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Myalgic encephalomyelitis/chronic fatigue syndrome is associated with distinct changes in the microbiome and gut metabolites

Source: Cell Press
Date: 2/8/2023
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Over the past three years, the emergence of long-term effects associated with COVID-19 has led to increased focus on a disease with similar hallmarks and symptoms—myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two studies publishing February 8 in the journal Cell Host & Microbe are taking a closer look at ME/CFS as it relates to the microbiome and the metabolites that microbial species produce. Both studies found that ME/CFS is associated with reduced levels in the gastrointestinal microbiome of microbes known to produce the fatty acid butyrate. These microbiome disruptions could explain in part how the immune system becomes disrupted in people with ME/CFS.

“It’s important to note that this research shows correlation, not causation, between these microbiome changes and ME/CFS,” says Julia Oh (@jjsso0), an associate professor at the Jackson Laboratory and senior author of one of the two papers. “But these findings are the prelude to many other mechanistic experiments that we hope to do to understand more about ME/CFS and its underlying causes.”

“This research demonstrates that there are robust bacterial signatures of gut dysbiosis in individuals with ME/CFS,” says Brent L. Williams, an assistant professor at Columbia University and senior author of the other paper. “It helps to expand on this growing field of research by pinpointing the structural and functional disturbances in the microbiome in a chronic disease that affects the quality of life of millions of people.”

ME/CFS is a chronic, complex, and systemic disease associated with neurological, immunological, autonomic, and energy metabolism dysfunctions. It has been recognized for decades, but its causes remain poorly understood. Like long COVID, it is believed in most cases to be triggered by exposure to viruses or other infectious agents. One thing that’s made ME/CFS difficult to study is that it tends to be heterogenous—not all people with the disease have the same medical history or symptoms. Both research teams say that’s why it’s important to do studies like these that analyze data from a large number of patients. The microbiome has recently emerged as a potential contributor to and biomarker for ME/CFS, making it important to study.

Oh’s study used shotgun metagenomics to compare microbiome samples from people with both short-term ME/CFS (defined as those diagnosed in the previous four years; 74 patients) and long-term ME/CFS (defined as those who have had symptoms for more than 10 years; 75 patients) as well as 79 age- and sex-matched healthy controls. The investigators also looked at plasma samples from the participants. The patients were being treated at the Bateman Horne Center in Salt Lake City, Utah, which has a longstanding collaboration with members of the Jackson Laboratory.

The analysis showed that patients with short-term disease had a number of changes to their microbiomes with regard to diversity. Most notably, they had a depletion of microbes known to be butyrate producers. Butyrate is important for protecting the integrity of the gut barrier and is also known to play an important role in modulating the immune system.

In contrast, those with long-term disease had gut microbiomes that had reestablished and were more similar to the healthy controls. However, those participants had accumulated a number of changes in the metabolites in their blood plasma, including many of those related to the immune system. They also had differences in levels of certain types of immune cells compared with the healthy controls.

Williams’s study used shotgun metagenomic sequencing to look at the microbiomes of 106 people with ME/CFS and 91 healthy controls that were matched for age, sex, geography, and socioeconomic status. This study was undertaken by an interdisciplinary, multi-institutional research group, the Center for Solutions for ME/CFS, and recruited patients from five different sites across the United States, which helped to control for microbiome differences that may be present in different geographic regions.

This study also looked at levels of microbial species in the stool. It didn’t include analysis of plasma, though this group has already published plasma metabolomics analyses from their cohort elsewhere. It did look at metabolites in the stool, which demonstrated reduced levels of butyrate metabolites in ME/CFS.

The study from the Columbia team found significant relationships between the severity of fatigue symptoms and levels of specific species of gut bacteria—in particular the butyrate-producing bacterium Faecalibacterium prausnitzii. It also revealed a higher overall load of bacteria in the stool and disturbances in the interactions among bacterial species in patients with ME/CFS.

More research is needed before these findings can be applied directly to new treatments, but the researchers say these findings will aid in the development of new diagnostic tools and could help with the development of better animal models.

“While these findings don’t unequivocally demonstrate causative relationships between disturbances in the microbiome and symptoms, these microbiome-symptom relationships present potentially actionable, manipulatable targets for future therapeutic trials,” Williams says. “These trials could perhaps focus on dietary, probiotic, prebiotic, or synbiotic interventions and could provide direct evidence that gut bacteria influence chronic symptom presentation.”

Oh notes that her future studies will help to further subdivide patients by the features of their disease, including those with conditions frequently associated with ME/CFS—like irritable bowel syndrome and neuroinflammatory disorders. “This will help us pinpoint specific microbial and metabolomic factors that are associated with this disease,” she says.

Williams plans to further investigate his findings in animal models. “A tractable mouse model to study the gut microbiome disturbances found in ME/CFS would provide an important tool to evaluate causal hypotheses, mechanisms, and treatments,” he says.  

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Researchers propose widespread banking of stool samples for fecal transplants later in life

Source: Cell Press
Date: 6/30/2022
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Changes in the way that humans live and eat have resulted in tremendous alterations in the gut microbiome, especially over the past few decades. These changes have been linked to increased rates of asthma, allergies, diseases of the digestive system, type 2 diabetes, and other conditions. In an opinion article published June 30 in the journal Trends in Molecular Medicine, a team from Harvard Medical School and Brigham and Women’s Hospital (BWH) proposes that we can combat these trends by having individuals bank samples of their own gut microbiota when they are young and healthy for potential use later in life in an autologous fecal microbiota transplant (FMT).

