Host Tissue T Cells May Have an Unexpected Role in Graft-Versus-Host Disease
Results could someday change therapy for hematopoietic stem cell transplant patients and prevent progression of the disease
Allogenic hematopoietic stem cell transplantation (HSCT) is a procedure that infuses a donor’s healthy blood-forming stem cells into a recipient as part of a potentially curative therapy for cancer. While this therapy can be life-saving, a major complication is the development of graft-versus-host disease (GVHD), which causes significant morbidity and can be fatal. Before allogenic HSCT, a patient receives a conditioning regimen, chemotherapy designed to deplete his/her normal white blood cells, including T cells. But a new study by investigators from Brigham and Women’s Hospital, University of Oslo (Norway) and University of Newcastle (UK) has found that skin and intestinal T cells in the recipient survive conditioning regimens and continue to perform their normal functions. But, under certain conditions, these T cells can become activated by donor white blood cells and play a previously unappreciated role in acute GVHD. The investigators’ results are published in The Journal of Clinical Investigation.
“In all the years that GVHD has been studied, it has been an article of faith that graft T cells mediate the disease and attack the body,” said Thomas Kupper, MD, chair of the Department of Dermatology at the Brigham. “We discovered in skin and gastrointestinal tract that the T cells that cause GVHD are also from the host — that is, the patient’s own T cells. These durable T cells from the host become activated by cells from the graft, thus causing tissue injury. This completely novel finding was unexpected and opens the door to new approaches to treatment and prevention.”
Conditioning regimens are meant to deplete the host of normal white blood cells, including T cells, in order to make room for the new immune system that will develop from the graft. When recipient blood has been examined after conditioning, T cells are difficult to detect. But Kupper and colleagues found that while the recipients blood T cells were depleted, their tissue T cells in the skin and gut were not. The researchers used high throughput DNA sequencing of T cells and “short tandem repeat”/STR analysis, which together determines the proportion of blood (or tissue) cells that derive from the donor (graft) or the recipient (host), respectively. They further studied male-female host/donor mismatch transplants, using XY sex chromosomes to determine the origin of the cells. The team also used mouse models, grafting human skin onto immunocompromised mice to avoid rejection and test the ability of host skin T cells to mediate GVHD without donor T cells.
Based on the high throughput sequencing and STR analysis, the team saw that there were still abundant host T cells present in the skin and small intestine during GVHD, even when blood cells were 100% of donor origin. The mouse models demonstrated that skin-resident host T cells could be activated by donor non-T cell white blood cells to generate GVHD-like skin inflammation. The results indicate that unexpectedly, skin- and intestinal-resident T cells not only survive conditioning regimens, but are present in tissues during acute GVHD and very likely play an important role in the pathphysiology of this disease.
“Our new understanding of GVHD allows us to think about tissue resident memory T cells in the host/recipient as a new target for therapy, which is potentially game changing,” said Kupper. “Hypothetically, we could use this information to intervene earlier and perhaps even prevent the emergence of GVHD. This study is an example of how we must never assume we know everything about disease mechanism and must always be willing to challenge prevailing paradigms if that’s where the data leads.”
Funding for this work was provided by the NIH (DP5OD023091 to Sherrie Divito; T32AR007098, R01AR065807 and R01AI127654 to Thomas Kupper; R01CA203721 and P30AR069625 to Rachael Clark). Divito received the Dermatology Foundation Physician-Scientist Career Development Award. Frode Jahnsen received a PhD grant from the South Eastern Norway Regional Health Authority. The project was also supported by the Research Council of Norway through its Centers of Excellence funding scheme (project number 179573/V40 to FLJ).
Paper cited: Divito, S. et al. “Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease” J Clin DOI: https://doi.org/10.1172/JCI129965
Researchers Pursue ‘Hidden Pathology’ to Explain Fatigue in Multiple Sclerosis
Imaging reveals new insight into a debilitating symptom and opens new avenues for further diagnostic and therapeutic research
Up to 60 percent of patients with multiple sclerosis (MS) report that fatigue is the disease’s most debilitating symptom. And yet, fatigue remains one of MS’s mysteries — despite its prevalence and significance, the root cause of the symptom remains unclear. In a study published in Neurology: Neuroimmunology & Neuroinflammation, investigators from Brigham and Women’s Hospital used positron emission technology (PET) imaging to look for brain’s immune cells that may become erroneously activated in MS, leading to fatigue. The team describes a potential link to brain inflammation that may help explain the connection between MS and fatigue.
