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Researchers Explore How to Protect Gut Integrity to Improve Outcomes in Blood Cancers

AHA Publisher — Fri, 12 Feb 2021 08:00:23 +0000

Medical University of South Carolina via EurekAlert – MUSC Hollings Cancer Center researchers 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 transplant can be a lifesaving procedure for patients with blood cancers. However, GVHD is a potentially fatal side effect of transplantation, and it 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, M.D., associate director of Basic Science at 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 figure out how to keep a patient’s intestinal tissue healthy before and after bone marrow transplant, then the patient’s outcome will be much better. We know that restoring the microbiota diversity in the gut is an effective solution, but that comes with many challenges,” said Yu. Patients with blood cancers, such as leukemia, must undergo radiation and chemotherapy before they can get their new cancer-free immune system through bone marrow transplantation. The balance between the immune system and intestinal microbiota, communities of microorganisms that live in the gut, is especially important for proper intestinal health. Unfortunately, the radiation and chemotherapy radically throw off this balance, and the diversity of the microbiota is reduced 100- or even 1,000-fold. This leads to a condition called “leaky gut.” Clinical studies have shown that patients who recover microbiota diversity faster have better outcomes and less severe GVHD. Reduced microbiota diversity is associated with more severe GVHD. Other studies have shown that fecal microbial transplantation (FMT) can be effective at reducing GVHD, but the challenge is how to get the right donor. Patients are heavily immune-deficient after bone marrow transplantation, and there is a great risk of bad infection if FMT is used in humans. The Yu laboratory used two different strains of mice to establish a GVHD model 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 donor T cell proliferation in the organs, which is what triggers GVHD. The researchers then used genetic sequencing to see which bacteria strains were most different between the fecal material of GVHD mice that received FMT and those that did not receive FMT. Mice that had the best outcome, the lowest GVHD, had the highest levels of a bacteria called B. fragilis. Mice given this single bacterial strain had significantly reduced acute and chronic (long-term) GVHD compared to mice that did not get B. fragilis. In fact, B. fragilis alone was as good or even better than FMT. Administration of B. fragilis increased overall gut microbial diversity, including increasing the amount of other beneficial bacteria strains. Surprisingly, GVHD was reduced in this model not only by live bacteria but also by bacteria that had been killed by short exposure to high heat. The observation that B. fragilis was the main effective bacteria 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 for the GVHD-reducing functions of this bacteria. When the bacteria were modified to lack polysaccharide A, GVHD was not reduced compared to mice that did not receive any B. fragilis. Secondly, the administration of B. fragilis did not reduce the graft-versus-leukemia or cancer-killing effect of the bone marrow transplantation, even though it did reduce donor T cell expansion in the gut. This is critical, since GVHD treatment options that reduce the graft-versus-leukemia effect would not be clinically significant. “If this can be translated into the clinic, it would be a safer, easier and more effective treatment option,” said Yu. Further study in humans is needed to get this potential treatment into the clinic. Hematopoietic stem cells, given via bone marrow transplant, are classic immunotherapies for liquid tumors, but strategies to make the transplantation safer and more beneficial are sorely needed. Hollings Cancer Center researchers continue to search for the most effective therapies to improve patient outcomes and quality of life, he said. To read the original article click here.

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Heat and Gut Microbiota Promote Stronger Bones