“The idea of ‘rewilding’ the human microbiome has taken off in recent years and has been hotly debated from medical, ethical, and evolutionary perspectives,” says corresponding author Yang-Yu Liu, an Associate Professor of Medicine at Harvard and an Associate Scientist in the Channing Division of Network Medicine at BWH. “It is still unknown if people in industrialized societies can gain some health benefit by restoring their microbiome to an ancestral state. In this paper, we proposed a way to rejuvenate the human gut microbiome.”

FMTs using donor stool have shown benefit for treating some conditions, primarily infections with Clostridioides difficile (C. diff), which affect about half a million people and kill about 29,000 in the United States every year. However, one limitation of using donor stool is variability in the host’s response, likely due to genetic and environmental differences between the donor and host.

Efforts in Yang’s lab focus on understanding the ecological dynamics and organizational principles of the human microbiome to inform the design of microbiome-based therapeutics. OpenBiome, a nonprofit stool bank based in Somerville, Massachusetts, is the first stool bank to offer an option for individuals to bank their own stool for future treatment of C. diff infection. Yang and his colleagues looked at whether this approach might be feasible on a large scale for many other diseases.

“Conceptually, the idea of stool banking for autologous FMT is similar to when parents bank their baby’s cord blood for possible future use,” says Yang. “However, there is greater potential for stool banking, and we anticipate that the chance of using stool samples is much higher than for cord blood.”

“But there are many practical issues to implementing this idea,” says Yang. The article takes a closer look at some of those issues, including optimal storage methods, how much stool should be banked, and what the costs might be.

“Autologous transplants would naturally avoid or at least mitigate donor-recipient compatibility issues, but a major disadvantage of autologous transplants is the need for long-term cryopreservation of stool samples, typically requiring liquid nitrogen storage,” says co-author Shanlin Ke, a postdoctoral research fellow in Yang’s lab. “The long-term safe storage and subsequent resuscitation and cultivation of stool samples is a fundamental research question by itself. To inform practical guidelines for stool banking, further research is needed to systematically test longer storage times and preservation, resuscitation, and cultivation procedures.”

Yang acknowledges that widespread banking could lead to a system in which those with more financial resources are more likely to have banked stool for future use. “We do not anticipate that all individuals in our society are willing or able to pay the cost associated with the service of ‘rejuvenating’ their gut microbiome, in the same way that not all parents pay the cost of cord blood banking for their newborns,” he says. “But as scientists our job is to provide a scientific solution that may eventually benefit human well-being. Developing a reasonable business model and pricing strategy so that the solution is affordable to everyone would require the joint force of entrepreneurs, scientists, and perhaps governments.”

“Autologous FMTs have the potential to treat autoimmune diseases like asthma, multiple sclerosis, inflammatory bowel disease, diabetes, obesity, and even heart disease and aging,” says co-author Scott T. Weiss, a Professor of Medicine at Harvard and Associate Director of the Channing Division of Network Medicine at BWH. “We hope this paper will prompt some long-term trials of autologous FMTs to prevent disease.”

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Gut microbiota differences seen in people with autism may be due to dietary preferences

Source: Cell Press
Date: 11/11/2021
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Research suggested that autism spectrum disorder (ASD) may be at least partly caused by differences in the composition of the gut microbiota, based on the observation that certain types of microbes are more common in people with autism. But a paper appearing November 11 in the journal Cell suggests that the link may actually work the other way around: the diversity in species found in the guts of children with autism may be due to their restricted dietary preferences associated with autism, rather than the cause of their symptoms.

“There’s a lot of interest surrounding the role of the gut microbiome in autism, but not a lot of hard evidence,” says senior author Jacob Gratten, of Mater Research in partnership with The University of Queensland in Brisbane, Australia. “Our study, which is the largest to date, was designed to overcome some of the limitations of prior work.”

Over the past decade, as next-generation sequencing of the microbial species in the gut has made analysis of the microbiome more automated and less-time consuming, a number of studies have examined the link between particular species of microbes in the gut and mental health. The gut-brain axis has been linked not only to ASD but also to anxiety, depression, and schizophrenia. The possibility of targeting the microbiota is a growing area of research for new treatments.

In the Cell study, the investigators analyzed stool samples from a total of 247 children between the ages of 2 and 17. The samples were collected from 99 children diagnosed with ASD, 51 paired undiagnosed siblings, and 97 unrelated, undiagnosed children. The subjects included in the analysis were from the Australian Autism Biobank and Queensland Twin Adolescent Brain Project.

The investigators analyzed the samples by metagenomic sequencing, which looks at the entire genome of microbial species rather than short genetic barcodes (as with 16S analysis). It also provides gene-level information rather than just species-level information, and provides a more accurate representation of microbiome composition than 16S analysis, a technique used in many of the earlier studies linking the microbiome to autism.

“We also carefully accounted for diet in all our analyses, along with age and sex,” says first author Chloe Yap, an MD-PhD student who works with Gratten. “The microbiome is strongly affected by the environment, which is why we designed our study with two comparison groups.”

Based on their analysis, the researchers found limited evidence for a direct association of autism with the microbiome. However, they did find a highly significant association of autism with diet and that an autism diagnosis was associated with less-diverse diet and poorer dietary quality. Moreover, psychometric measures of degree of autistic traits (including restricted interests, social communication difficulties, and sensory sensitivity) and polygenic scores (representing a genetic proxy) for ASD and impulsive/compulsive/repetitive behaviors were also related to a less-diverse diet.

