Tag Archives: Liver Cancer

Research identifies western diet-induced microbial and metabolic contributors to liver disease

New research from the University of Missouri School of Medicine has established a link between western diets high in fat and sugar and the development of non-alcoholic fatty liver disease, the leading cause of chronic liver disease.

The research, based in the Roy Blunt NextGen Precision Health Building at MU, has identified the western diet-induced microbial and metabolic contributors to liver disease, advancing our understanding of the gut-liver axis, and in turn the development of dietary and microbial interventions for this global health threat.

We’re just beginning to understand how food and gut microbiota interact to produce metabolites that contribute to the development of liver disease. However, the specific bacteria and metabolites, as well as the underlying mechanisms were not well understood until now. This research is unlocking the how and why.”

Guangfu Li, PhD, DVM, co-principal investigator, associate professor in the department of surgery and Department of Molecular Microbiology and Immunology

The gut and liver have a close anatomical and functional connection via the portal vein. Unhealthy diets change the gut microbiota, resulting in the production of pathogenic factors that impact the liver. By feeding mice foods high in fat and sugar, the research team discovered that the mice developed a gut bacteria called Blautia producta and a lipid that caused liver inflammation and fibrosis. That, in turn, caused the mice to develop non-alcoholic steatohepatitis or fatty liver disease, with similar features to the human disease.

“Fatty liver disease is a global health epidemic,” said Kevin Staveley-O’Carroll, MD, PhD, professor in the department of surgery, one of the lead researchers. “Not only is it becoming the leading cause of liver cancer and cirrhosis, but many patients I see with other cancers have fatty liver disease and don’t even know it. Often, this makes it impossible for them to undergo potentially curative surgery for their other cancers.”

As part of this study, the researchers tested treating the mice with an antibiotic cocktail administered via drinking water. They found that the antibiotic treatment reduced liver inflammation and lipid accumulation, resulting in a reduction in fatty liver disease. These results suggest that antibiotic-induced changes in the gut microbiota can suppress inflammatory responses and liver fibrosis.

Li, Staveley-O’Carroll and fellow co-principal investigator R. Scott Rector, PhD, Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research -; are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society. The team recently received a $1.2 million grant from the National Institutes of Health to fund this ongoing research into the link between gut bacteria and liver disease.

Journal reference:

Yang, M., et al. (2023). Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nature Communications. doi.org/10.1038/s41467-023-35861-1.

Study identifies Δ42PD-1 as novel therapeutic target for hepatocellular carcinoma immunotherapy

HKUMed researchers at AIDS Institute, Department of Microbiology and Department of Surgery, School of Clinical Medicine, and School of Biomedical Sciences discover the role of an isoformic programmed cell death protein 1 (PD-1), namely Δ42PD-1, in suppressing the function of killer T cells, which is a type of immune cells essential for killing cancer cells among hepatocellular carcinoma (HCC) patients. The study is a breakthrough because it demonstrates that Δ42PD-1 causes stronger functional loss of killer T cells, revealing a molecular mechanism underlying the failure of PD-1-targeted immune checkpoint blockade (ICB) therapy. Moreover, antibody drug targeting at Δ42PD-1 inhibits HCC progression in animal models, which is independent of the PD-1 pathway. The full research article is now published online in the journal of Gut, a top-tier academic journal.


It is well known that HCC accounts for up to 92.3% of liver cancer cases in China. The 2018 Nobel Prize in Physiology or Medicine was awarded for the discovery of cancer ICB therapy by inhibition of negative immune regulation using PD-1-targeted antibody, such as Nivolumab. The ICB therapy has resulted in prolonged survival and even cure in some cancer patients. The ICB therapy, however, is not effective for about 80% of HCC patients. Understanding the mechanism of unsuccessful ICB, therefore, would be essential for discovering a novel therapeutic target to save more lives of HCC patients.

Research methods and findings

The research team found that human T cells, which express Δ42PD-1 but not PD-1, account for up to 71% of killer T cells in untreated HCC patients. Δ42PD-1 positive T cells are mainly found in tumor tissues, associated significantly with HCC poor prognosis. Moreover, Δ42PD-1 positive T cells have weaker killing function than PD-1 positive T cells. Treatment of HCC patients using Nivolumab, the PD-1-targeted ICB drug, even increases the number of Δ42PD-1 positive T cells, especially in patients with tumor progression. We demonstrated that Δ42PD-1 positive T cells inside tumors promote HCC growth through activating toll-like receptors-4-mediated inflammation. Instead of Nivolumab, anti-Δ42PD-1 antibody inhibits tumor growth in three HCC/humanized murine models through blocking of the Δ42PD-1-TLR4 axis, reducing the number of Δ42PD-1 positive T cells and increasing functional killer T cells inside tumor. These findings not only revealed a mechanism underlying the unsuccessful PD-1-targeted ICB therapy but also identify Δ42PD-1 as a novel therapeutic target for HCC immunotherapy.

Significance of the study

This important discovery has provided scientific evidence that Δ42PD-1 may serve as a novel drug target against HCC or other relevant cancers and may warrant the clinical development of a humanized Δ42PD-1-specific antibody for immunotherapy against HCC and related human cancers/diseases.

‘We were the first research group discovering the Δ42PD-1 protein in the world’, commented by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. ‘In this study, we not only further discover the dual activities of Δ42PD-1 on human T cells in both suppressing anti-tumor immune response and promoting tumorigenesis but also generate a potential anti-Δ42PD-1 antibody drug for HCC treatment’.

‘Besides immunotherapy against HCC, the anti-Δ42PD-1 antibody can also be used as a drug to prevent HCC recurrence without induction of graft rejection after liver transplantation’, added by Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed.

About the research team

The collaborative research team was led by Professor Chen Zhiwei, Director of AIDS Institute and Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, together with Professor Nancy Man Kwan, Department of Surgery, School of Clinical Medicine, HKUMed and Dr Tan Zhiwu, research assistant professor at AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed. This collaborative team includes Chiu Mei-sum, Dr Zhou Dongyan, Yan Chi-wing, Kwan Ka-yi, Dr Wong Yik-chun, Li Xin, Dr Li Liu from AIDS Institute and Department of Microbiology, School of Clinical Medicine, HKUMed; Dr Yang Xinxiang, Dr Cheung Tan-to, Dr Wang Yuewen, Dr Zhu Jiye, Professor Lo Chung-mau, Department of Surgery, School of Clinical Medicine, HKUMed; Dr Yue Ming and Dr Song Youqiang from School of Biomedical Sciences, HKUMed; and Dr Anthony Chan Wing-hung, Dr Zhou Jingying, Professor To Ka-fai, Professor Alfred Cheng Sze-lok, Professor Stephen Lam Chan from the Chinese University of Hong Kong.

Journal reference:

Tan, Z., et al. (2022) Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients. Gut. doi.org/10.1136/gutjnl-2022-327133.