Researchers explore how to protect intestinal integrity to improve blood cancer outcomes

Researchers at the MUSC Hollings Cancer Center found that a single strain of bacteria may be able to reduce the severity of graft versus host disease (GVHD), as reported online in February 2021 in JCI Insight.

Bone marrow transplantation can be a life-saving procedure for patients with blood cancer. However, GVHD is a potentially fatal side effect of transplantation and has limited treatment options. This proof-of-concept study demonstrates that better treatment options may be on the horizon for patients with GVHD.

Xue-Zhong Yu, MD, associate director of Basic Science at the Hollings Cancer Center, and lead author Hanief Sofi, Ph.D., realized that protecting the health of the gastrointestinal tract is a good target for reducing severe GVHD.

“If we can find out how to keep a patient’s intestinal tissue healthy before and after bone marrow transplantation, the patient’s outcome will be much better. We know that restoring the diversity of the microbiota in the intestine is an effective solution, but it comes with many challenges “said Yu.

Blood cancer patients, such as leukemia, must undergo radiation and chemotherapy before obtaining their new cancer-free immune system through bone marrow transplantation. The balance between the immune system and the intestinal microbiota, communities of microorganisms that live in the intestine, is especially important for proper intestinal health. Unfortunately, radiation and chemotherapy unbalance this balance radically, and the diversity of the microbiota is reduced by 100 or even 1,000 times. This leads to a condition called “leaky gut”.

Clinical studies have shown that patients who recover microbiota diversity more quickly have better results and less severe GVHD. The reduced diversity of the microbiota is associated with more severe GVHD.

Other studies have shown that fecal microbial transplantation (FMT) can be effective in reducing GVHD, but the challenge is how to get the right donor. Patients become highly immunodeficient after bone marrow transplantation and there is a high risk of serious infection if FMT is used in humans.

Yu’s laboratory used two different strains of mice to establish a model of GVHD that closely resembles the biology that occurs in humans after bone marrow transplantation. The mice developed acute GVHD. FMT significantly reduced acute GVHD in this model and reduced the proliferation of donor T cells in the organs, which is what triggers GVHD.

The researchers then used genetic sequencing to see which strains of bacteria were most different between the fecal material of GVHD mice that received FMT and those that did not receive FMT.

The mice that had the best result, the lowest GVHD, had the highest levels of a bacterium called B. fragilis. Mice that received this single bacterial strain significantly reduced acute and chronic (long-term) GVHD compared to mice that did not contract B. fragilis. In fact, B. fragilis alone was as good or even better than FMT.

Administration of B. fragilis increased the overall microbial diversity of the intestine, including an increase in the amount of other strains of beneficial bacteria. Surprisingly, GVHD was reduced in this model not only by live bacteria, but also by bacteria that were killed by short exposure to high temperatures.

The observation that B. fragilis was the main bacterium effective in the FMT process was not entirely new: B. fragilis also reduces autoimmunity in type 1 diabetes and colitis.

The current study by Yu and colleagues has two important findings. First, a molecule called polysaccharide A on the surface of B. fragilis appears to be critical to the GVHD-reducing functions of this bacterium. When the bacteria was modified to lack polysaccharide A, GVHD was not reduced compared to mice that did not receive any B. fragilis.

Second, the administration of B. fragilis did not reduce the graft effect against leukemia or the elimination of cancer from bone marrow transplantation, although it did reduce the expansion of donor T cells in the intestine. This is critical, since GVHD treatment options that reduce the graft-against-leukemia effect would not be clinically significant.

“If this can be translated in the clinic, it would be a safer, easier and more effective treatment option,” said Yu.

Further human studies are needed to bring this potential treatment to the clinic. Hematopoietic stem cells, administered via bone marrow transplantation, are classic immunotherapies for liquid tumors, but strategies to make the transplant safer and more beneficial are extremely necessary. Hollings Cancer Center researchers continue to seek the most effective therapies to improve patients’ outcomes and quality of life, he said.

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Founded in 1824 in Charleston, MUSC is the oldest medical school in the South, as well as the only integrated health science academic center with the sole responsibility of serving the state through education, research and patient care. Each year, MUSC educates and trains more than 3,000 students and about 800 residents in six faculties: Dentistry, Graduate Studies, Health Professions, Medicine, Nursing and Pharmacy. The state’s leader in obtaining funds for biomedical research, in fiscal 2019, MUSC set a new record, raising more than $ 284 million. For information on academic programs, visit musc.edu.

Like the medical health system at the Medical University of South Carolina, MUSC Health is dedicated to providing high quality patient care that is available, while training generations of competent and compassionate healthcare providers to serve the people of South Carolina. South and beyond. Comprised of nearly 1,600 beds, over 100 extension sites, MUSC College of Medicine, the doctors’ practice plan and nearly 275 telehealth locations, MUSC Health owns and operates eight hospitals located in Charleston, Chester, Florence counties , Lancaster and Marion. In 2019, for the fifth consecutive year, the US News & World Report named MUSC Health the number one hospital in South Carolina. To learn more about clinical patient services, visit muschealth.org.

MUSC and its affiliates have collective annual budgets of $ 3.2 billion. The more than 17,000 members of the MUSC team include professors, doctors, specialist suppliers and world-class scientists who offer innovative education, research, technology and patient care.

The MUSC Hollings Cancer Center is a cancer center designated by the National Cancer Institute and the largest academic cancer research program in South Carolina. The cancer center comprises more than 100 faculty scientists and 20 academic departments. He has an annual research funding portfolio of more than $ 44 million and a dedication to reducing the burden of cancer in South Carolina. Hollings offers state-of-the-art diagnostic resources, therapies and surgical techniques in multidisciplinary clinics that include surgeons, oncologists, radiotherapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer treatment, including more than 200 clinical tests. For more information, visit hollingscancercenter.musc.edu.