“Taken together, the data support a strikingly simple and intuitive model, whereby autism-related traits promote restricted dietary preferences,” Yap says. “This in turn leads to lower microbiome diversity and more diarrhea-like stool.”

The researchers acknowledge several limitations to the current work. One is that the design of the study can’t rule out microbiome contributions prior to ASD diagnosis, nor the possibility that diet-related changes in the microbiome have a feedback effect on behavior. Another is that they could only account for the possible effect of antibiotics on the microbiome by excluding those taking these medications at the time of stool collection. Finally, no comparable datasets are currently available to confirm the findings.

“We hope that our findings encourage others in the autism research community to routinely collect metadata in “omics” studies to account for important (but often underappreciated) potential confounders such as diet,” Gratten says. “Our results also put the spotlight on nutrition for children diagnosed with autism, which is a clinically important (but underrecognized) contributor to overall health and wellbeing.”

The researchers plan to generate new data in a larger sample to replicate their findings.

The authors acknowledge the financial support of the Cooperative Research Centre for Living with Autism (Autism CRC), established and supported under the Australian Government’s Cooperative Research Centres Program. Additional funding support was provided by the Australian National Health and Medical Research Council, the Australian Research Council, and the University of Queensland.

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Global study of 60 cities’ microbes finds each has a signature microbial fingerprint

Source: Cell Press
Date: 5/26/2021
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An international consortium has reported the largest-ever global metagenomic study of urban microbiomes, spanning both the air and the surfaces of multiple cities. The international project, which sequenced and analyzed samples collected from public transit systems and hospitals in 60 cities around the world, features comprehensive analysis and annotation for all the microbial species identified—including thousands of viruses and bacteria and two archaea not found in reference databases. The study appears May 26 in the journal Cell.

“Every city has its own ‘molecular echo’ of the microbes that define it,” says senior author Christopher Mason, a professor at Weill Cornell Medicine (WCM) and the director of the WorldQuant Initiative for Quantitative Prediction. “If you gave me your shoe, I could tell you with about 90% accuracy the city in the world from which you came.”

The findings are based on 4,728 samples from cities on six continents taken over the course of three years, characterize regional antimicrobial resistance markers, and represent the first systematic worldwide catalogue of the urban microbial ecosystem. In addition to distinct microbial signatures in various cities, the analysis revealed a core set of 31 species that were found in 97% of samples across the sampled urban areas. The researchers identified 4,246 known species of urban microorganisms, but they also found that any subsequent sampling will still likely continue to find species that have never been seen before, which highlights the raw potential for discoveries related to microbial diversity and biological functions awaiting in urban environments.

This project began in 2013, when Mason started collecting and analyzing microbial samples in the New York City subway system. After he published his first findings, he was contacted by researchers from all over the world who wanted to do similar studies in their own cities. He developed a protocol for collecting the samples and posted an instructional video on YouTube. The samples were collected with DNA- and RNA-free swabs and sent to a lab at WCM for analysis, along with positive and negative controls. Much of the analysis and assemblage of sequences is done on an Extreme Science and Engineering Discovery Environment (XSEDE) supercomputer in Pittsburgh, which led to the discovery of 10,928 viruses and 748 bacteria that are not present in any reference databases.

The worldwide interest inspired Mason in 2015 to create the International MetaSUB Consortium (short for Metagenomics and Metadesign of Subways and Urban Biomes), which has since expanded to collecting samples from air, water, and sewage in addition to hard surfaces. The group oversees projects such as Global City Sampling Day (gCSD), held every year on June 21, and has done wide-ranging studies including a comprehensive microbial analysis of Rio de Janeiro’s city surfaces and its mosquitoes before, during, and after the 2016 Summer Olympics. Another project, launched in 2020, is focused on investigating the prevalence of SARS-CoV-2 and other coronaviruses in domestic cats, and a project also is planned for the 2021 Tokyo Olympics.

The new research has implications for detecting outbreaks of both known and unknown infections and for studying the prevalence of antibiotic resistant microbes in different urban environments. It also can contribute to new discoveries about the evolution of microbial life. MetaSUB researchers in Switzerland (Andre Kahles and Gunnar Rätsch) also released a searchable, global DNA sequence portal (MetaGraph, https://metagraph.ethz.ch/search) that indexed all known genetic sequences (including MetaSUB data), which maps any known or newly discovered genetic elements to their location on Earth and can aid in the discovery of new microbial interactions and putative functions.

“There are millions of species on Earth, but we have a complete, solid genome reference for only 100,000 to 200,000 at this point,” Mason says, explaining that the discovery of new species can help with the building of microbial family trees to see how different species are related to one another.

The findings also have many potential practical applications. “Based on the sequence data that we’ve collected so far, we’ve already found more than 800,000 new CRISPR arrays,” he says. Additionally, the findings indicate the presence of new antibiotics and small molecules annotated from biosynthetic gene clusters (BGCs) that have promise for drug development.

“One of the next steps is to synthesize and validate some of these molecules and predicted BGCs, and then see what they do medically or therapeutically,” Mason says. “People often think a rainforest is a bounty of biodiversity and new molecules for therapies, but the same is true of a subway railing or bench.”

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Translating Discoveries Into Better Treatments for IBD

Source: Brigham and Women's Hospital
Date: 5/16/2022
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Current treatments for inflammatory bowel disease (IBD) can help manage the disease’s effects, but improved treatments are desperately needed. To develop those treatments, it’s important to understand the underlying biological causes that drive different forms of IBD, including Crohn’s disease and ulcerative colitis.

