Precision identification of diverse bloodstream pathogens in the gut microbiome

Abstract

A comprehensive evaluation of every patient with a bloodstream infection includes an attempt to identify the infectious source. Pathogens can originate from various places, such as the gut microbiota, skin and the external environment. Identifying the definitive origin of an infection would enable precise interventions focused on management of the source1,2. Unfortunately, hospital infection control practices are often informed by assumptions about the source of various specific pathogens; if these assumptions are incorrect, they lead to interventions that do not decrease pathogen exposure3. Here, we develop and apply a streamlined bioinformatic tool, named StrainSifter, to match bloodstream pathogens precisely to a candidate source. We then leverage this approach to interrogate the gut microbiota as a potential reservoir of bloodstream pathogens in a cohort of hematopoietic cell transplantation recipients. We find that patients with Escherichia coli and Klebsiella pneumoniae bloodstream infections have concomitant gut colonization with these organisms, suggesting that the gut may be a source of these infections. We also find cases where typically nonenteric pathogens, such as Pseudomonas aeruginosa and Staphylococcus epidermidis, are found in the gut microbiota, thereby challenging the existing informal dogma of these infections originating from environmental or skin sources. Thus, we present an approach to distinguish the source of various bloodstream infections, which may facilitate more accurate tracking and prevention of hospital-acquired infections.

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Fig. 1: BSI pathogens are present in the gut microbiota at varying relative abundance prior to BSI.
Fig. 2: Gut and BSI strains from the same patient are more closely related than strains from different patients.
Fig. 3: Antibiotic resistance gene predictions in bloodstream isolate genomes.

Data availability

All sequencing data sets from the current study have been deposited in the Sequence Read Archive under BioProject PRJNA477326. Accession numbers are listed in Supplementary Table 14.

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Acknowledgements

We thank J. Kang for her assistance with stool sample processing, as well as the other members of the Bhatt laboratory for providing feedback on the study design, bioinformatics pipeline and manuscript revisions. We also thank N. Greenfield and the One Codex team for help with using their platform. We appreciate M. Kelly, C. Severyn and D. Ward for their feedback on the manuscript. We especially thank the patients and nurses on the Blood and Marrow Transplantation service for their enthusiastic participation in this project. This work was supported in part by the National Science Foundation Graduate Research Fellowship (F.B.T.), the National Institutes of Health (NIH), National Center for Advancing Translational Science, Clinical and Translational Science Awards KL2 TR001083 and UL1 TR001085 and the American Society of Blood and Marrow Transplantation New Investigator Award (T.M.A.). A.S.B. was funded in part by the National Cancer Institute NIH K08 award, no. CA184420, the Damon Runyon Clinical Investigator Award and the Amy Strelzer Manasevit Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Contributions

F.B.T. generated the bloodstream isolate sequencing libraries, developed the StrainSifter pipeline and performed the sequencing data analysis. T.M.A. developed the stool biospecimen collection, assisted in study design, extracted clinical metadata from the electronic medical record and generated the stool sample sequencing libraries. E.T. contributed to the generation of stool sample sequencing libraries. F.S. and N.B. provided blood culture isolates. A.S.B. was responsible for study design and manuscript feedback. T.M.A., F.B.T. and A.S.B. wrote and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ami S. Bhatt.

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Tamburini, F.B., Andermann, T.M., Tkachenko, E. et al. Precision identification of diverse bloodstream pathogens in the gut microbiome. Nat Med 24, 1809–1814 (2018). https://doi.org/10.1038/s41591-018-0202-8

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