Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on a framework for identifying keystone microbioal species, a vaccine to prevent organ transplant rejection, aspirin and heart pumps, HIV persistence, anti-inflammatory medications and frailty and more.
Microbial communities are thought to contain keystone species, which can disproportionately affect the stability of the communities, even if only present in low abundances. Identifying these keystone species can be challenging, especially in the human gut, since it is not feasible to isolate them through systematic elimination.
Researchers led by a team at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have designed a new data-driven keystone species identification (DKI) framework that uses machine learning to resolve this difficulty.
Using a deep-learning model trained on real human gut microbiome data from a curated metagenomic database, the investigators were able to simulate the removal of any species in any gut microbiome sample. This “thought experiment” enabled them to calculate the “keystoneness” or the relative essentiality of each species in each community.
The scientists found that the predicted keystone species varied across communities. Some scored low median keystoneness across all samples, and were unlikely to be essential to any community. By contrast, those species with high median scores were likely to be keystone in some communities, but not in others. Similar results were also observed from human oral microbiome and environmental microbiomes. These results imply that the notion of keystone microbial species is community specific or context dependent.
Many human gut microbial species are known to have essential functions such as breaking down complex starches or maintaining healthy intestinal environments. The authors were able to use their DKI framework to identify potential keystone species involved in such functions, including one that aids digestion in formula-fed infants and adults.
“Our DKI framework demonstrates the power of machine learning in tackling a fundamental problem in community ecology,” said Yang-Yu Liu, PhD, of the Channing Division of Network Medicine at Brigham and Women’s Hospital. “Our DKI framework can be adapted to facilitate future data-driven work on complex microbial communities.”
Read more in Nature Ecology & Evolution.
Transplant Researchers Develop Vaccine in Preclinical Models to Regulate Immune Responses to Prevent Kidney and Heart Transplant Rejection
A subtype of CD8 T cells, which are classically known to promote immune system responses, may be in fact regulating the immune system by suppressing immune cells causing self-destructive responses leading to autoimmune disorders and organ graft rejection. A team led by researchers from the Department of Medicine and the Transplant Research Center at Brigham and Women’s Hospital in collaboration with researchers from the Dana-Farber Cancer Institute has developed a vaccine in preclinical models to promote immune regulation. This vaccine utilizes synthetically modified natural peptides to stimulate CD8 T regulatory cells. Using a mouse model, the researchers discovered that those self-peptides, presented by a specific class of major histocompatibility complexes, flag harmful immune cells for the body’s own regulatory CD8 Tregs to attack and eliminate. The vaccine stimulated and promoted those regulatory T cells that in turn kept the harmful cells under check. These cells are crucial for maintaining immune responses and preventing inflammation. The researchers found that the developed vaccine prolongs allograft survival in mice and tested anti-allograft immunity on mismatched kidney transplants. An analogous pathway in humans was also identified, implying that this research could protect those with autoimmune disorders or organ transplant patients.
“This new vaccine promotes immune regulation that treats autoimmunity and prolongs kidney allograft survival in mice. Our research identifies an analogous pathway in humans that we hope to target soon,” said co-corresponding author Jamil R. Azzi, MD, PhD, of the Brigham’s Transplant Research Center. “Identification of human T cell receptors homologous to the mouse model tested may form the basis of a novel and effective treatment for disorders that reflect excessive or dysregulated immune responses.” This work was done in collaboration with co-corresponding author, Harvey Cantor MD, of the Dana-Farber Cancer Institute.
Read more in the Journal of Clinical Investigation.
Left ventricular assist devices (LVADs) are pumps that are used to circulate blood in patients with weakened hearts due to advanced heart failure. Mechanical stress on these implants can make patients susceptible to blood clots, and patients are required to take anti-clotting medications including vitamin-k antagonists (VKA) and aspirin. Modern heart pump models are designed to reduce malfunction, with frictionless motors and fewer mechanical parts. For decades, aspirin has been thought to be necessary in addition to VKA therapy to prevent clotting in patients with these heart pumps.