Scott B. Snapper, MD, PhD, a physician-scientist in the Crohn’s and Colitis Center within the Division of Gastroenterology, Hepatology and Endoscopy at Brigham and Women’s Hospital, has devoted his research to this topic—both in the lab and the clinic. His current work focuses on determining the causes of IBD and employing novel animal models as well as direct human studies, including early-stage clinical trials, to study it.

“Since I began my research career, my goal has always been to better understand these diseases,” says Dr. Snapper, who trained as a microbiologist and immunologist in addition to training as a gastroenterologist. “All of that work has been leading up to developing new therapeutics.”

Mouse Models Reveal Disease Mechanisms

When Dr. Snapper started his research, there was a need for better animal models for studying IBD. One reason was that most cases of IBD are caused by numerous genetic factors. He realized that by studying the rare cases caused by single genes, he could pull apart the mechanisms that contribute to these conditions in more common cases as well.

“We use these rare examples to help us understand the cellular and molecular mechanisms and the host-microbial interactions that occur in all people who get Crohn’s disease and ulcerative colitis,” he says.

The first mouse model he worked with was one for Wiskott-Aldrich syndrome, a rare monogenic disease characterized by abnormal immune system function, among other issues. All the mice with the disease developed IBD. Today, there are more than 60 mouse models for studying different forms of IBD.

The Snapper Laboratory employs a number of basic, translational and clinical research strategies to understand and define not only the constituents but also the mechanisms that regulate intestinal homeostasis as it pertains to gastrointestinal health and IBD. Among the ongoing projects in his lab are the study of intestinal epithelial cells, immune cells and cytokines as well as translational work using humanized mice. This research is laying the foundation for the development of clinical trials.

Decoding the Underlying Causes of IBD

Among the findings that have come out of Dr. Snapper’s lab are that some cases of IBD presenting in very young children are caused by the absence of the interleukin-10 receptor.

“Patients lacking this receptor make a lot of the cytokine interleukin-1,” says Dr. Snapper, who is also chief of the Division of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital. “We’ve shown in early studies that in these patients, you can ameliorate much of their disease by blocking interleukin-1.”

Dr. Snapper says that this treatment has served as a bridge to offering bone marrow transplants for children with this rare immunodeficiency syndrome. He also notes ongoing efforts to identify subsets of all IBD patients with an enhanced interleukin-1 signature who might benefit from IL-1 blockade.

Research employing several mouse models of IBD, including the murine model of the Wiskott-Aldrich syndrome, has revealed another underlying mechanism of IBD, this one related to regulatory T cells.

“We’ve found in a novel humanized mouse model of IBD that you can expand regulatory T cells by giving low doses of interleukin-2 and improve disease,” Dr. Snapper says. This work has been used for treating graft-versus-host disease in patients who have undergone bone marrow transplants, but studies in mice suggest it could be an effective treatment for IBD as well.

Applying Lab Findings to Clinical Trials

At the 2021 Digestive Disease Week conference, Dr. Snapper and Brigham colleagues including Jessica R. Allegretti, MD, MPH, Vanessa Mitsialis, MD, Matthew J. Hamilton, MD, and Joshua R. Korzenik, MD, presented the results from an open-label, single-arm, phase 1b/2a trial that looked at whether subcutaneously administered, low-dose interleukin-2 is safe and results in a biological response. The study, which enrolled 26 patients with ulcerative colitis, showed that this treatment was well-tolerated, and was associated with a biological response and the expansion of regulatory T cells in patients with moderate to severely active ulcerative colitis.

“This treatment led to clinical improvement in more than 50% of the patients and complete remission in about a quarter of them,” Dr. Snapper says. “These are patients who had already failed multiple drugs.”

A new early-stage study has enrolled eight patients to look at whether expanding regulatory T cells with interleukin-2 can provide the same benefit in people with Crohn’s disease.

Outside of his clinical trials, Dr. Snapper was instrumental in establishing the Very Early Onset Inflammatory Bowel Disease (VEO-IBD) Consortium, an international group of investigators studying IBD in young children. The group includes scientists from North America, Europe, Australia, South America, Israel and the Middle East who are all focused on these efforts.

The VEO-IBD Consortium has identified numerous genetic defects that cause IBD and has developed novel therapeutic approaches. The group has received support from a number of philanthropies, including the Helmsley Charitable Trust and the National Institutes of Health, as well as support from the pharmaceutical and biotechnology industries.

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MSK Study Is the First to Link Microbiota to Dynamics of the Human Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 11/25/2020
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In recent years, the microbiota — the community of bacteria and other microorganisms that live on and in the human body — has captured the attention of scientists and the public, in part because it’s become easier to study. It has been linked to many aspects of human health.

A multidisciplinary team from Memorial Sloan Kettering has shown for the first time that the gut microbiota directly shapes the makeup of the human immune system. Specifically, their research demonstrated that the concentration of different types of immune cells in the blood changed in relation to the presence of different bacterial strains in the gut. The results of their study, which used more than ten years of data collected from more than 2,000 patients, is being published November 25, 2020, in Nature.

“The scientific community had already accepted the idea that the gut microbiota was important for the health of the human immune system, but the data they used to make that assumption came from animal studies,” says Sloan Kettering Institute systems biologist Joao Xavier, co-senior author of the paper together with his former postdoc Jonas Schluter, who is now an assistant professor at NYU Langone Health. “At MSK, we have a remarkable opportunity to follow how the composition of the microbiota changes in people being treated for blood cancers,” Dr. Xavier adds.