“Fatigue correlates poorly with the conventional markers of multiple sclerosis — the brain lesions we see using magnetic resonance imaging (MRI) don’t associate well with fatigue,” said corresponding author Tarun Singhal, MD, a neurologist and nuclear medicine physician in the Department of Neurology and director of the PET Imaging Program in Neurologic Diseases at the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital. “So we went searching for a hidden pathology; something that has gone undetected until now in the context of fatigue in MS.”
Singhal and colleagues used a second-generation radioligand known as [F-18]PBR06 to conduct PET imaging. Singhal describes this tracer as a “radiolabel detective” that can snoop for clues. Once injected, the tracer travels to the brain, binds to abnormally activated immune cells called microglia (and to some extent, additionally, to other immune and support cells called astrocytes) and emits gamma rays that can be picked up by a scanner.
The team performed PET scans on 12 MS patients and 10 healthy controls, finding strong correlations between MS patients’ self-reported fatigue risk scores and activation of immune cells in very specific regions of the brain. These regions included the substantia nigra — which translates literally to “the dark substance.” The substantia nigra is the site where dopamine is produced (dopaminergic neurons appear darker on pathology, giving the region its name). Dopamine plays many roles in the body and is required for stimulating attention and wakefulness patterns in the brain. Several additional areas of the brain also correlated significantly with fatigue scores, but there was no association between fatigue scores and brain atrophy and lesion load in MS patients.
The researchers note that given the study’s small sample size, additional study is needed to validate their findings.
“We detected a widespread network of very specific regions whose inflammation correlates with fatigue scores and all have implications for contributions to fatigue,” said Singhal. “We are now pursuing further study to confirm our findings in a larger sample size and are looking at interactions between neurochemistry and neuroinflammation.”
Funding for this work was provided by the Nancy Davis Foundation’s ‘Race to Erase MS’ program, Ann Romney Center for Neurologic Diseases, Harvard NeuroDiscovery Center, and Water Cove Charitable Foundation.
Paper cited: Singhal T et al. “Regional Microglial Activation in Substantia Nigra is linked with Fatigue in Multiple Sclerosis” Neurol Neuroimmunol Neuroninflamm DOI: 10.1212/NXI.0000000000000854
Gastrointestinal Innovation Holds Potential for Treating Variety of Conditions
- Newly developed synthetic lining could deliver drugs in a sustained way to the small intestine
- Proof-of-concept studies in models of lactose intolerance, diabetes and infectious disease demonstrate potential applications
Investigators from Brigham and Women’s Hospital and the Massachusetts Institute of Technology are working on an innovative way of sustainably delivering drugs and influencing nutrient absorption in the gut. The gastrointestinal synthetic epithelial lining (GSEL) system is designed to coat the small intestine, an organ that plays a key role in drug and nutrient absorption. The team has demonstrated the GSEL system’s ability to adhere to segments of the gastrointestinal tract from pigs and humans, and, in porcine models, has reported potential applications for the system in treating a variety of conditions, ranging from lactose intolerance to diabetes and obesity to tropical diseases such as schistosomiasis. Results of the team’s proof-of-concept studies are published in Science Translational Medicine.
“The small intestine is an amazing organ — it’s the main site of drug and nutrient absorption and digestion and plays an important role as a barrier. We recognized its potential: If we could specifically target this location, it would open up new avenues for drug delivery and nutritional modulation,” said corresponding author C. Giovanni Traverso, MB, BChir, PhD, a gastroenterologist and biomedical engineer in the Division of Gastroenterology at the Brigham. “The system we’ve developed has the potential to treat and manage a variety of diseases.”
“We found that enzymes in the digestive tract can help synthesize polymers in the small intestine,” said first author Junwei Li, who will become a research fellow at the Brigham this fall. “We anticipate broad adoption of this in-situ biomaterial generation idea for various applications.”