A team led by investigators at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, conducted an international clinical trial to determine the impact of removing aspirin, while continuing VKA, in patients supported with modern LVADs. The study found that patients who did not receive aspirin were not at increased clotting-related risk of stroke or pump malfunction and fared comparably to those who were prescribed the drug. In addition, the researchers found that aspirin avoidance was associated with a reduction in bleeding events, reduced hospital days and decreased cost of care for such events.
The study involved a randomized, double-blind, placebo-controlled trial involving 628 patients with advanced heart failure and a specific type of LVAD, the HeartMate 3 pump. The enrolled population comprised a diverse population from nine countries across the globe, including the United States, Canada, France, Italy, Austria, Czech Republic, United Kingdom, Kazakhstan, and Australia.
After exclusions, 296 patients who received a placebo and 293 patients who received aspirin in addition to VKA therapy were assessed for major adverse events at the end of 12 months. The researchers found no difference in clotting-related risks between the two groups, and noted that for every 100 patients, 14.5 major bleeding events were prevented per year in the placebo group.
“Our findings suggest that avoidance of aspirin meaningfully improves clinical outcomes in patients with advanced heart failure supported with a heart pump,” said corresponding author Mandeep R. Mehra, MD, the executive director of the Center for Advanced Heart Disease in the Brigham’s Division of Cardiovascular Medicine. “A reduction in bleeding events translates to lower hospitalization rates, fewer days spent in the hospital, and reduced cost of care for patients.”
Read more in JAMA.
Human immunodeficiency virus (HIV) works by entering specific immune cells and replicating inside them. People with HIV are treated with antiretroviral therapy (ART), which prevents viral replication, but some individuals taking ART continue to have low levels of viral presence in the bloodstream, or viremia. This condition is usually attributed to drug resistance or ineffectiveness of ART, but recent studies have found that low-level viremia can occur even without these driving forces, a condition known as non-suppressible HIV viremia (NSV).
A team led by researchers at the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, recruited eight participants with NSV despite receiving ART and analyzed both the virus and host immune response.
Using sequencing assays, the researchers found large reservoirs of proviruses — viral genetic material that has been integrated into host DNA — inserted into transcriptionally active regions of immune cell genomes. Although unable to replicate due to ART, these proviruses contained mutations that helped them evade detection and were able to express genes leading to the NSV phenotype. In addition, the investigators found that the study participants had altered gene expression patterns that led to dampened immune responses and increased survival of cells infected with HIV.
The authors also suggest that these mechanisms could contribute to low levels of residual viremia in most individuals with HIV, even if they successfully undergo ART.
“Our study has identified potential mediators of non-suppressible viremia,” said Jonathan Li, MD, of the Division of Infectious Diseases. “Furthering our understanding of these mechanisms could help develop strategies to disrupt viral persistence in all patients living with HIV.”
Read more in Nature Medicine.
Frailty is a common condition in older populations that increases the risk of adverse health outcomes and mortality. Inflammation, associated with other aging-related conditions, has been proposed as one possible underlying mechanism for frailty. It was previously unclear if anti-inflammatory medications like canakinumab can also reduce risk of frailty.
Researchers led by a team at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, tested if canakinumab affected frailty incidence in adults with atherosclerosis.
The investigators performed post-hoc analysis on a dataset from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) to examine the effects of the medication on frailty, self-reported functional ability and cardiovascular events. The multinational, double-blind trial involved almost 10,000 stable post-myocardial infarction patients who were randomly allocated to receive either canakinumab or placebo every three months from 2011-2017.
During the trial, 1,080 patients became frail over a period of five years. The post-hoc analysis by the researchers did not find an effect of random allocation of canakinumab on frailty incidence or self-reported function. In addition, frailty status did not affect the relative efficacy of canakinumab for preventing cardiovascular events.
The study was limited to patients with atherosclerosis and does not include those without cardiovascular diseases. The authors suggest that it is possible that frailty in these participants could develop independent of canakinumab-affected pathways.
“It’s still unclear whether inflammation is a bystander or a causal factor in the development of frailty,” said corresponding author Ariela Orkaby, MD, MPH, of the Division of Aging. “More randomized trials with anti-inflammatory medications will help understand their role in preventing frailty and functional decline in older adults.”
Read more in Aging Cell.