A Unique System for Studying Changes in the Body

The data that were used in the study came from people receiving allogeneic stem cell and bone marrow transplants (BMTs). After strong chemotherapy or radiation therapy is used to destroy cancerous blood cells, the patient’s blood-forming system is replaced with stem cells from a donor. For the first few weeks until the donor’s blood cells — including the white blood cells that make up the immune system — have established themselves, the patients are extremely vulnerable to infections. To protect them during this time, patients are given antibiotics.

But many of these antibiotics have the unwanted side effect of destroying healthy microbiota that live in the gut, allowing dangerous strains to take over. When the patient’s immune system has reconstituted, the antibiotics are discontinued, and the gut microbiota slowly starts to grow back.

“The parallel recoveries of the immune system and the microbiota, both of which are damaged and then restored, gives us a unique opportunity to analyze the associations between these two systems,” Dr. Schluter says

A Years-Long Effort to Find Answers

For more than ten years, members of MSK’s BMT service have regularly collected and analyzed blood and fecal samples from patients throughout the BMT process. The bacterial DNA were processed by the staff at MSK’s Lucille Castori Center for Microbes, Inflammation, and Cancer, which played a key role in creating the massive microbiota dataset. “Our study shows that we can learn a lot from stool — biological samples that literally would be flushed down the toilet,” Dr. Xavier notes. “The result of collecting them is that we have a unique dataset with thousands of datapoints that we can use to ask questions about the dynamics of this relationship.”

This wider effort has been led by Marcel van den Brink, Head of the Division of Hematologic Malignancies, and a team of infectious disease specialists, BMT doctors, and scientists. “For a fair number of patients, we collected daily samples so we could really see what was happening day to day,” Dr. van den Brink says. “The changes in the microbiota are rapid and dramatic, and there is almost no other setting in which you would be able to see them.”

Previous research using samples collected from this work has looked at how the gut microbiota affects patients’ health during the BMT process. A study published in February 2020 reported that having a greater diversity of species in the intestinal microbiota is associated with a lower risk of death after a BMT. It also found that having a lower diversity of microbiota before transplant resulted in a higher incidence of graft-versus-host disease, a potentially fatal complication in which the donor immune cells attack healthy tissue.

New Clues about a Complicated Relationship

The databank that the MSK team created contains details about the types of microbes that live in the patients’ guts at various times. The computational team, including Drs. Schluter and Xavier, then used machine learning algorithms to mine electronic health records for meaningful data. The data from the health records included the types of immune cells present in the blood, information about the medications that patients were given, and the side effects patients experienced. “This research could eventually suggest ways to make BMTs safer by more closely regulating the microbiota,” Dr. van den Brink says.

Analyzing this much data was a huge undertaking. Dr. Schluter, who at the time was a postdoctoral fellow in Dr. Xavier’s lab, developed new statistical techniques for this. “Because experiments with people are often impossible, we are left with what we can observe,” Dr. Schluter says. “But because we have so many data collected over a period of time when the immune system of patients as well as the microbiome shift dramatically, we can start to see patterns. This gives us a good start toward understanding the forces that the microbiota exerts on the rebuilding of the immune system.”

“The purpose of this study was not to say whether certain kinds of microbes are ‘good’ or ‘bad’ for the immune system,” Dr. Xavier explains, adding that this will be a focus of future research. “It’s a complicated relationship. The subtypes of immune cells we would want to increase or decrease vary from day to day, depending on what else is going on in the body. What’s important is that now we have a way to study this complex ecosystem.”

The researchers say they also plan to apply their data to studying the immune system in patients receiving other cancer treatments.

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Proof that Fecal Transplants Can Restore a Gut’s Natural Balance of Microbes

Source: Memorial Sloan Kettering - On Cancer
Date: 09/26/2018
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Fecal microbiota transplants (FMTs) are also known as stool transplants. The process involves collecting feces from a healthy donor, processing it, and then delivering it into the colon of the recipient. Just a decade ago, FMTs were unconventional. But they are becoming accepted by the medical establishment. The procedure is primarily used to treat intestinal infections from a bacterium called Clostridium difficile (C. diff), but it’s being studied for other conditions as well. 

FMTs are not formally approved by the US Food and Drug Administration. But in 2013, the FDA said that doctors could use them to treat chronic C. diff infections that have not responded to other treatments, opening the door for more controlled clinical studies.

A clinical trial at Memorial Sloan Kettering is now showing for the first time that FMTs can reestablish the health-promoting bacteria that are often lost in people who have stem cell or bone marrow transplants for blood cancer. The trial involves collecting and storing a person’s own stool prior to the procedure. After the stem cell or bone marrow transplant, the FMT is given to the patient. Because the FMT comes from a person’s own body, it is called an autologous FMT. The results are being published today in Science Translational Medicine.

“When we started this trial three years ago, we knew much less about FMTs than we know today,” says MSK infectious diseases specialist Ying Taur, the study’s first author. “This study is really a milestone. It removes whatever trepidation there may have been about exploring this procedure in people who have recently undergone cancer treatment.” 

Addressing Serious Complications from Bone Marrow Transplant

People who have stem cell or bone marrow transplants to treat blood cancer face a number of challenges. These complications especially affect those whose transplanted blood cells come from a donor, called an allogeneic transplant. In order for the body to accept the donor’s cells, the recipient’s own blood cells are wiped out with high doses of chemotherapy. During the time when the new blood cells are growing, recipients are prone to infections and require high doses of antibiotics. But those antibiotics can, in turn, destroy the healthy microorganisms that live in the body and allow more dangerous microbes to take over.