AHA Publisher — Tue, 15 Sep 2020 07:00:01 +0000

University of Geneva via News-Medical Net – Osteoporosis, a bone disease linked to ageing, is characterized by a loss of bone density, micro-architectural deterioration of the bones and an increased risk of fractures. With one third of postmenopausal women affected, it is a major public health problem. Through epidemiological analyses, laboratory experiments and state-of-the-art metagenomic and metabolomics tools, a research team from the University of Geneva (UNIGE), in Switzerland, has observed that exposure to warmer ambient temperatures (34 °C) increases bone strength, while preventing the loss of bone density typical of osteoporosis. Moreover, this phenomenon, linked to a change in the composition of gut microbiota triggered by heat, could be replicated by transplanting the microbiota of mice living in a warm environment to mice suffering from osteoporosis. Indeed, after the transplant, their bones were stronger and denser. These results, to be discovered in Cell Metabolism, make it possible to imagine effective and innovative interventions for prevention and treatment of osteoporosis. Many biologists are familiar with Allen’s Rule, from 19th-century naturalist Joel Asaph Allen, according to which animals living in warm areas have a larger surface area in relation to their volume than animals living in colder environment. Indeed, a larger skin surface allows better evacuation of body heat. “In one experiment, we placed newborn mice at a temperature of 34 °C in order to minimise the heat shock associated with their birth. We found that they had longer and stronger bones, confirming that bone growth is affected by ambient temperature,” explains Mirko Trajkovski, Professor at the Department of Cell Physiology and Metabolism and at the Diabetes Centre of the UNIGE Faculty of Medicine, who led the study. But what about adulthood? Consistent Epidemiological Data By placing several groups of adult mice in a warm environment, the scientists observed that while bone size remained unchanged, bone strength and density were largely improved. They then repeated their experiment with mice after an ovariectomy modelling post-menauposal osteoporosis. “The effect was very interesting. The simple fact of warming the living environment of our mice protected them from the bone loss typical of osteoporosis!” (Claire Chevalier, Study First Author and Researcher in Professor Trajkovski’s Laboratory) What about human beings? The research team analysed global epidemiological data on the incidence of osteoporosis in relation to the average temperature, latitude, calcium consumption and vitamin D levels. Interestingly, they found that the higher the temperature, the fewer hip fractures –one of the main consequences of osteoporosis– regardless of other factors. “We found a clear correlation between geographical latitude and hip fractures, meaning that in the northern countries the incidence is higher compared to the warmer south”, says Mirko Trajkovski. “Normalising the analysis of the known players such as vitamin D or calcium did not modify this correlation. However, when we excluded the temperature as the determinant, the correlation was lost. This is not to say that calcium or vitamin D do not play a role, either alone or in combination. However, the determining factor is heat -or lack thereof.” How the Microbiota Adapts Specialists in the microbiota, the Geneva scientists wanted to understand its role in these metabolic modifications. To this end, they transplanted the microbiota of mice living in a 34° environment to osteoporotic mice, whose bone quality was rapidly improved. “These findings may imply an extension to Allen’s rule, suggesting elongation-independent effects of the warmth, which predominantly favours bone density and strength during adulthood through microbiota alterations”, says Mirko Trajkovski. Thanks to the state-of-the-art metagenomic tools developed in their laboratory, the scientists then succeeded in understanding the role played by microbiota. When adapts to heat, it leads to a disruption in the synthesis and degradation of polyamines, molecules that are involved in ageing, and in particular in bone health. “With heat, the synthesis of polyamines increases, while their degradation is reduced. They thus affect the activity of osteoblasts (the cells that build bones) and reduce the number of osteoclasts (the cells that degrade bones). With age and menopause, the exquisite balance between the osteoclast and osteoblast activity is disrupted,” explains Claire Chevalier. “However, heat, by acting on the polyamines, which we found to be partly regulated by the microbiota, can maintain the balance between these two cell groups.” These data therefore indicate that exposure to warmth could be a prevention strategy against osteoporosis. Developing New Treatments The influence of microbiota on metabolism is being better understood. However, in order to be able to use this knowledge to develop therapeutic strategies, scientists must identify precisely the role of particular bacteria in particular diseases. In the context of their work on osteoporosis, Professor Trajkovski’s team has been able to identify certain important bacteria. “We still need to refine our analyses, but our relatively short-term goal would be to identify candidate bacteria, and develop several ‘bacterial cocktails’ to treat metabolic and bone disorders, such as osteoporosis, but also to improve insulin sensitivity, for example,” the authors conclude. To read the original article click here.

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