. Using approaches that are complementary to ours, Mouzaki et al 17 concluded that bile acid production is elevated in NAFLD livers, based on the findings that faecal total bile acid and faecal primary bile acid levels are elevated in patients with NAFLD, and that serum marker of bile acid synthesis 7-alpha-hydroxy-4-cholesten-3-one is elevated in NAFLD. In support of increased bile acid production, Min et al 38 also observed elevated hepatic expression of CYP7A1 in NAFLD livers.…”

“…Recently, Mouzaki et al 17 examined the gut microbiome composition in NAFLD. Using PCR-based method, they found that patients with NASH exhibited small but significant changes in faecal microbiome, which is in line with altered faecal bile acid composition.…”

Non-alcoholic fatty liver and the gut microbiota

“…A recent study by Mouzaki et al. [121] shows that NASH patients had a reduction in the secondary bile acids pool and in fecal levels of Bacteroidetes and Clostridium leptum . However, a direct role of the gut microbiome in controlling FXR-bile acids signaling in NAFLD and NASH development has not been elucidated.…”

Gut Microbiota and Complications of Liver Disease

“…Lake et al studied the composition of BA’s in the human livers of NAFLD patients and interestingly found a reduced level of CA and glycodeoxycholic acid and an increase in taurocholic acid and taurodeoxycholic acid 54 . A recent study looking at the fecal composition of NAFLD and NASH adults confirmed a higher fecal bile acid level with a predominance of primary bile acids in the stool of NASH patients (NASH>NAFLD), further clarifying the mechanism by which BA’s regulate dysbiosis 55 . To further aseess the interplay Tetri et al in a multicenter randomized trial studied the effect of obeticholic acid (BA derivative that activates FXR) in NASH patients and noted improvement in the histological features of NASH based on the NAFLD activity score on liver biopsies 56 ..…”