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.

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.

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.”

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.”

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.

Gut microbes respond differently to foods with similar nutrition labels

Source: Cell Press
Date: 06/12/2019
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Foods that look the same on nutrition labels can have vastly different effects on our microbiomes, report researchers in a paper publishing June 12 in the journal Cell Host & Microbe. The researchers’ observations of participants’ diets and stool samples over the course of 17 days suggested that the correlation between what we eat and what’s happening with our gut microbes might not be as straightforward as we thought. This adds an increased level of complexity to research focused on improving health by manipulating the microbiome.

“Nutrition labels are human-centric,” says senior author Dan Knights (@KnightsDan), of the Department of Computer Science and Engineering and the BioTechnology Institute at the University of Minnesota. “They don’t provide much information about how the microbiome is going to change from day to day or person to person.”

In the study, the investigators enrolled 34 participants to record everything they ate for 17 days. Stool samples were collected daily, and shotgun metagenomic sequencing was performed. This allowed the researchers to see at very high resolution how different people’s microbiomes, as well as the enzymes and metabolic functions that they influence, were changing from day to day in response to what they ate. It provided a resource for analyzing the relationships between dietary changes and how the microbiome changes over time.

“We expected that by doing this dense sampling–where you could see what people were eating every single day and what’s happening to their microbiome–we would be able to correlate dietary nutrients with specific strains of microbes, as well as account for the differences in microbiomes between people,” Knights says. “But what we found were not the strong associations we expected. We had to scratch our heads and come up with a new approach for measuring and comparing the different foods.”

What the researchers observed was a much closer correspondence between changes in the diet and the microbiome when they considered how foods were related to each other rather than only their nutritional content. For example, two different types of leafy greens like spinach and kale may have a similar influence on the microbiome, whereas another type of vegetable like carrots or tomatoes may have a very different impact, even if the conventional nutrient profiles are similar. The researchers developed a tree structure to relate foods to each other and share statistical information across closely related foods.

Two people in the study consumed nothing but Soylent, a meal replacement drink that is popular with people who work in technology. Although it was a very small sample, data from these participants showed variation in the microbiome from day to day, suggesting that a monotonous diet doesn’t necessarily lead to a stable microbiome.

“The microbiome has been linked to a broad range of human conditions, including metabolic disorders, autoimmune diseases, and infections, so there is strong motivation to manipulate the microbiome with diet as a way to influence health,” Knights concludes. “This study suggests that it’s more complicated than just looking at dietary components like fiber and sugar. Much more research is needed before we can understand how the full range of nutrients in food affects how the microbiome responds to what we eat.”

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This work was supported by General Mills Inc.

Cell Host & Microbe, Johnson et al.: “Daily longitudinal sampling reveals personalized diet-microbiome associations.” https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30250-1

Researchers alter mouse gut microbiomes by feeding good bacteria their preferred fibers

Source: Cell Press
Date: 09/19/2019
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Humans choose food based on the way it looks, smells, and tastes. But the microbes in our guts use a different classification system–one that is based on the molecular components that make up different fibers. In a study published September 19 in the journal Cell, investigators found particular components of dietary fiber that encourage growth and metabolic action of beneficial microbes in the mouse gut.

The research aims to develop ways to identify compounds that can enhance the representation of health-promoting members of the gut microbial community. The goal is to identify sustainable, affordable dietary fiber sources for incorporation into next-generation, more nutritious food products.

“Fiber is understood to be beneficial. But fiber is actually a very complicated mixture of many different components,” says senior author Jeffrey Gordon, a microbiologist at the Washington University School of Medicine in St. Louis. “Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents. Unfortunately, we lack detailed knowledge of these differences and their biological significance. We do know that modern Western diets have low levels of fiber; this lack of fiber has been linked to loss of important members of the gut community and deleterious health effects.”

The researchers started by testing 34 food-grade fiber preparations, many purified from byproducts of food manufacturing such as peels from fruits and vegetables that are thrown out during production of processed foods and drinks. They used mice initially raised under sterile conditions and then colonized with human gut microbes. The animals were fed a high-fat, low-fiber diet representative of diets typically consumed in the United States, with or without different types of supplemental fibers. The goal was to identify those fibers that were best at boosting the levels of key fiber-degrading bacterial species and promoting the expression of beneficial metabolic enzymes in the microbiome.

Since the mice had been colonized with a defined collection of human gut bacteria with sequenced genomes, the researchers knew all the genes that were present in their model human gut microbial community. This allowed them to perform a comprehensive, high-resolution proteomics study of all bacterial proteins whose expression changed in response to the different fiber types they tested. Combining these results with genetic screens, they were able to identify particular fiber sources, their bioactive molecular components, and the bacterial genes that increased for different Bacteroides species when they encountered different fibers. They focused on Bacteroides because members of this group of bacterial species contain genes responsible for metabolizing dietary fiber that are not present in the human genome.

