ABSTRACT
The gut microbiota influences development and homeostasis of the mammalian immune system1–3, can alter immune cell compositions in mice4–7, and is associated with responses to immunotherapy that rely on the activity of peripheral immune cells8–12. Still, our understanding of how the microbiota modulates immune cells dynamics remains limited, particularly in humans where a lack of deliberate manipulations makes inference challenging. Here we study hundreds of hospitalized—and closely monitored—patients receiving hematopoietic cell transplantation as they recover from chemotherapy and stem cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, allowing the relationships between the two to be studied simultaneously. We analyzed daily changes in white blood cells from 2,235 patients, and 10,680 longitudinal microbiota samples to identify bacteria associated with those changes. Bayesian inference and validation across patient cohorts revealed consistent associations between gut bacteria and white blood cell dynamics in the context of immunomodulatory medications, clinical metadata and homeostatic feedbacks. We contrasted the potency of fermentatively active, obligate anaerobic bacteria with that of medications with known immunomodulatory mechanism to estimate the potential of the microbiota to influence peripheral immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.
Competing Interest Statement
. This work was supported by the National Institutes of Health (NIH) grant U01 AI124275 to JBX and grant R01 AI137269 to JBX, by the MSKCC Cancer Center Core Grant P30 CA008748, the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, the Sawiris Foundation, the Society of Memorial Sloan Kettering Cancer Center, MSKCC Cancer Systems Immunology Pilot Grant and Empire Clinical Research Investigator Program. MS received funding from the Burroughs Wellcome Fund Postdoctoral Enrichment Program, the Damon Runyon Physician-Scientist Award, and the Robert Wood Johnson Foundation. MRMvdB and JUP received financial support from Seres Therapeutics. TMH is investigator in the Pathogenesis of Infectious Diseases from the Burroughs Wellcome Fund, and funded via an award from Geoffrey Beene Foundation, and NIH RO1 AI093808. M-AP has received honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda; has received research support for clinical trials from Incyte, Kite (Gilead) and Miltenyi Biotec; and serves on data and safety monitoring boards for Servier and Medigene and scientific advisory boards for MolMed and NexImmune. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Footnotes
Major revisions. Revisions to analyses of FMT effect on WBC counts, and additional, new analyses. These include an analysis of associations in the reverse direction from the main analysis, i.e. from the reconstituting immune system onto the microbiota. This required conducting qPCR of the 16 rRNA gene in 3,995 samples from 481 patients.