St George Hospital researchers have made a major breakthrough that could hold the key to predicting a person's risk of developing one of the most deadly forms of liver cancer.
The findings have also paved the way for future studies to increase the chances of treatment being successful.
The Sir Owen Glenn Liver Research Group based at the University of NSW Microbiome Research Centre at St George Hospital has discovered the distinctive gut microbiome profile of a person with liver cancer is linked to non-alcoholic fatty liver disease.
They believe this could hold the key to predicting the risk of developing liver cancer.
The study, overseen by Associate Professor Amany Zekry and Professor Emad El-Omar, was recently published in Nature Communications.
It found the gut microbiome - the group of microorganisms living in our digestive tracts - can modulate the immune response in liver cancer patients with non-alcoholic fatty liver disease in a way that promotes the cancer's survival.
While the research is still in its early stages, this finding could lead to more effective preventative and therapeutic treatments for people at risk of developing non-alcoholic fatty liver disease-related liver cancer.
Non-alcoholic fatty liver disease is linked to obesity and metabolic risk factors such as diabetes, hypertension and high cholesterol.
The study's senior author, Associate Professor Zekry, said the researchers looked at the most common type of primary liver cancer - hepatocellular carcinoma, or HCC - which is the third leading cause of cancer-related deaths in the world.
"Chronic liver inflammation and liver cirrhosis - or scarring - are key to a patient developing liver cancer, with non-alcoholic fatty liver a common risk factor," she said.
"So because of the global pandemic of obesity and type 2 diabetes, non-alcoholic fatty liver is emerging as the key reason for liver disease and liver cancer - particularly in Western countries.
"Liver cancer generally has a bad outcome because it's usually detected at the late stages of the disease due to the liver's resilience - liver cirrhosis can go undiagnosed for many years until cancer develops."
The UNSW-led study included medical researchers from its St George and Sutherland Clinical School and major hospitals in NSW.
Associate Professor Zekry, who is St George Hospital's head of gastroenterology and hepatology, said the research was the first to comprehensively investigate the microbiome in the context of this form of liver cancer.
"Another unique feature of our research is how we used a human cell culture model to examine the effect of the gut microbiome on the immune response in liver cancer patients," she said.
"This study is part of a larger research project we are doing involving about 200 patients, with the ultimate aim of identifying gut microbiome biomarkers or indicators to predict someone's risk of developing liver cancer."
The researchers recruited 90 adult patients from several Sydney hospitals, two-thirds of whom had just been diagnosed with either non-alcoholic fatty liver-related liver cancer or cirrhosis. They were aged in their 50s to 70s and their cancer had been detected early.
The remaining patients were a control group without liver disease.
All provided blood and stool samples, which the researchers used to create cell culture models for analysis.
The researchers found patients with non-alcoholic fatty liver-related liver cancer had a distinctive and characteristic gut microbiome profile, which was different to those with liver disease generally.
"If we know what happens in the early stage, then we can intervene to stop the cancer progressing to the late stage," Associate Professor Zekry said.
"So if people can be diagnosed early with liver cancer, there is the potential to cure them with definitive therapy.
"Our study findings also open the door to harness gut-based interventions, by manipulating the microbiome as a preventative strategy against the development of liver cancer."
The study's first author Jason Behary said no previous studies had reported a non-alcoholic fatty liver-related liver cancer "signature".
"This means in the future we will be able to harness the gut microbiome to predict disease occurrence, which is highly relevant for liver cancer because it's almost always detected in the late stages," Dr Behary said.
"We also found the genes and function of the gut microbiome in non-alcoholic fatty liver-related liver cancer patients promoted increased production of short-chain fatty acids - namely butyrate - which stem from intestinal microbial fermentation of indigestible foods, like beans and grains.
"Excess butyrate in the context of liver cancer is hazardous, because we found it obstructs the immune system from functioning.
"In addition, we found certain bacteria species correlated with this unfavourable immune response."
Dr Behary said cell culture studies confirmed the gut microbiome of patients with non-alcoholic fatty liver-related liver cancer modulated the immune response in a way that favoured the cancer's survival - rather than its elimination - which "opens the door for intervention".
He said that given the growing interest in new liver cancer treatments like immunotherapy, which changes the immune response to make it fight the cancer, the findings paved the way for future studies to look at how we can change the microbiome to increase the chances of immunotherapy being successful.
The research program was funded by a major donation to the St George and Sutherland Medical Research Foundation (SSMRF) by Sir Owen Glenn.