This is where an FMT comes in: The procedure helps restore a balance of healthy bacteria in the gut.

In earlier work, MSK physician-scientists Eric Pamer and Marcel van den Brink found that out-of-balance intestinal microbes can contribute to serious side effects. This disparity can affect outcomes after stem cell transplants. In particular, when harmful bacteria like C. diff dominate in the intestine, people are more likely to suffer complications from graft-versus-host disease. This potentially fatal side effect occurs when immune cells from the donor attack healthy tissues in the recipient, especially the intestinal lining. Dr. Pamer is one of the senior authors on the new paper; Dr. van den Brink is a coauthor.

Restoring the Balance of Microorganisms after Transplant

In the current study, participants’ own fecal material is collected before beginning the stem cell transplant process. Using their own feces helps ensure that the transplant won’t expose them to any unfamiliar flora. Any new bacteria could cause problems after the FMT. The collected stool is frozen to preserve the healthy microbe balance when the processed fecal material is reintroduced after the stem cell transplant.

The paper reports the results from the first 25 people in the study, 14 of whom received a transplant of their own fecal material and 11 controls, who did not.

The investigators looked at a number of measures. They considered levels of beneficial microbes as well as potentially harmful microbes. The mixture of microorganisms that came from the stored fecal material was able to reestablish itself after transplant. This resulted in more diverse, balanced microbiota.

“The important message here is that we showed we could bring the microbiota back to a level that was much closer to what people came in with before their stem cell transplant,” says Dr. Pamer, who heads a lab in the Sloan Kettering Institute’s Immunology Program.

Wide-Ranging Implications for the Health of People with Cancer

Another study from MSK researchers reported that having higher numbers of certain healthy bacteria in the intestinal tract contributed to fewer viral infections in the lungs after a stem cell transplant. Respiratory infections are another major complication in people who have stem cell transplants. This study points to the importance of maintaining healthy microbiota for overall recovery, not just for the health of the intestinal tract. The results were published online in April in the journal Blood.

Drs. Pamer and Taur say that since assembling the results in the current report, they have brought the total number of people in the FMT trial to 59. The MSK team is continuing to follow them, with the goal of determining whether autologous FMT can affect overall clinical outcomes and improve survival. They expect those results to be available next year.

Investigators plan to study using fecal material from healthy donors rather than a patient’s own stool for the transplant.

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Gut Microbes May Protect People Having Bone Marrow Transplants

Source: Memorial Sloan Kettering - On Cancer
Date: 12/02/2018
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One of the most serious complications of blood stem cell or bone marrow transplants (BMTs), which are used to treat many types of blood cancer, is graft-versus-host disease (GVHD). In this condition, a donor’s immune cells attack the vital organs of a transplant recipient. It can cause death in some cases.

In the past few years, researchers from Memorial Sloan Kettering and other institutions have found that a transplant recipient’s microbiota plays an important role in their survival after a BMT. (The microbiota is the community of organisms, or flora, that live in the body, especially in the gut.) Now, for the first time, investigators have found an association between the health of the microbiota before a transplant and a person’s survival afterward. The findings were presented December 2, 2018, at the annual meeting of the American Society of Hematology (ASH).

“Patients who went into the BMT process with a gut flora that was already disrupted had a higher risk of death after the transplant,” says the study’s senior author, Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “The thing that we keep coming back to is that preserving the commensal flora in the microbiome is good for transplant patients.” Commensal flora are microbes that live in the body without causing disease. In some people, they may be beneficial.

The Forgotten Organ

Many of those who study the gut microbiota refer to it as the “forgotten organ.” It can have a huge impact on someone’s health. But scientists are still learning what makes it healthy or damaged, and what can be done to correct that damage.

“There are as many bacterial cells as there are human cells in our bodies,” says first author Jonathan Peled, an MSK medical oncologist who specializes in BMTs. “In addition, these bacteria are really important for the way our bodies function.”

“Before someone has a BMT to treat their cancer, we do a lot of screening tests to make sure they are otherwise healthy. We look at things like their heart, lung, and kidney function,” says Dr. van den Brink, who runs a lab in the Sloan Kettering Institute’s Immunology Program. “This study suggests that we should also screen the microbiota. If we find out that it’s in bad shape, we could do something to repair it.”

Dr. Peled adds, “This study opens the door to repairing the microbiota in the pretransplant period. Because this is a time when we’re usually not in a rush to move forward with treatment, it’s also a good time to look for ways to do this before continuing the transplant.” Interventions that could improve the health of the microbiota include changes to diet, using or avoiding certain antibiotics, and fecal transplants of healthy gut microbes.

MSK doctors are already conducting research on fecal transplants that make use of a patient’s own stool. The stool is preserved before the BMT and given back to the patient after the process. A recent study led by MSK physician-scientists Eric Pamer and Ying Taur found that fecal transplants are effective in restoring the balance of healthy microbes that is lost during a BMT. Researchers also plan to study the safety of providing fecal transplants with material from a healthy donor. Donor stool may ultimately prove to be a better option for people who come to a BMT with a microbiota that’s damaged.

Throwing Off the Healthy Balance of the Gut

In the analysis presented at ASH, the researchers studied 1,922 stool samples from 991 people having allogeneic BMTs. “Allogeneic” means the blood or marrow stem cells come from a donor. (In the other type of transplant, an autologous procedure, a patient’s own blood cells are stored before treatment and later infused back into the body.) The people were treated at MSK and three other hospitals. The samples were evaluated for a range of bacteria types, including commensal strains and those that are known to cause disease.

