By Eduardo Longoria
An article published recently in the journal Nature reported findings on how the gut microbiota influences the development and maintenance of the mammalian immune system. Our understanding of how the immune system is modulated remains limited, particularly in humans, where the difficulty of direct experimentation makes the inference challenging. Despite these difficulties, the study managed to find valuable insights regarding three bacterial genera.
“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,” said Dr. Joao Xavier, co-senior author of the study.
This study investigated whether the gut microbiota could influence the day-to-day changes in peripheral immune cell counts. This was done by analyzing the study results of hundreds of hospitalized and monitored cancer patients who were receiving hematopoietic cell transplantation (HCT) as part of their chemotherapy recovery. The HCT treatment dramatically affects both circulatory, immune cell, and microbiota populations, enabling the relationships between the two to be studied easily. The vast dataset of immune-reconstitution dynamics after HCT was taken from patients treated at the Memorial Sloan Kettering Cancer Center (MSK) between 2003 and 2019.
Data regarding the population of bacteria in the patient’s GI tract was estimated using the 16S rRNA gene counts in their stool. These rRNA samples were then sequenced to ascertain which species, in particular, lived within the patients.
Conditioning for HCT treatment depletes white blood cell (WBC) counts, leading to neutropenia (less than 500 neutrophils per μl blood) and damage to the gut microbiota. These conditions continue until transplanted stem cells begin to release granulocytes from the bone marrow, initiating immune reconstitution.
Immune and microbiome reconstitution vary considerably between patients and treatment types. The observed daily changes in circulating neutrophil, lymphocyte, and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics.
To detect a directional and causal link between the microbiota and circulatory WBCs, the research team used high-resolution clinical metadata and Bayesian inference (statistical inference making use of Bayes theorem to adapt to new information). There were two stages of data analysis.
The first stage was done on 1096 patients using blood and medication data to detect medications and HCT parameters associated with WBC dynamics. This approach was validated with clinical and metadata-feature-selection (selecting a subset of relevant features for use in model construction) and was made with no microbiome information. The team analyzed the changes in neutrophils, lymphocytes, and monocytes during recovery from more than 20,000 pairs of post-engraftment blood samples. This analysis allowed a comparison of the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota on systemic immune cell dynamics.
Stage 2 was comprised of 841 individuals and primarily focused on the PBSC (peripheral blood stem cells) graft recipients while withholding the bone marrow and umbilical cord cohorts. The dynamic systems model of stage 2 included bacterial genera as predictors of daily changes in WBC counts clinical features (conditioning intensity, age, and sex), and the current state of the blood in the form of counts of neutrophils, lymphocytes, monocytes, eosinophils, and platelets.
Simulations predict that microbiota enriched with the Faecalibacterium, Ruminococcus, and Akkermansia accelerate immune reconstitution and reduce the time until neutrophils reach a level of more than 2,000 μl−1 in the absence of GCSF by 2.4 days, from a predicted 6.8 days (95% confidence interval (CI) (6.5, 7)) to 4.4 days (95% CI (4.3, 4.5)) days.
The effect of intestinal bacteria on WBC counts may be caused by influencing either their sources in the bone marrow, their sinks in different organs, or both. The immune system can interact with the microbiota and modulate its composition, for example, via immunoglobulin A, as studied in mice. This direct relationship between these three genera of bacteria and the recovery speed of the immune system is potentially applicable in aiding patient recovery.
“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 data points that we can use to ask questions about the dynamics of this relationship.”
The human gut microbiota is considered a major modulator of the immune system. However, for the first time, the study shows how the concentration of different types of immune cells in the blood is affected by different bacterial strains in the gut. This further establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity. This paper validates a lot of the general research that many startups and mature companies like Ginkgo and Zymergen are working on today.
Moreover, the medical community stands to benefit from the wealth of genetic information contained in the human microbiome. While the human genome itself has 23,000 unique protein-encoding genes, the human microbiome project reports 3.3 million unique protein-encoding genes for the gut microbes.
In the future, patients could benefit immensely by increasing their recovery speed from the immune system damaging medical treatments. By inoculating their GI tract with Faecalibacterium, Ruminococcus, and Akkermansia post the loss of microbiome population, individuals can help rebuild their immune systems more quickly.
By Eduardo Longoria