The GSEL system combines two nature-inspired innovations. The first takes advantage of a chemical reaction triggered by catalase, an enzyme that helps break down hydrogen peroxide into oxygen in the small intestine. The second is a mussel-inspired tissue adhesive, similar to what mollusks use to attach themselves to rocks. Using these two concepts, Traverso, Li and colleagues designed a synthetic gut lining that can target the small intestine. Their goal is to develop a capsule, pill or gel that could be ingested, but for now, the team has tested administering the GSEL system endoscopically — that is, directly inserting it into the small intestine.
To test the lining’s therapeutic potential, the team looked at pig models for testing lactose intolerance, glucose absorption and the delivery of praziquantel, a drug for treating schistosomiasis. The team found evidence that the lining could deliver the drug in a sustained way, potentially reducing treatment to a once-a-day dose instead of three time a day. It also improved lactose digestion and regulated glucose absorption, indicating its potential for treating type 2 diabetes and preventing obesity.
In order to move from pig models into human trials, several hurdles remain, including further developing the GSEL system into an ingestible form. For now, Traverso, Li and colleagues are focused on continuing to evaluate safety in preclinical studies.
“For our studies, safety is a key focus of our work,” said Traverso. “There are indications that this system can help patients suffering from many diseases, but before we can translate this technology for humans, we need to fully validate its safety and the effects of chronic use.”
This work was supported by the Bill and Melinda Gates Foundation grants (OPP1179091), the NIH (EB000244) and funds from the Department of Mechanical Engineering, MIT. Traverso and co-authors declare submission of provisional patent applications describing the materials and applications of GSELs described here. Complete details of all relationships for profit and not for profit for Traverso can be found at the following link: www.dropbox.com/sh/szi7vnr4a2ajb56/AABs5N5i0q9AfT1IqIJAE-T5a?dl=0.
Paper cited: Li J et al. “Gastrointestinal synthetic epithelial linings” Science Translational Medicine DOI: 10.1126/scitranslmed.eabc0441
Black Children with Cancer Three Times Less Likely to Receive Proton Radiotherapy Than White Children
Retrospective analysis highlights racial disparities that exist in clinical trials for a cancer therapy that may reduce long-term adverse effects
A deep concern among pediatric oncologists has been confirmed by the data: Black children enrolled in national clinical trials have been found to be three times less likely to receive proton radiotherapy than their white counterparts. Previous studies have shown that proton radiotherapy is equally effective at treating cancer and may decrease the incidence of long-term side effects in children compared to other forms of radiation therapy. But a retrospective analysis led by investigators from Brigham and Women’s Hospital has found racial disparities in the use of the therapy for patients enrolled in trials. Results are published in JAMA Oncology.
“We were motivated to carry out this investigation based on our anecdotal experiences in clinic that children who receive proton therapy are predominantly white,” said corresponding author Daphne Haas-Kogan, MD, chair of the Department of Radiation Oncology at the Brigham. “The strongest evidence for proton therapy is in childhood cancer, and we were concerned that imbalances in who receives this treatment could translate to long-term health disparities in our patients. This question was particularly urgent to us because of the rapidly growing number of proton centers in the country, which could potentiate any existing disparities if there is imbalanced distribution and use of these expensive technologies.”
“We found that even when we think we are treating patients in as standard a way as possible, we may not be offering the same access to advancements in treatment,” said lead author Danielle Bitterman, MD, a resident in the Department of Radiation Oncology at the Brigham. “These results call for introspection and to proactively address barriers to access to make sure patients who most need proton therapy are prioritized based on medical need so that these treatments are distributed equitably and fairly.”
Proton radiotherapy is a high-cost, limited resource but may offer increased quality of life for pediatric patients compared to standard photon therapy. Cancer centers that offer proton radiotherapy are concentrated in metropolitan areas and may require travel or even relocation for families seeking treatment.
Most children with cancer enroll in clinical trials. To assess access to proton radiotherapy, Haas-Kogan, Bitterman and colleagues analyzed data from children enrolled in the Children’s Oncology Group prospective trials between 2010 and 2018. They found that among 1,240 patients, approximately 85 percent received photon therapy and 15 percent received proton therapy.
Black pediatric patients were less likely to receive proton therapy than non-Hispanic white patients. While the study is retrospective and could not account for all confounding variables, the team did adjust for many confounders, including distance to the cancer center, metastatic disease and more. Even with these adjustments, Black patients remained less likely to receive proton therapy.