For the second phase of the study, the investigators wanted to determine how different members of the microbial community interact with each other as they dine on dietary fiber. First author Michael Patnode, a postdoctoral fellow in Gordon’s lab, developed fluorescently labeled artificial food particles with different types of bound carbohydrates from different fibers. Collections of these nutrient-containing particles were fed to mice colonized with defined microbial communities containing different combinations of Bacteroides species.

“We were excited to see how these ‘biosensors’ could be used to assess the processing of particular fiber components by particular bacterial species,” Patnode says. By feeding these particles to mice that either carried or did not carry a dominant fiber-consuming species, the authors found that subordinate species were waiting in line to step up and consume the fiber.

“We had suspected there might be competition going on among the different strains and that some would be stronger competitors than others,” Patnode says. Proteomics analyses and genetic screens confirmed that there was a hierarchy of fiber consumption among the species present in this model bacterial community.

Gordon explains that “it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms–in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”

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This work was supported by the National Institutes of Health, Mondelez International, and the U.S. Department of Energy. Gordon is a co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. Elements of this report are the subject of patent applications that are currently being submitted.

Cell, Patnode et al.: “Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans” https://www.cell.com/cell/fulltext/S0092-8674(19)30899-2

Research Uncovers Details about How Gut Microbes Influence the Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 04/22/2020
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The microscopic organisms that live in our intestines perform many jobs to keep us healthy, such as helping our bodies digest nutrients from food. They keep harmful microbes under control and prevent them from taking over the gut, and also play a role in regulating the immune system.

Researchers at Memorial Sloan Kettering are studying the connections between gut microbes and human health. In a study published April 15 in Nature, an MSK team uncovered new findings about an important relationship: the way that gut microbes promote the formation of a type of immune cell called regulatory T cells (Tregs).

Tregs help keep powerful immune responses in check. They are crucial for preventing autoimmunity, when the immune system mistakenly attacks the body. Tregs also play a role in cancer: Cancer is more likely to develop when malfunctioning Tregs lead to chronically inflamed tissue. This is seen in conditions such as inflammatory bowel disease (IBD).

Focusing on the Microbe–T Cell Connection

“Life in all mammals, including humans, is impossible without regulatory T cells,” says the study’s senior author, Alexander Rudensky, Chair of the Immunology Program in the Sloan Kettering Institute and a Howard Hughes Medical Institute investigator. “This study builds on previous research from our lab and others that looked at how these cells are made and why they are so important.

“It’s already been shown that disturbance of the microbial community in the gut is associated with autoimmune and inflammatory diseases, like IBD,” he adds. “These findings have illustrated the importance of the relationship between the microbes that live in our guts and our immune systems.”

To better understand this relationship, Dr. Rudensky and his team study how different microbes in the gut affect the production of Tregs that protect against inflammation and autoimmune conditions. They do this by looking at the molecules that microbes make to carry out their metabolic functions. Then they study how those metabolites in turn influence the manufacturing of Tregs.

In the experiments, the investigators concentrated on a class of metabolites called secondary bile acids. These are produced by gut microbes. Bile acids help the digestion of dietary fats.

Members of Dr. Rudensky’s team focused on a type of gut bacteria belonging to a group called Bacteroides and engineered them to produce a particular bile acid, called isoDCA. They exposed naive T cells, which had not yet developed into a specific T cell type, to isoDCA during the process of their activation. They found that isoDCA caused the immature T cells to become Tregs.

Ultimately, these findings could lead to a bacterial-based therapy for the treatment of IBD associated with imbalanced microbes and diminished Treg activity. (Currently, IBD is treated with anti-inflammatory drugs, which can have many side effects.) But Dr. Rudensky says much more work is needed before this kind of treatment could be tested. Many parts of the process are still not well understood. In addition, researchers would have to do extensive testing in mice before designing a clinical trial. “We plan to continue exploring the possibility of using metabolic products from microbes for the treatment of inflammatory disorders,” he says.

The two first authors on the paper were research fellow Clarissa Campbell and research associate Peter McKenney in Dr. Rudensky’s lab. Investigators in MSK’s Donald B. and Catherine C. Marron Cancer Metabolism Center, including the center’s director, Justin Cross, also contributed to the research.

Gut microbe movements regulate host circadian rhythms

Source: Cell Press
Date: 12/01/16
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Even gut microbes have a routine. Like clockwork, they start their day in one part of the intestinal lining, move a few micrometers to the left, maybe the right, and then return to their original position. New research in mice now reveals that the regular timing of these small movements can influence a host animal’s circadian rhythms by exposing gut tissue to different microbes and their metabolites as the day goes by. Disruption of this dance can affect the host. The study appears December 1 in Cell.

