AS608 - Metabolomics, bacterial translocation and risk of liver cancer

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Investigator Names and Contact Information

Katherine A. McGlynn [mcglynnk@mail.nih.gov]

Abstract

Liver cancer, the second leading cause of cancer mortality in the world, has one of the most rapidly increasing incidence rates in the U.S. and other Western countries [1, 2]. Incidence in the U.S. has been increasing since 1980 [3]. Between 1999 and 2006, liver cancer experienced the second greatest annual percent increase in incidence (2.3%) and the single greatest annual percent increase in mortality (2.0%) of all major cancers [4]. These increases are particularly notable as liver cancer has the third worst prognosis among major cancers in the U.S. [4], with a 5-year survival rate of less than 15%. It is estimated that approximately 5% of cancer deaths among men and 3% among women are due to liver cancer, making liver cancer one of the top ten causes of cancer death in the U.S. [4].

The most common histological types of liver cancer are hepatocellular carcinoma (HCC, ~80%) and intrahepatic cholangiocarcinoma (ICC, ~15%). Major risk factors for HCC, including hepatitis B virus (HBV), hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, smoking, obesity and diabetes, all contribute to chronic hepatic inflammation [5]. Growing evidence suggests that the gut microbiome, and the cross-talk between the microbiome and metabolome, are critically related to the development of hepatic inflammation, liver disease and liver cancer [6-9].

Although the liver does not contain a known microbiome of its own, it receives approximately 70% of its blood supply from the portal vein, which carries blood from the intestines.[10] HCC risk factors such as obesity and alcohol abuse, as well as other insults, can trigger intestinal dysbiosis (i.e., altered microbiota composition and decreased bacterial diversity). When dysbiosis is coupled with subsequent gut barrier damage, the liver is exposed to an elevated level of gut-derived bacterial products via the portal circulation [11]. Animal studies have demonstrated that exposure to bacterial products causes inflammation and oxidative stress in the liver, and can promote HCC [12-14]. Similarly, evidence from human studies suggests that bacterial translocation is positively associated with systemic inflammation [15] and chronic liver diseases [16-22]. In the sole published human study to examine bacterial translocation and risk of liver cancer, a significant association between antibodies to bacterial products (anti-lipopolysaccharide, anti-flagellin) and risk of liver cancer was reported [15].

Gut bacterial metabolites that may have particular relevance to liver cancer are the secondary bile acids, such as deoxycholic acid (DCA) and lithocholic acid (LCA), that are the products of bacterial metabolism of primary bile acids in the gut [8]. For example, DCA has been found to promote the development of obesity-associated HCC in an animal model and to induce the expression of inflammatory genes in an in vitro model [23, 24]. To date, no targeted examinations of secondary bile acid concentrations in relationship to risk of liver cancer in humans have been reported.

Although more evidence exists for a role of bacterial metabolites, particularly secondary bile acids, in liver cancer, a role for other metabolites found in serum has also been suggested. Human metabolomic studies of liver cancer have reported roles for lipid metabolism, fatty acid oxidation and increased levels of amino acids, among others [25, 26]. Except for one study nested in the EPIC cohort [27], all other human studies of the metabolome and liver cancer have been retrospective in design, suggesting that the associations could have been the result of cancer. Therefore, an agnostic examination of the metabolome in association with liver cancer would offer the opportunity to not only test existing hypotheses (i.e., bile acids, lipids, short-chain fatty acids) but also the opportunity to generate new hypotheses.

In order to study the etiology of liver cancer using a prospective design, the Liver Cancer Pooling Project (LCPP), a pooling project within the NCI Cohort Consortium, was initiated in 2009. Fourteen U.S. based cohorts are contributing questionnaire data and serum samples to the LCPP. Questionnaire data from WHI participants, as well as serum for HBV/HCV determinations, have already been approved for this consortia effort. While known risk factors, such as HBV/HCV and alcohol consumption, have been studied extensively, an examination of other putative factors, such as components of the metabolome (including the bile acids and the lipidome) and markers of gut bacterial translocation, might greatly enhance the current understanding of the etiology of liver cancer in the U.S.

Specific Aims

Determine whether components of the metabolome (including the bile acids and the lipidome) and/or markers of gut bacterial translocation are related to the development of liver cancer in a U.S. population.

References

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