The study did not assess survival or patient side effect outcomes and cannot make conclusions about the clinical effect of the imbalance in proton treatment on patients. However, the findings suggest that Black children with solid cancers may be at higher risk for more side effects, some of which may be severe and lifelong.
“Future research should drill down on whether and how geography contributes to disparities, as this could guide more ethical distribution of high cost technologies,” said Haas-Kogan. “And, perhaps most importantly, health care provider bias and racism may influence referral and treatment patterns for high cost medical treatments. This needs to be measured, recognized, and addressed in order to narrow the glaring health care disparities in our country.”
The data were obtained from the Children’s Oncology Group, which is supported by the NCTN Operations Center Grant U10CA180886 and NCTN Statistics & Data Center Grant U10CA180899 and IROC Grant U24A180803. Bitterman reported personal fees from Agios Pharmaceuticals outside of the submitted work.
Paper cited: Bitterman DS et al. “Race Disparities in Proton Radiotherapy Use for Cancer Treatment in Patients Enrolled in Children’s Oncology Group Trials” JAMA Oncology DOI: 10.1001/jamaoncol.2020.2259
Potential Link Found Between Alzheimer’s Disease and Common Brain Disease that Mimics its Symptoms
Conducting genetic screening in hundreds of autopsied brain samples, investigators identified shared molecular mechanisms in Alzheimer’s disease and LATE, a common brain disorder
Alzheimer’s disease is one of the most common causes of dementia, and while most people might know someone who is affected by it, the genetic factors behind the disease are less known. A new study by investigators from Brigham and Women’s Hospital uncovered a group of closely related genes that may capture molecular links between Alzheimer’s disease and Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE, a recently recognized common brain disorder that can mimic Alzheimer’s symptoms. LATE is often combined with Alzheimer’s disease to cause a more rapid cognitive decline. The study’s results are published in Neuron.
“Genetic variants that regulate other genes’ expressions are thought to play an important role in human disease, but genome-wide discovery of these variants has been difficult given the large numbers of genes and genetic variants that have to be tested,” said Philip De Jager, MD, PhD, formerly of the Brigham. De Jager is now the chief of the Division of Neuroimmunology at Columbia University and senior author of the study. “We decided to leverage a previously developed data-driven approach to group closely correlated genes together into gene modules so that we can focus on the expression of 47 gene modules, rather than targeting more than 13,000 individual brain-expressed genes.”
Gene expression is the process in which the information encoded in a gene is used to assemble a protein. The investigators conducted a genome-wide screen of genetic variants that regulate gene expression using 494 autopsied brain samples from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), community-based clinical-pathologic studies of aging and Alzheimer’s disease. They observed that two genes, named TMEM106B and RBFOX1, regulate gene expression in the aging brain. The research team replicated their finding in an independent dataset from the Mayo RNAseq study, and analyzed clinical, autopsy, and genetic data to connect their findings with brain diseases that cause dementia.
The authors note that the study mainly analyzed people whose average age was close to 90 at their time of death and brain donation. Therefore, the study results should be interpreted cautiously outside of this context, and further studies are required to investigate whether their findings could be extended to other TDP-43 related conditions that affect younger patients, such as frontotemporal dementia and amyotrophic lateral sclerosis.
The research team also found that amyloid-β accumulation, a hallmark of Alzheimer’s disease, and the TMEM106B risk variant both increased the expression of the same set of genes that are important in the function of lysosome, a cell compartment specializing in cellular waste removal. In turn, the increased expression of lysosomal genes correlated with LATE neuropathological change in human brain.
“It is becoming increasingly apparent that the frequent coexistence of Alzheimer’s disease and LATE is not a coincidence,” said Hyun-Sik Yang, MD, of the Division of Cognitive and Behavioral Neurology at the Brigham, who is the first author of the study. “We should further investigate the shared molecular links between Alzheimer’s and LATE, so that one day we can treat and even prevent two of the most common causes of dementia in our rapidly aging population.”
Funding for this work was provided by the National Institute on Aging and Alzheimer’s Association.