“This research highlights how interconnected the behavior is between prokaryotes and eukaryotes, between mammalian organisms and the microbes that live inside them,” says Eran Elinav, an immunologist at the Weizmann Institute of Science, who led the work with co-senior author Eran Segal, a computational biologist also at the Weizmann. “These groups interact with and are affected by each other in a way that can’t be separated.”

The new study had three major findings:

  • The microbiome on the surface layer of the gut undergoes rhythmical changes in its “biogeographical” localization throughout the day and night; thus, the surface cells are exposed to different numbers and different species of bacteria over the course of a day. “This tango between the two partners adds mechanistic insight into this relationship,” Elinav says.
  • The circadian changes of the gut microbiome have profound effects on host physiology, and unexpectedly, they affect tissue that is far away from the gut, such as the liver, whose gene expression changes in tandem with the gut microbiome rhythmicity. “As such,” adds Elinav, “disturbances in the rhythmic microbiome result in impairment in vital diurnal liver functions such as drug metabolism and detoxification.”
  • The circadian rhythm of the host is deeply dependent on the gut microbiota oscillations. Although some circadian machinery in the host was maintained by its own internal clock, other components of the circadian clock had their normal rhythms destroyed. Most surprising, another set of genes in the host that normally exhibit no circadian rhythms stepped in and took over after the microbial rhythms were disrupted.

Previous work by Elinav and Segal revealed that our biological clocks work in tandem with the biological clocks in our microbiota and that disrupting sleep-wake patterns and feeding times in mice induced changes in the microbiome in the gut.

“Circadian rhythms are a way of adapting to changes in light and dark, metabolic changes, and the timing of when we eat,” says Segal. “Other studies have shown the importance of the microbiome in metabolism and its effect on health and disease. Now, we’ve shown for the first time how circadian rhythms in the microbiota have an effect on circadian rhythms in the host.”

The investigators say their work has potential implications for human health in two important ways. First of all, because drugs ranging from acetaminophen to chemotherapy are metabolized in the liver, understanding — and potentially being able to manipulate — the circadian rhythms of our microbiota could affect how and when medications are administered.

Second, understanding more about this relationship could help to eventually intervene in health problems like obesity and metabolic syndrome, which are more common in people whose circadian rhythms are frequently disrupted due to shift work or jet lag.

“What we learned from this study is that there’s a very tight interconnectivity between the microbiome and the host. We should think of it now as one supraorganism that can’t be separated,” Segal says. “We have to fully integrate our thinking with regard to any substance that we consume.”

Newly discovered gut organism protects mice from bacterial infections

Source: Cell Press
Date: 10/06/16
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While bacteria are often stars of the gut microbiome, emerging research depicts a more complex picture, where microorganisms from different kingdoms of life are actively working together or fighting against one another. In a study published October 6 in Cell, scientists reveal one example: a newly discovered protist that protects its host mice from intestinal bacterial infections.

“This was a serendipitous finding, but an important one,” says senior author Miriam Merad, a Professor of Oncological Sciences and of Medicine at the Icahn School of Medicine at Mount Sinai. “This study shows how vital it is to go beyond bacteria when studying the microbiome.”

The investigators made the discovery when they realized that mice that had been bred at their own facility had a greater number of immune cells in the gut than mice purchased from an outside vendor. Graduate student Aleksey Chudnovskiy, the study’s first author, together with postdoctoral fellow Arthur Mortha, decided to figure out why that was the case. When they performed an intestinal cleanse on the two groups of mice, they were surprised to find that the mice from the Mount Sinai facility had flagellated protozoa living in their guts. DNA sequencing revealed that the microorganism was a new protozoan parasite, which they named Tritrichomonas musculis (T. mu).

Further investigations showed that when this protist was given to the mice that didn’t have it, they, too, had an increase in the number of immune cells in their guts and also increased inflammatory cytokines. The researchers set out to discover the underlying mechanism. They found that T. mu activates the inflammasome in the gut epithelial cells of the mice, which in turn led to the activation of cytokines. They also found that dendritic cells were required to induce inflammation.

To determine whether colonization of T. mu in the gut affected the mice’s ability to fight off infection, they infected mice with Salmonella and found that the animals that had T. mu as part of their microbiome were very resistant to Salmonella infection. “The protective effect of this species is very striking,” Chudnovskiy says.

T. mu was found to be an ortholog of Dientamoeba fragilis, a parasite that’s found in the guts of many humans, but the researchers don’t know if D. fragilis also has a protective effect. It’s something they plan to study. “People from industrialized countries traveling to emerging countries are more susceptible to intestinal infection than the indigenous population,” Merad explains. “It’s possible that protists, which are known to be common in emerging countries, contribute to the protective effect against intestinal pathogenic infections.”

She adds: “The fight against pathogens determined the survival of the human species, and those with stronger immune systems are the ones who survived. It is likely that the microbiome is a big part of the evolutionary process. Thus, identifying those commensals that confer immune strength in exposed communities should help identify novel therapeutics.”