The impact of the gut microbiota on circulating leukocyte levels

We posted our new study on bioRxiv were we compared the impact of the microbiota white blood cells dynamics in patients receiving hematopoietic cell transplantation.

We estimate that microbiota diversity can have a suppressive effect on circulating lymphocytes similar to that of immunosuppressive drugs administered to reduce graft vs host disease. This may help explain previous studies from our MSKCC collaborators that associated microbiota diversity to lower transplant-related mortality. There’s more work to be done for a mechanism linking the microbiota to systemic immunity, of course. But this study stands out because it addresses the problem directly in humans.

We are going to wait a few days before we submit the paper for peer review. We appreciate any comments to improve the paper.

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Antibiotics and weight gain

Martin Blaser’s lab showed a few years ago that exposing mice to low doses of antibiotics very early in their lives changes their gut microbiota and makes the mice gain more fat and gain more body weight later in life. Jonas Schluter and I started collaborating with Blaser’s group three years ago.  In a paper published today in the ISMEJ we analyzed one of their latest experiments–one with a large scale cohousing scheme that sought to determine whether exchanging gut microbes with untreated mice would lower the tendency that antibiotic-exposed mice to had to gain more weight.

We saw that mice exposed to antibiotics in early life mice got on a weight-gain trajectory, and they stayed on that trajectory despite exchanging microbes with mice who were never exposed to antibiotics.  We ran many statistical tests as part of our analysis. The paper shows that the effect of antibiotics is reproducible and robust.

Our paper has implication for obesity in people too. We are frequently exposed to low doses of antibiotics that could cause us to gain more weight. The impact of antibiotics is robust, and reversing the propensity to gain weight may not be solved simply by borrowing excrement from someone else to do a fecal microbiota transplant, appealing as that may sound.

Read the paper: The impact of early-life sub-therapeutic antibiotic treatment (STAT) on excessive weight is robust despite transfer of intestinal microbes.
Anjelique F. Schulfer, Jonas Schluter, Yilong Zhang, Quincy Brown, Wimal Pathmasiri, Susan McRitchie, Susan Sumner, Huilin Li, Joao B. Xavier & Martin J. Blaser. ISMEJ
[Open access]

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Results from auto-FMT pilot

Our team at Memorial Sloan Kettering has been investigating the intestinal microbiota of patients receiving bone marrow transplantations for more than eight years now. We have found through several studies that these patients lose important healthy bacteria from their microbiota and that these losses are mostly caused by the antibiotics given as prophylaxis or to treat infections. We also found that the drastic changes in the microbiota composition, especially the intestinal dominations by bacteria such as Enterococcus, increase the risk of transplant-related complications and lowered patient survival. Here we tested whether autologous microbiota transplant (auto-FMT) could reconstitute lost bacteria. In this randomized study led by Ying Taur and Eric Pamer we could see that auto-FMT indeed reconstituted important microbial groups to patients.

The success of auto-FMT varied from patient to patient, though. In the best case a patient recovered practically 100% but in the worst case, recovery was 50%. The effect of auto-FMT was statistically significantly overall, but understanding why its success can vary between patients (which could be due to factors like the actual composition of the transplant, the state of the microbiota before the transplant or even personal factors like host genetics or the underlying disease) is an important direction for future research, and for future microbiota therapies.

As the pilot study continues we should be able to determine whether auto-FMT also improves clinical outcomes for this patients. This is a question left unanswered in our report but which will be addressed in the near future.


Timeline for a study patient undergoing allo-HSCT and randomized to receive auto-FMT.  Allo-HSCT was initiated with pretransplant conditioning [chemotherapy and total body irradiation (TBI)], followed by allogeneic hematopoietic stem cell infusion (day 0). Various antibiotics were given throughout this period for prophylactic and treatment purposes. After stem cell engraftment, randomization assigned this patient to the treatment arm and the patient received an auto-FMT on day 49 using the patient’s initial pretreatment feces, which had been collected and stored before allo-HSCT (initial feces collected at day −21). The intestinal microbiota was restored to that before the transplant.

Read the paper: Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Taur et alScience Translational Medicine [PDF]

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Machine learning in simple biochemical networks

Our bow-tie paper is finally out. Here’s the teaser:


Bow-tie: never out of style

How does evolution shape living organisms that seem so well adapted that they could be intelligently designed? Here, we address this question by analyzing a simple biochemical network that directs social behavior in bacteria; we find that it works analogously to a machine learning algorithm that learns from data. Inspired by new experiments, we derive a model which shows that natural selection—by favoring biochemical networks that maximize fitness across a series of fluctuating environments—can be mathematically equivalent to training a machine learning model to solve a classification problem. Beyond bacteria, the formal link between evolution and learning opens new avenues for biology: machine learning is a fast-moving field and its many theoretical breakthroughs can answer long-standing questions in evolution.