Paper cited: Yang, HS et al. “Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology” Neuron DOI: https://doi.org/10.1016/j.neuron.2020.05.010
Casting a Wider Net to Catch More Cases of Pulmonary Hypertension
- Using information from a national database, investigators took an evidence-based approach to defining the lower limit of pulmonary vascular resistance
- This new lower parameter can capture more patients who have pulmonary hypertension and are at risk for death or hospitalization
When most people think of high blood pressure, they think of being tested with an arm cuff at a doctor’s appointment. That type of blood pressure is separate from pulmonary hypertension (PH), which is high blood pressure in the lung arteries. In a study published today in The Lancet Respiratory Medicine, investigators from Brigham and Women’s Hospital took an evidence-based approach to determine the lower end of the risk spectrum for PH based on pulmonary vascular resistance (PVR), which is resistance against blood flow from the pulmonary artery to the lungs. The team presents evidence that by redefining the lower risk level for PVR, 60 percent more patients who are at risk for death due to PH can be diagnosed.
“The findings of this study cast the clinical profile of patients who have PH and are at risk for major clinical events into a new and wider light,” said corresponding author Bradley Maron, MD, an associate physician in the Division of Cardiovascular Medicine at the Brigham. “We can use this information to raise awareness among clinicians on those patients that may need reconsideration for risk factor modification, conventional treatment, and potential clinical trial enrollment.”
PH affects 70 million people worldwide across a broad age, geographic and socioeconomic spectrum. Left untreated, average survival is 2 to 3 years after diagnosis. PH can cause serious problems because changes in blood pressure in the lung arteries are not tolerated well by the heart and can lead to hospitalization, heart failure and death. Despite being a grave condition, the way PH was defined in clinical practice previously was not evidence-based and did not account for physiological changes in blood pressure, such as may occur due to circumstances that are immediately reversible. Although PVR was already considered important in the prognosis of PH, the actual range of PVR that is informative of PH was not known.
The researchers analyzed the association of PVR and mortality using the Veterans Association (VA) national database, which includes comprehensive information on patients’ medical histories and clinical events. The researchers acknowledge the limitations to working with a national population relative to errors in measurements. Also, the VA population is almost entirely male, so the team validated the findings in a sex-balanced cohort at Vanderbilt University Medical Center to account for both men and women. The data analysis did account for comorbidities but was not positioned to distinguish between the different stages of diseases that could affect outcome, such as the degree of lung disease in individual patients.
The results indicated that starting at a PVR of around 2.2 Wood Units (a standard unit of measurement for PVR), there is an increase in association with mortality among patients with increased pulmonary artery pressure. This 2.2 level is well below what is currently associated with the disease in clinical practice. The new, lower threshold expands the range of patients who are considered to have PH and optimizes the specificity of PH criteria used clinically.
“Pulmonary hypertension is often overlooked in clinical practice, but this study provides a specific context for clinicians and health care workers to understand the range of risk for a large group of patients,” said Maron. “We have established an evidence-based way to recognize patients with PH who would have otherwise been considered to be normal, but, in fact, have a concerning profile.”
From here, the team is interested in looking at populations that were not included in this study, including patients with less common forms of PH or PH that exists in the absence of heart and lung disease.
Funding for this work was provided by NIH grants (R56HL131787, R01HL139613-01, R01HL153502, R21HL14542) to Bradley Maron, who also received support from National Scleroderma Foundation, Cardiovascular Medical Research Education Foundation, and McKenzie Family Charitable Trust. Evan Brittain received funding from NIH grants (R01 HL146588, R01 HL146588-01S1). Bradley Wertheim received salary support to conduct research from NIH grant 5T32HL007633-32. George Alba received support from NIH grant 5KL2TR002542-02. Gourav Choudhary received salary support from the Department of Veterans Affairs MERIT award I01CX001892, NIH/NHLBI R01HL128661 and R01HL148727.
Paper cited: Maron, B. et al. “The Association Between Pulmonary Vascular Resistance and Clinical Outcomes in Patients with Pulmonary Hypertension: A Retrospective Cohort Study” The Lancet Respiratory Medicine DOI: 10.1016/S2213-2600(20)30317-9
Gender Gaps in Surgical Specialties May Take Decades to Close
In specialties such as neurosurgery and orthopaedic surgery, analysis of national data finds little progress made in equal representation for women
Women compose half of the entering classes of medical students, yet they are underrepresented in many of the largest surgical specialties. While some efforts are underway to recruit more women into surgical specialties, little information has been available on the rate at which the gender gap is closing. A new study led by investigators from Brigham and Women’s Hospital analyzed national data available through the National Graduate Medical Education Census to determine how rates of women in surgical specialties have changed over the last 11 years and use that to project how they might change in the future. In JAMA Surgery, the team reports that, among the largest resident specialties in the U.S., little progress has been made, with most of the largest residencies demonstrating a less than 1 percent increase in women trainees per year. For many specialties, including neurosurgery and orthopaedic surgery, it will take decades to reach equal female representation if progress continues at the current pace.
