Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma

Abstract

Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune‐related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case‐control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow‐up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76‐3.00), and choline‐ and taurine‐conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine‐conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine‐conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Development of a Bile Acid-Related Gene Signature for Predicting Survival in Patients with Hepatocellular Carcinoma

“…In the past decades, more investigations are emerging on the correlations between gut microbiota and hepatocellular carcinoma (HCC) [ 5 , 6 ]. The gut microbiota produces numerous metabolites in the human body, including lipopolysaccharides (LPS), short-chain fatty acids, and BAs, which could promote haptic inflammation, resulting in liver diseases such as liver fibrosis, liver cirrhosis, and HCC [ 5 ].…”

Bile acids as drivers and biomarkers of hepatocellular carcinoma

“…Several other studies have also confirmed higher levels of specific bile acids (most frequently GCA, but also taurodeoxycholic acid, taurocholate, glycocholate, CDCA and cholic acid) in the serum or plasma of patients with HCC when compared to healthy controls[ 27 - 33 ]. However, there is some variability as to the underlying etiology of chronic liver disease predisposing to HCC in these cohorts and direct comparison of BA profiles amongst these etiologies has not been made.…”

Functional, Diagnostic and Therapeutic Aspects of Bile

“…This study may indicate that an altered bile acid metabolism may have a role in developing HCC. 59 Under cholestatic conditions, conjugated bile acids can activate the S1PR2 and the AKT and ERK1/2 signaling pathways and play a critical role in promoting invasive growth of cholangiocarcinoma, as shown in the mouse model. 60 Primary sclerosing cholangitis (PSC) combined with inflammatory bowel disease (IBD) has a high risk of developing colon cancer with a cumulative risk of 50% after 25 years of illness, ie, 5-fold higher than in IBD without PSC, possibly due to exposure of the colon to toxic bile.…”