For the first time, bacteria in the gut have been shown by researchers to play a direct role in the human immune system by impacting levels of white blood cells, potentially opening doors for improvements in immunotherapy.
The findings, published in Nature in November, represent a unique look into the wide-ranging effects of gut inhabitants on the human body.
Led by researchers at a New York-based cancer center, the study involved crunching 17 years’ worth of medical data from hundreds of cancer patients receiving bone-marrow transplants. The information was used to build a mathematical model that could determine how the presence of individual strains of gut bacteria caused changes in white blood cell counts, the most-detailed analysis ever of their interactions.
Numerous rat and mouse studies had previously shown that the gut microbiome — the community of bacteria and other organisms living in the digestive tract of humans — is an important part of immune-system function. The rodent research relied on wiping clean the test subjects’ microbiomes, a level of intervention not usually possible in humans during a controlled experiment, said Jonas Schluter, a professor at New York University’s Institute for Computational Medicine and the study’s lead author.
Instead, he and his colleagues turned to the medical records of blood-cancer patients receiving new stem cells via bone-marrow transplants at the Memorial Sloan Kettering Cancer Center. The transplants, in addition to chemotherapy, wipe out immune cells and require the temporary use of antibiotics, which prevent and treat infections but also destroy many bacteria in the gut. These “massive perturbations” in both the immune system and gut microbiome made the patients valuable sources of data, Schluter said.
“Because it's such a highly dynamic process with repeatedly observed dynamics over time,” Schluter said, “We can then ... sample the microbiome in these patients and see if there's any correspondence between these weakened immune system reconstitution trajectories and the gut microbiome present in these patients.”
Schluter, a postdoctoral researcher at the cancer center during the research, created a statistical model to track how both systems changed over time within nearly 2,000 patients from 2003 to 2019. The model was applied to measurements of white blood cells from more than 20,000 blood samples and of the populations of several bacterial strains in the gut from more than 10,000 stool samples.
This high-resolution analysis led the researchers to conclude that numerous gut bacteria caused either increases or decreases in different kinds of white blood cells when present in the gut, including Faecalibacterium prausnitzii, one of the most prevalent members of the microbiome.
The passage of time captured by the findings allowed the team to conclude that these relationships are causal, save for potential confounding factors such as diet.
The evolutionary history of humans and their gut microbiomes provides crucial context to understanding their current relationship and developing treatments, Schluter explained. He said gut bacteria have evolved not in the dedicated service of human beings, like organs have, but instead for their own survival within the body’s constraints.
Although humans and the gut microbiome have adapted to function alongside each other — as demonstrated in this study — the bacteria are not necessarily looking out for their hosts, an evolutionary attitude crucial to understanding their modern functions, Schluter said.
“I feel that we need to have this thorough rooting of microbiome research in evolutionary ecological theory to make sense of this complicated community of selfish microorganisms inside of our intestines and elsewhere if we want to develop a therapeutic target,” the NYU professor said.
Schluter said his team’s study opens up new lines of inquiry into the gut bacteria that interact with the immune system, and that other researchers can conduct additional analysis on the cancer-patient dataset. He is currently involved in research investigating the molecular mechanisms behind the interactions with the hope of harnessing them to design a therapy.
Schluter is also interested in applying the new mathematical methods to study the gut microbiome’s role in maintaining homeostasis: By putting even a single person “under the microscope” with numerous measurements over time, he said, one may discover new systems and relationships within the human body that could lead to new treatments.
“In an ideal world, I'd measure every single thing every minute of your day in 1,000 patients over a year, and then we just run a gigantic model of all of this,” Schluter said.
The article “The gut microbiota is associated with immune cell dynamics in humans” was published Nov. 25 in Nature. The authors of the study were Jonas Schluter, New York University; Jonathan Peled, Bradford Taylor, Kate Markey, Melody Smith, Ying Taur, Anqi Dai, Emily Fontana, Luigi Amoretti, Roberta Wright, Sejal Morjaria, Maly Fenelus, Melissa Pessin, Tobias Hohl, Miguel-Angel Perales, Marcel van den Brink and Joao Xavier, Memorial Sloan Kettering Cancer Center; Rene Niehus, Harvard University; Anna Staffas, University of Gothenburg; and Nelson Chao, Meagan Lew, Lauren Bohannon, Amy Bush and Anthony Sung, Duke University. The lead author was Jonas Schluter.