“This paper shows that not all fields are created equal,” said co-senior author Erika Rangel, MD, MS, a surgeon and researcher in the Division of Trauma, Burn and Surgical Critical Care. “Some fields are reaching parity or have surpassed it, but many are lagging behind.”
The research team analyzed publicly available, deidentified, aggregate data from 2007 to 2018 and looked across 20 specialties with the most residents. Of the 20 programs, women were underrepresented in 13. Specialties with the lowest representation included otolaryngology, plastic surgery, urology, orthopaedic surgery and neurosurgery. The researchers then estimated how long it would take to reach gender parity at the current rate of change. They found that for orthopaedic surgery, for instance, it would require more than 100 years for female residents to be equitably represented in the specialty.
“Using the rate of change that we saw in those specialties, we did further analyses to create projections to see how long it would take the specialties with the least representation to reach levels of female representation seen among all residents overall and then that of the US population,” said corresponding author Christopher L. Bennett, MD, MA, a former resident in the Brigham and Women’s/Massachusetts General Hospital Harvard Affiliated Emergency Medicine Residency.
The authors describe several strategies that could help to improve female student recruitment to specialties. These include recognizing and rewarding mentorship; early outreach to medical students; and implicit bias training.
“At the current pace, gender parity among many surgical specialties is still decades away,” the authors write. “These data call for concerted efforts to increase the pipeline for female surgical residents.”
Funding for this work was provided by the Brigham’s Department of Emergency Medicine.
Paper cited: Bennett CL et al. “The Gender Gap in Surgical Residencies” Journal DOI: 10.1001/jamasurg.2020.2171
Insights on the Gut Microbiome Could Shape More Powerful, Precise Treatment
- Using real-world data and predictive models, investigators identify key factors that determine success of fecal microbiota transplantation
- Framework also provides an algorithm for designing a personalized probiotic cocktail to decolonize harmful bacteria in the gut
We may not think about it often, but our gut is home to a complex ecosystem of microorganisms that play a critical role in how we function. The system is delicate — one small change can cause a major shift in the microbiome, resulting in serious consequences. When a person takes an antibiotic, it can wipe out multiple bacterial species and throw this delicate balance off-kilter. Clostridioides difficile is a common pathogen that colonizes a disrupted gut microbiota. Fecal microbiota transplantation (FMT), in which stool from a healthy donor is transplanted into the colon of a recipient, is a successful treatment for recurrent C. difficile infection (rCDI). In a recently published study, investigators from Brigham and Women’s Hospital explore how the dynamics of bacterial species may influence the success of FMT in treating rCDI. In Nature Communications, the team presents an algorithm to design personalized probiotic cocktails for patients with unhealthy gut microbiomes due to rCDI.
“Designing a probiotic cocktail is challenging,” said Yang-Yu Liu, PhD, an assistant professor in the Department of Medicine at the Brigham. “All of the species in the cocktail interact within a complicated network. When we look at one species that directly inhibits the growth of C. difficile, we must also make sure that it does not indirectly promote growth of C. difficile through interactions with other species in the cocktail.”
C. difficile is transmitted through the fecal-oral route — poor hygiene or the contamination of food or water supply — and is found all over the world. Although C. difficile will not typically colonize a healthy colon, it can grow unchecked in a gut that has been disrupted due to antibiotics. rCDI is not responsive to standard antibiotics and therefore can recur in patients, increasing the risk each time. FMT has been shown to cure about 80 percent of rCDI cases that did not respond to antibiotics.
The researchers began by modeling a microbial community and simulating the FMT process of treating rCDI. Next, they estimated how effective FMT would be at restoring the recipient’s healthy gut microbiota. The team then analyzed real-world data from a mouse model and from human patients to validate the modeling.