The investigators found that, on average, the people about to have BMTs had decreased diversity of bacteria in their guts. They also found that different strains were dominant, compared with healthy volunteers. This was a new finding, but it was not surprising. Most people with blood cancer who need transplants have gone through months or years of treatment with chemotherapy drugs and antibiotics that throw off the normal, healthy balance.

Diversity in the microbiota is important because commensal bacteria help keep more dangerous strains in check. Previous studies have also shown that certain commensal strains actually provide specific benefits for people having transplants. Some strains release substances that protect the walls of the intestines, for example.

In the current study, only 10 to 30% of patients had what researchers considered a balanced gut flora before their transplant. The more the ecology of the microbiota was disrupted, the more likely it was that patients had fatal complications from GVHD. However, the researchers emphasize that this study showed only an association, not direct causation.

A Study with a Broad Geographic Scope

Investigators at three other transplant centers also participated in the research and contributed patient samples: Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Different locations were included because other research has shown that microbiotas across geographic regions vary widely. Factors like environment and diet are thought to play a role.

All of the samples were analyzed in MSK labs, Dr. Peled says, improving the validity of the results across the sites.

“One of the main findings of this study was that the injury patterns that we saw in people’s microbiotas were comparable across geography,” he concludes. “This suggests that if we find interventions to correct these imbalances at one center, they will also apply to people being treated in other parts of the world.”

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Researchers Identify a Bacterial Species That Could Protect against Hospital-Acquired Infections

Source: Memorial Sloan Kettering - On Cancer
Date: 08/21/2019
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Hospital-acquired infections are a major threat, especially for people whose immune systems may be compromised because of cancer treatment. In recent years, researchers have been studying fecal microbiota transplants as a way to treat this serious complication. These transplants involve collecting stool from a healthy donor and delivering it into the intestine of the patient. The beneficial microorganisms from the transplant restore the balance of healthy bacteria in the gut.

Little is known, however, about which species of bacteria offer protection against harmful pathogens or exactly how they provide this benefit. A new study from Memorial Sloan Kettering is reporting the first evidence of a bacterial species that appears to maintain the balance of healthy microbes by killing dangerous ones. The findings also suggest how it mounts this attack. The research was reported August 21 in Nature.

“A lot of work is being done to figure out how harmful pathogens are able to colonize the human body,” says first author Sohn Kim, an MD-PhD student in the Tri-Institutional MD-PhD Program of MSK, Weill Cornell Medicine, and The Rockefeller University. “This project provides important new information about the bacteria that keep them in check.”

Focus on a Deadly Infection

The study focused on a particularly threatening hospital-acquired infection called vancomycin-resistant Enterococcus (VRE). VRE sickens about 20,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and kills up to 10% of them. Earlier work led by former MSK graduate student Silvia Caballero, a co-author on the current study, showed that a mixture of four bacterial strains protect lab mice from VRE. These strains are normally found in the gastrointestinal tracts of healthy people.

The new study built on this earlier work by conducting a series of experiments to isolate one of these four bacterial strains: Blautia producta. “The next step was to determine the mechanism by which Blautia producta mediates protection against VRE,” Dr. Kim says. It turned out that a protein produced by Blautia producta is able to kill VRE even when the bacterial cells themselves aren’t present. Further study revealed that this protein is a lantibiotic, a type of antibiotic that is manufactured by microorganisms.

“If you think of Blautia producta as a member of the microbiota that helps maintain order within the gut, this lantibiotic is what it uses to do that,” says MSK infectious diseases expert Ying Taur, a co-author on the study. “This study really helps further our understanding of how all this works and provides important new insight.”

Evaluating the Effects of a Bacterial Product

The researchers did a number of additional studies. These included sequencing the gene that codes for the lantibiotic and performing RNA sequencing to determine when the gene is expressed.

They also tested the lantibiotic against about 150 strains of intestinal bacteria, to gain a sense of its spectrum of activity. This part of the research was significant because a major side effect of the antibiotics that doctors prescribe is that they can wipe out these healthy strains.

The team found that Blautia producta and the lantibiotic did not damage healthy strains. In fact, when they reviewed their library of samples collected from healthy donors, the researchers learned that about half of them already had Blautia producta and this lantibiotic product.

“It’s remarkable how precise this product is at targeting harmful microbes while sparing healthy ones,” Dr. Taur notes. “This is something we do not know how to do with any antibiotics that we have now. Our antibiotics are very clunky in comparison to the precision of what these bacteria do.”

Moving Forward with More Research

More work is needed before this approach can be tested in people with VRE infections. Drs. Kim and Taur say they haven’t even determined how a treatment would be best administered or whether they would use Blautia producta or the isolated lantibiotic. The treatment could possibly be given as a pill, or the findings from this study could be used to develop a more specialized type of fecal microbiota transplant. They plan to study various approaches in mouse models.

“Previously, studies have shown that Blautia is associated with better outcomes in people who have developed graft-versus-host disease (GVHD) after having a bone marrow transplant with donor cells,” says study co-author Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “In addition, we have recently found that Enterococcus is associated with increased incidence of GVHD. These findings offer exciting opportunities to control GVHD and improve outcomes for people having transplants.”

“There are a lot of things we still don’t know, but we have learned so much from this study,” Dr. Taur concludes. “It was really an amazing piece of detective work.”

