Tag Archives: liver disease

Microbiology

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

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Reviewed by Emily Henderson, B.Sc.Mar 15 2023

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.

Source:

University of Missouri-Columbia

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.

Microbiology

Cancer immunotherapy does not interfere with COVID-19 immunity in vaccinated patients, study shows

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Reviewed by Emily Henderson, B.Sc.Jan 31 2023

Research findings published in Frontiers in Immunology show that cancer immunotherapy does not interfere with COVID-19 immunity in previously vaccinated patients. These findings support recommending vaccination for patients with cancer, including those receiving systemic therapies, say Saint Louis University scientists.

Immunotherapy is a treatment strategy that boosts a patient’s immune system to attack cancerous cells. In this novel study led by Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine, the Teague lab studied T cell responses and antibody responses against the SARS-CoV-2 spike protein in vaccinated and unvaccinated patients receiving immunotherapy.

Their research found data to support the clinical safety and efficacy of COVID-19 vaccination in patients receiving immune checkpoint inhibitors, a class of immunotherapy drugs.

It was thought that patients who had recently been vaccinated for or exposed to COVID-19 may have boosted inflammatory responses after immune checkpoint blockade treatment. The study found that immunotherapy did not tend to boost immune responses against COVID-19 in vaccinated patients, supporting the safety of receiving immune checkpoint inhibitors and the vaccine simultaneously.”

Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine

Teague notes that several timely factors came together to enable this research. In July 2022, the Teague lab published a study in Cancer Immunology Immunotherapy using a new technique known as Single-Cell RNA Sequencing, which allows researchers to study genetic information at the individual cell level to characterize immune responses after cancer treatment to identify biomarkers that could predict better patient outcomes.

Having collected blood from more than 100 patients with cancer during the COVID-19 pandemic, Teague recognized the opportunity to extend the benefit of this collection toward improving our understanding of patient immune responses against the vaccine.

“The COVID paper came from a unique window of time where we had a pandemic, and we had this valuable collection of patient samples that we could use to ask this timely question,” Teague said.

Additional authors include graduate students Alexander Piening, Emily Ebert, Niloufar Khojandi, and Assistant Professor Elise Alspach, Ph.D., from the Department of Molecular Microbiology and Immunology at SLU’s School of Medicine.

This work was supported by grant number NIH NCI R01 CA238705 from the National Institutes of Health.

Source:

Saint Louis University School of Medicine

Journal reference:

Piening, A., et al. (2022) Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer. Frontiers in Immunology. doi.org/10.3389/fimmu.2022.1022732.

Microbiology

Research findings could bolster the effectiveness of immune-checkpoint therapy

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Reviewed by Emily Henderson, B.Sc.Nov 16 2022

Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapy.

Rather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells-;with dramatic results.

We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer.”

Xingxing Zang, M.Med., Ph.D., Study Leader

Xingxing Zang is the the Louis Goldstein Swan Chair in Cancer Research and professor of microbiology & immunology, of oncology, of urology, and of medicine at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.

Telling friend from foe

The surfaces of immune cells are studded with receptors known as “checkpoint” proteins, which prevent immune cells from straying beyond their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind with proteins expressed by the body’s own normal cells, the interaction puts the brakes on a possible immune-cell attack. Diabolically, most types of cancer cells express proteins that bind with checkpoint proteins, tricking immune cells into standing down and not attacking the tumor.

Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit immune-cell/cancer-cell interactions by blocking either the tumor proteins or the immune-cell receptors that bind with tumor proteins. With no brakes to impede them, immune cells can attack and destroy cancer cells.

New focus on natural killer cells

The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and other scientists to look at checkpoint pathways involving NK cells, which-;like T cells-;play major roles in eliminating unwanted cells. A cancer-cell protein called PVR soon captured their attention. “We realized that PVR may be a very important protein that human cancers use to hobble the immune system’s attack,” said Dr. Zang.

PVR protein is usually absent or very scarce in normal tissues but is found in abundance in many types of tumors including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancer as well as myeloid leukemia and melanoma. Moreover, PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT-;prompting efforts to interrupt the TIGIT/PVR pathway by using monoclonal antibodies made against TIGIT. More than 100 clinical trials targeting TIGIT are now in progress worldwide. However, several clinical studies including two large phase 3 clinical trials have recently failed to improve cancer outcomes.

Recognizing the role of a new receptor

Meanwhile, the cancer-cell protein PVR was found to have another “binding partner” on NK cells: KIR2DL5. “We hypothesized that PVR suppresses NK cell activity not by binding with TIGIT but by binding with the recently recognized KIR2DL5,” said Dr. Zang. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and carried out in vitro and in vivo experiments using the antibody.

In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells, which PVR cancer proteins use to suppress immune attack. In studies involving humanized animal models of several types of human cancers, the researchers showed that their monoclonal antibody against KIR2DL5-;by blocking the KIR2DL5/PVR pathway-;allowed NK cells to vigorously attack and shrink human tumors and prolong animal survival (see accompanying illustration). “These preclinical findings raise our hopes that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we’ve developed may be an effective immunotherapy,” said Dr. Zang.

Einstein has filed a patent application for KIR2DL5/PVR immune checkpoint including antibody drugs and is interested in a partnership to further develop and commercialize the technology.

Dr. Zang has previously developed and patented more than 10 immune checkpoint inhibitors. One of those inhibitors is now being tested in China in phase 2 clinical trials involving several hundred patients with advanced solid cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes). Another of Dr. Zang’s immune checkpoint inhibitors will be evaluated starting next year in cancer clinical trials in the United States.

Source:

Albert Einstein College of Medicine

Journal reference:

Ren, X., et al. (2022) Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell-mediated antitumor immunity. Journal of Clinical Investigation. doi.org/10.1172/JCI163620.