The theoretical model helped the team predict what factors determine the efficacy of FMT. They learned that FMT efficacy decreases as the species diversity of the infected person’s gut microbiome increases. The team also developed an optimization algorithm to design a personalized probiotic cocktail to help individuals with rCDI. The algorithm is based on ecological theory that designs a cocktail with the minimum number of bacterial species, while keeping the complicated ecological network of the species in mind. The personalized probiotic cocktails contain species that are effective inhibitors of C. difficile and can be administered to patients with rCDI in order to restore their gut microbiota.
“We now have an ecological understanding of FMT — why it works and why it sometimes fails for rCDI,” said Liu. “We can move forward to better understand the efficacy of FMT and how we can use it to treat other diseases associated with disrupted microbiota, such as IBD, autism and obesity.”
Funding for this work was provided by grants from the National Institutes of Health (R01AI141529, R01HD093761, UH3OD023268, U19AI095219, and U01HL089856) to Yang-Yu Liu and Scott Weiss. Yangdong Xiao received support from China Scholarship Council and Natural Science Foundation of China (grant no. 61902418). Marco Tulio Angulo received support from CONACyT project A1-S-13909, México.
Paper cited: Xiao, Y. et al. “An ecological framework to understand the efficacy of fecal microbiota transplantation” Nat Communication DOI: https://doi.org/10.1038/s41467-020-17180-x
Researchers propose novel approach to limit organ damage, improve outcomes for patients with severe COVID-19
Patients with severe COVID-19 frequently experience a life-threatening immune reaction, sometimes called a cytokine storm, which can lead to respiratory failure, organ damage and potentially death. With no FDA-approved treatment currently available for SARS-CoV-2, the virus that causes COVID-19, researchers are racing to find ways to stop the virus or the inflammatory overreaction it provokes in its tracks.
In a paper published in Cancer and Metastasis Reviews and selected by the journal as the featured publication, a team of researchers from Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital propose that controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral and other therapies.
Led by Dipak Panigrahy, MD, of the Cancer Center at BIDMC, and Charles N. Serhan, PhD, DSc, director of the Center of Experimental Therapeutics and a member of the Department of Anesthesiology, Perioperative and Pain Medicine at Brigham and Women’s Hospital, the researchers suggest that a family of molecules naturally produced by the human body may be harnessed to resolve inflammation in patients with severe COVID-19, thereby reducing the acute respiratory distress and other life-threatening complications associated with the viral infection.
“Controlling the body’s inflammatory response is key to the management of COVID-19 and may be as important to managing the pandemic as anti-viral therapies or a vaccine,” Panigrahy said. “Our team proposes using molecules made by the body called pro-resolution lipid mediators — which are currently in clinical trials for other inflammatory diseases — as a novel approach to turning off the inflammation and preventing the cytokine storm caused by COVID-19.”
Cytokines are released by the body as part of its normal immune response to injured or infected tissues. Typically, the body also releases chemicals to put an end to — or resolve — the inflammatory response. But in a significant percentage of patients with severe COVID-19, the cytokines unleashed to kill the virus also do damage to infected lung cells. In turn, this injury to the lung tissues triggers additional inflammation, and the so-called “cytokine storm” begins to spiral out of control.
Naturally occurring molecules called resolvins — discovered by Serhan and colleagues at BWH in 2002 — actively turn off inflammation. Panigrahy, Serhan and colleagues have previously demonstrated that resolvins and related pro-resolution molecules could play a role in preventing cancer metastasis and progression. This class of molecules are also currently in clinical trials investigating their use against other inflammatory diseases, such as ocular, periodontal, and inflammatory bowel disease. Now, the scientists suggest, they could be re-deployed for the management of COVID-19.
“A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process,” said Serhan. “Activating the body’s own resolution pathways with the use of resolvins and related pro-resolution molecules —which, importantly, promote blog clot removal— may complement current treatment strategies while limiting severe organ damage and improving outcomes in COVID-19 patients.”
The Panigrahy laboratory is supported by the Credit Unions Kids at Heart Team; the C.J. Buckley Pediatric Brain Tumor Fund; and the Joe Andruzzi Foundation. This work also was funded in part by grants from the National Institutes of Health grants, including (R01GM038765).