SUMMARY The gut microbiota influences development 1 – 3 and homeostasis 4 – 7 of the mammalian immune system, and is associated with human inflammatory- 8 and immune diseases 9 , 10 as well as patients’ responses to immunotherapy 11 – 14 . Still, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans where a lack of deliberate manipulations makes inference challenging. Here we study hundreds of hospitalized—and closely monitored—cancer 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. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and >10,000 longitudinal microbiota samples from patients revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera relative to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota—in concert and over time—on systemic 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.

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We have previously described clinically relevant reductions in fecal microbiota diversity of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1,161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma and amyloidosis in an observational study conducted at two transplant centers in the United States. Using 16S ribosomal gene sequencing, we assessed fecal microbiota diversity as measured by the inverse Simpson index, and composition. At both centers, early pre-transplant fecal microbiota diversity was lower than in healthy control subjects and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to allo-HCT. Above-median fecal intestinal diversity in the peri-engraftment period was associated with decreased risk of death or progression (PFS HR 0.46 [95% CI, 0.26-0.82], P=0.008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and post-transplant outcomes should be undertaken.

Hospitalized patients receiving hematopoietic cell transplants provide a unique opportunity to study the human gut microbiome. We previously compiled a large-scale longitudinal dataset of fecal microbiota and associated metadata, but we had limited that analysis to taxonomic composition of bacteria from 16S rRNA gene sequencing. Here we augment those data with shotgun metagenomics. The compilation amounts to a nested subset of 395 samples compiled from different studies at Memorial Sloan Kettering. Shotgun metagenomics describes the microbiome at the functional level, particularly in antimicrobial resistances and virulence factors. We provide accession numbers that link each sample to the paired-end sequencing files deposited in a public repository, which can be directly accessed by the online services of PATRIC to be analyzed without the users having to download or transfer the files. Then, we show how shotgun sequencing enables the assembly of genomes from metagenomic data. The new data, combined with the metadata published previously, enables new functional studies of the microbiomes of patients with cancer receiving bone marrow transplantation.

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