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Tiny microscopic bacterial communities that live within and on us are known as the human microbiome. Research linking the human microbiome to cancer has skyrocketed in the last two decades and has largely focused on the relationship between the microbiome of the digestive tract with stomach and intestinal cancer. Interestingly, a paper published in 2021 described a link between bacteria that live in the gut and liver cancer.
With only 20% of liver cancer patients surviving 5 years after diagnosis, liver cancer is considered one of the deadliest cancers. Unlike many other cancers, it does not have effective treatments that target specific genes or mutations. Hepatitis C virus (HCV) is one of the major risk factors for liver cancer. Long term HCV infection can result in chronic liver disease (CLD) and eventually cancer. Despite the emergence of effective antiviral treatments against HCV, it is the third leading cause of cancer related death in the world.
Previous work studying the correlation of cancer and microbiome, has shown that alterations in the gut microbiome can lead to carcinogenesis (generation of cancer) through a variety of mechanisms. Moreover, specific bacterial species have been associated with an increased risk for certain types of cancers. One of the most well known and well studied relationships is that of the bacterium Heliobacter pylori and stomach cancer. H. pylori is thought to promote cancer through inflammation and tissue damage. While the relationship between the microbiome and cancer has been investigated for years, studies showing causal relationships through a specific mechanism are difficult to come by.
In a new study, the authors illustrate the link between the mouth and gut microbe Enterococcus faecalis and liver cancer by utilizing fecal samples from patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC) to perform experiments in mice. The authors use a technique called fecal transplants. In these experiments, mice are raised in germ-free facilities that are free of bacteria or mice are treated with antibiotics. These techniques are used to ensure that the mice are free of bacteria prior to transplanting fecal samples from human patients to observe how different microbiomes might promote liver cancer.
First, the authors demonstrated that the microbiomes of healthy donors, patients with CLD, and patients with HCC are distinct and show that mice transplanted with fecal samples from patients with CLD or HCC have an increased incidence of HCC. They narrowed in on the bacterial species Enterococcus faecalis because the guts of mice with more liver tumors were colonized by this microbe. They further identified that E. faecalis secreting the protein gelE colonized the mice and had even more tumors than mice colonized by E. faecalis that do not secrete gelE. gelE, along with other enzymes that break down proteins produced by bacteria, cause increased gut damage leading to higher concentrations of lipopolysaccharide (LPS), a component of the bacterial cell wall, in the blood and increased tumor incidence. Increased tumor incidence in the mice was thought to occur through the stimulation of the innate immune system by LPS, which prevents cell death and promotes liver cell proliferation.
Next, they asked what factor might allow the guts of patients with CLD or HCC to become occupied by E. faecalis. They found that human patients with CLD and HCC had decreased deoxycholic acid (DCA), a bile acid that helps breakdown fat in the stomach. The authors found that DCA inhibits growth of E. faecalis suggesting that decreased DCA may promote the colonization of the gut by E. faecalis and therefore lead to liver cancer.
DCA can be produced by bacteria and it was thought that the presence or absence of other bacterial species is correlated with the colonization of E. faecalis. They indeed found that the absence of bacteria that would normally outcompete E. faecalis were not present in the microbiomes of patients with CLD and HCC. This is a common theme in microbiome and disease research, where the lack of healthy bacteria allows for harmful bacteria to occupy organs and cause disease.
This scientific report helps understand the specific link between a single microbial species E. faecalis and the incidence of liver cancer. Furthermore, the authors describe a number of mechanisms that could be contributing to promotion of liver cancer by E. faecalis, including making the gut more permeable allowing for LPS to leak out and promote cancer in the liver. Additionally, they provide a mechanism for why E. faecalis might be allowed to colonize the guts of patients with CLD and HCC.
One of the most common risk factors for liver cancer is infection with hepatitis C virus (HCV). Patients with HCV often develop chronic liver disease and liver cancer. However, with the development of antiviral treatment for HCV, future work on liver cancer will likely be done to understand the causes of liver cancer that are not HCV related. One cause that this paper suggests is the disruption of the gut microbiome by E. faecalis. Future work should focus on developing diagnostic tools and preventative treatments for chronic liver disease and liver cancer by taking advantage of the knowledge we have on the impacts of the gut microbiome on liver disease.
Edited by Namrata Nilavar
Header image: Darryl Leja, National Human Genome Research Institute, National Institutes of Health, https://www.flickr.com/photos/nihgov/29872812646