Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC

Abstract

OBJECTIVES: The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases. METHODS: To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence or presence of cirrhosis through the analysis of stool and serum samples from patients with NASH non-HCC and NASH-HCC and healthy volunteers. RESULTS: Serum levels of total and individual BA were higher in NASH compared with healthy controls. Furthermore, serum levels of the primary conjugated BAs glycine-conjugated cholic acid, taurine-conjugated cholic acid, glycine-conjugated chenodeoxycholic acid, and taurine-conjugated chenodeoxycholic acid were significantly increased in cirrhotic vs noncirrhotic patients, independent of the occurrence of HCC. By contrast, serum FGF19 levels were higher in patients with NASH-HCC and associated with tumor markers as well as an attenuation of BA synthesis. Specific alterations in the gut microbiome were found for several bacteria involved in the BA metabolism including Bacteroides and Lactobacilli. Specifically, the abundance of Lactobacilli was associated with progressive disease, serum BA levels, and liver injury in NASH and NASH-HCC. DISCUSSION: Here, we demonstrate a clear association of the altered gut microbiota and primary conjugated BA composition in cirrhotic and noncirrhotic patients with NASH-HCC. Microbiota-associated alterations in BA homeostasis and farnesoid X receptor signaling, via FGF19, might thus contribute to fibrogenesis, liver injury, and tumorigenesis in NASH-HCC.

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

“…FGFR4 polymorphisms have also been detected in patients with cirrhosis and HCC [95] and the overexpression of hepatic and serum FGF19/FGFR4 has been associated with a poor outcome in HCC patients [93,96,97]. This was confirmed by our own group, demonstrating increased serum FGF19 in NASH, NASH-HCC and in particular cirrhotic NASH-HCC [98]. FGF19 was also correlated to alterations in bile acids and tumour markers.…”

Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales

“…The intestinal microbiota synergize with genetic, inflammatory, and metabolic drivers of liver injury to promote pathology in NAFLD and NASH. In NAFLD, abnormal microbiota correlate with a leaky intestinal epithelium [ 12 ] and compromised gut vascular barrier integrity [ 13 ], due in part to altered bile acid signaling [ 14 , 15 ]. This increases hepatic delivery via the portal circulation of lipopolysaccharides (LPS) and other pathogen-associated molecular patterns (PAMPs), triggering inflammatory innate immune responses and promoting fibrosis through activation of hepatic stellate cells [ 16 ].…”

Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury

“…DNA was extracted from foecal content as previously described ( Sydor et al, 2020 ). All samples were resampled to the minimum sequencing depth of 17719 reads using phyloseq package ( Mcmurdie and Holmes, 2013 ) and returning 2,167 phylotypes ( Supplementary Figure S2 ).…”