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Study in Mice Suggests Lactose in the Diet Feeds Dangerous Gut Bacteria When the Immune System Is Compromised

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2019
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Infections with the Enterococcus bacterium are a major threat in healthcare settings. They can lead to inflammation of the colon and serious illnesses such as bacteremia and sepsis, as well as other complications.

Enterococcus infections are particularly risky for people having stem cell and bone marrow transplants (BMTs) to treat blood cancer. Studies have suggested that high levels of Enterococcus increase the incidence of graft-versus-host disease (GVHD), a potentially fatal condition in which immune cells from the donor’s stem cells attack the recipient’s organs.

Now, an international team led by scientists from Memorial Sloan Kettering has shown for the first time that foods containing lactose, a sugar that’s naturally found in milk and dairy products, help Enterococcus thrive in the gut, at least in mice. They also studied changes in the bodies of people having BMTs. The study was published November 29 in Science.

“These findings hint at a possible new way to reduce the risk of GVHD as well as dangerous infections,” says MSK physician-scientist and GVHD expert Jonathan Peled. “But they are still preliminary, and it’s too early to suggest cutting out lactose in the diets of people undergoing BMTs or other hospitalized patients who are at risk from Enterococcus.”

Focusing on the Microbiota

For several years, Dr. Peled and Marcel van den Brink, head of MSK’s Division of Hematologic Malignancies, have been studying the relationship between GVHD and microbiota — the community of microorganisms that inhabit the body. The two of them are co-senior authors of the new study.

Their previous research has shown that when harmless strains of microbes are wiped out, often due to treatment with antibiotics, Enterococcus and other harmful types of bacteria can take over due to lack of competition. As part of the new study, which included analysis of microbiota samples from more than 1,300 adults having BMTs, the team confirmed the link between Enterococcus and GVHD.

The investigators conducted further Enterococcus research in cell cultures and in mice. “Mouse models are very helpful for understanding the mechanisms in the gut that lead to GVHD,” says Dr. van den Brink, who is also Co-Director of the Parker Institute for Cancer Immunotherapy at MSK and leads a lab in the Sloan Kettering Institute’s Immunology Program. “We studied mice that had been given BMTs and found that the cells lining their intestines, called enterocytes, were no longer able to make lactase, the enzyme that breaks down lactose. The high levels of undigested lactose in turn led to a total domination of Enterococcus. It was shocking to see how one type of bacteria completely takes over.”

Dr. van den Brink adds that on top of the defective enterocytes, the loss of competing healthy strains of bacteria caused by antibiotic treatment makes problems in the gut even worse. “It’s a double whammy,” he says.

A Trip to the Pharmacy Leads to a Surprising Discovery

To study whether higher lactose levels were boosting the growth of Enterococcus, or whether the connection was only a coincidence, visiting researcher and first author Christoph Stein-Thoeringer went to the pharmacy to buy Lactaid®. These lactase-containing pills break down lactose, helping people who are lactose intolerant to eat dairy products without side effects.

The researchers discovered that when lactase was added to lab cultures of Enterococcus, the bacterial growth was blocked. So, they began to feed lactose-free chow to lab mice that had been given BMTs and found that mice on the special diet were protected against Enterococcus domination.

“We’re not suggesting this is a cure for GVHD,” Dr. van den Brink says. “But it appears to be an important modulator.”

The investigators have not yet tested the new findings in humans, but existing data suggests that the same connection between lactose and Enterococcus seen in the mice may be at play in people who have had BMTs. “We know which gene variants are associated with being lactose intolerant,” Dr. Peled notes. “We looked at our records and found that people who had these gene variants tended to have a harder time clearing Enterococcus from their guts than others did.”

He adds that many BMT recipients become temporarily lactose intolerant, likely due to the loss of enterocytes caused by chemotherapy. “We are considering doing a trial in which people eat a lactose-free diet or take Lactaid during their cancer treatment to see if the growth of Enterococcus is blocked,” Dr. Peled says.

A Global Effort

Another important aspect of the new study is that it didn’t just look at people treated at MSK. It also included patient samples from Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Researchers from those three institutions also contributed to the Science paper.

“Researchers who study the microbiome know that the environment in which a person lives is a major factor,” Dr. van den Brink says. “We’ve made a major effort to collect samples from all over the world, so we know that when we find common features, they are likely to hold up worldwide.”

This work was supported by the German Research Foundation, a Young Investigator-Award from the American Society of Bone Marrow Transplantation, the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSK, the Sawiris Foundation, the Society of MSK, an MSK Cancer Systems Immunology Pilot Grant, the Empire Clinical Research Investigator Program, Seres Therapeutics, the Japan Society for the Promotion of Science, the Center of Innovation Program from Japan Science and Technology, a Conquer Cancer Foundation Young Investigator Award/Gilead Sciences, and more than a dozen National Institutes of Health grants (R01-CA228358, R01-CA228308, P30 CA008748, P01-CA023766, R01-HL125571, R01-HL123340, P01-AG052359, U01 AI124275, R01 AI032135, AI095706, U01 AI124275, KL2 TR001115-03, 2P30AG028716-11, R01CA203950-01, 1R01HL124112-01A, R01 CA203950-01).

Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. Dr. van den Brink has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Magenta Therapeutics, WindMIL Therapeutics, Merck & Co. Inc., Acute Leukemia Forum (ALF), and DKMS Medical Council (Board). He also has IP licensing with Seres Therapeutics and Juno Therapeutics and stock options from Smart Immune.