Read the full paper:
Bow-tie signaling in c-di-GMP: machine learning in a simple biochemical network
Jinyuan Yan, Maxime Deforet, Kerry E. Boyle, Rayees Rahman, Raymond Liang, Chinweike Okegbe, Lars E. P. Dietrich, Weigang Qiu and Joao B. Xavier. PLOS Computational Biology
[Open access]

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Metabolism and the evolution of social behavior

Kerry Boyle’s PhD paper is out today. It’s still in the early-view, unformatted version but it is now officially published!

In this paper we addressed a fundamental question: Why do organisms of many species seem to change their behavior toward others depending on their internal metabolic state? To investigate this problem at an ultimate level we carried experiments with swarming Pseudomonas aeruginosa, a bacterial model of social behavior. Experiments with bacteria allowed us to alter the metabolic state genetically and to determine—with a level of detail that would be difficult in more complex model organisms—how those changes influenced the evolution of social social behavior.

Our paper uses a combination of experimental evolution, molecular microbiology, whole-genome sequencing and is—to the best of our knowledge—the first to use metabolomics to investigate the role of metabolism in the evolution of a social behavior. This was only possible thanks to our collaborators at Kyu Rhee‘s lab, experts in microbial metabolomics.


The implications go beyond P. aeruginosa: Natural selection favors organisms that can regulate their social behaviors and reduce their fitness cost-to-benefit ratio. Metabolism—currency of all physiological processes—is a very obvious away that social genes have to modulate the cost of a behavior; metabolism should influence social behavior in all organisms, including ourselves. For a review on genes and social behavior see Robinson et al, 2008, Science.

Metabolism and the evolution of social behavior
Kerry E. Boyle, Hilary T. Monaco, Maxime Deforet, Jinyuan Yan, Zhe Wang, Kyu Rhee and Joao Xavier. Molecular Biology and Evolution
[Open Access]

Watch a video abstract made by Natalie Anselmi:

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NYC BIG 2017

A conference that used to be a meeting for Bacillus researchers in the Northeastern United States and has broadened to other bacteria as well. This year the NYC/BIG is on June 8th. Hilary Monaco and Jinyuan Yan will talk about their work on Pseudomonas aeruginosa. See:


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Cancer metabolites organize the tumor microenvironment

Cancer cells are not alone: As cancerous tumors grow unregulated cancer cells engage other cells, in their path of destruction like macrophages which are part of the immune system and endothelial cells which make blood vessels. This collection of non-cancer cells that powers cancer growth is called the tumor microenvironment. How does the tumor microenvironment help cancer cells proliferate even more?

Answering this question is a holy grail of cancer science and holds the key to new therapies. Cancer cells, with their many mutations and unchecked DNA damage, change constantly: they can be a moving target for therapy and develop resistance to drugs that seemed to work at first. The non-cancer cells in the tumor microenvironment are genetically stable. If we knew how these cells interact we could to stop the tumor microenvironment from feeding the cancer, halt cancer growth or even reverse it. On February 28 a team of SKI scientists published a significant advance. The answer—surprisingly—is in metabolism.

All cells rely on metabolism, the engine-like process that requires constant fuel and oxygen to run. Cancer cells have altered metabolisms: they consume lots of oxygen and dump metabolic waste such as lactic acid. Because of this, cancerous tumors should only grow so large before the toxic effects accumulate like pollution in a jam-packed city, and eventually slow cancer growth. This is prevented, however, by tumor-associated macrophages (TAMs) that respond to the harsh environment and start a tissue-repair mechanism to clean it up.

The SKI team started by observing the behaviors of TAMs in a mouse model of cancer. Then, they fabricated tissue-mimetic systems to recreate the same process in vitro. Using this approach they discovered that TAMs respond to low oxygen and to the presence of lactic acid and start producing a vascular endothelial growth factor (VEGF). This growth factor commands endothelial cells to start producing blood vessels—called neo-angiogenesis—a process that can bring new blood to struggling cancer cells, replenishing oxygen and removing toxic waste.

The tissue-repair response of macrophages is normally a good thing: it is how our body heals wounds and clears out toxic waste from muscles after intense exercise. In cancers, however, it can make cells with complementary skills—cancer cells, TAMs and endothelial cells—work together in a terrible way. Rescuing cancer cells from dying because of their own altered metabolism boosts the cancer to grow even more.

The SKI study established a new role for cancer metabolism in the interactions between cancer cells and their microenvironment. These findings lay the foundations for our understanding of cancer development, diagnosis and treatment.

But the study also showed how an interacting team of multidisciplinary scientists could answer a difficult cancer question: Craig Thompson brought his expertise in cancer metabolism, Johanna Joyce her expertise in the tumor microenvironment, and João Xavier his expertise in cancer systems biology, a new field that aims to integrate cancer concepts. Cancers subvert cells with complementary features in their path to destruction; figuring out its complex mechanisms—and new ways to fight them—may require teams of scientist with complementary skills.

The study was spearheaded by Carlos Carmona Fontaine, former postdoctoral researcher at MSKCC who is now assistant professor of Biology at the New York University.

Metabolic origins of spatial organization in the tumor microenvironment
Carlos Carmona-Fontaine, Maxime Deforet, Leila Akkari, Craig B. Thompson, Johanna A. Joyce, Joao B. Xavier. PNAS
[Open Access]

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