Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development

Abstract

During the past several decades, the percentage of excess bodyweight and obese adults and children has increased dramatically, and is becoming one of the most serious public health problems worldwide. Extensive epidemiological studies have revealed that there is a strong link between obesity and some common cancers. However, the exact molecular mechanisms linking obesity and cancer are not fully understood yet. Recently, we have reported that dietary or genetic obesity provokes alterations of gut microbiota profile, thereby increasing the levels of deoxycholic acid (DCA), a secondary bile acid produced solely by the 7α-dehydroxylation of primary bile acids carried out by gut bacteria. The enterohepatic circulation of DCA provokes DNA damage and consequent cellular senescence in hepatic stellate cells (HSCs) which, in turn, secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating hepatocellular carcinoma (HCC) development in mice. Interestingly, signs of senescence-associated secretory phenotypes were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis, implying that a similar pathway is likely to contribute to at least certain aspects of obesity-associated HCC development in humans as well. In this review, I will provide an overview of our recent work and discuss the next steps, focusing on the potential clinical implications of our findings.

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

“…Few studies have reported the direct effect of primary bile acids on intestinal carcinogenesis. 53,58,[62][63][64][65] In addition, DCA-mediated gut dysbiosis has a crucial role in the progression of the intestinal adenoma-adenocarcinoma sequence. 59 In HCT116 colon cancer cells, CDCA could increase COX-2 promoter activity, which was an important marker in carcinogenesis.…”

Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle

“…Studies in animal models (murine) have shown that the enterohepatic circulation of dichloroacetic acid (DCA) provokes DNA damage and consequent cellular senescence in hepatic stellate cells which, in turn, secrete various inflammatory and tumour-promoting factors in the liver, thus facilitating HCC (Elinav et al, 2013;Hara, 2015;Ohtani, 2015). Another mechanism suggested is the conversion of ethanol into toxic and carcinogenic acetaldehyde by anaerobic bacteria in the colon.…”

Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma

“…Although the exact molecular pathogenesis of HCC development in these viral liver diseases have not been fully revealed, tremendous progresses have been made in terms of clinical features, managements, oncogenic potential of viral proteins, and the critical role of viral genomic integration into the host genomes, as well as positive correlations between success of anti-viral therapy and decrease in HCC incidence [23–27]. In contrast, basic and clinical studies of NASH-HCC are in their infancy [17], and many clinical issues and basic understanding of NASH-HCC pathogenesis remain unexplored and elusive.…”

“…One unsolved question remains whether cancer stem cells or tumor-initiating cells arise from transformation of normal tissue stem cells, or from dedifferentiation of mature hepatocytes or progenitor cells during steatohepatitis [90]. Other intriguing unsolved issues include, but are not limited to: 1) The impact of altered gut microbiome on bile acid metabolism and hepatic inflammation, steatosis and carcinogenesis [17]; 2) What is the epigenetic influence from aberrant adipokines, lymphokines, cytokines or transcription factors on normal stem cells, progenitor cells or mature hepatocytes [30, 90]; 3) Are there differences in energy and nutrient metabolism and the metabolomics profile between SFL, NASH and NASH-HCC; and 4) The molecular links between disordered lipid metabolism, ER stress, and insulin resistance and carcinogenesis [91]. Hopefully, reliable NASH-HCC models will be available in the near future which will enable these studies to be undertaken, and also be used to assess the effectiveness of potential therapeutics in the treatment of NASH and the prevention of HCC [46, 51].…”

“…Another area of active research employing a systems biology approach has discovered the clues of altered gut microbiota for NASH development and possible link to gut and liver malignancies through bile acid metabolites, such as increased levels of deoxycholic acid, which is toxic to hepatocytes and provokes senescence of hepatic stellate cells (HSC). Tumorigenic factors, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) released from senescent HSCs facilitate hepatocellular transformation to malignancy in mice [17–19]. These clinical or translational studies provide valuable hints of possible factors or pathways involved in NASH development and progression at population or individual levels.…”