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Translocation and dissemination of commensal bacteria in post-stroke infection

Abstract

Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.

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Figure 1: Stroke-induced infections are derived endogenously from the host.
Figure 2: Microbial communities in post-stroke mice.
Figure 3: Stroke induces robust changes in the gut permeability.
Figure 4: Stroke alters the cellular composition of the gut barrier.
Figure 5: Blockade of β-adrenergic receptors reduces gut permeability and post-stroke infections.
Figure 6: Evidence of bacterial translocation and dissemination after stroke.

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Acknowledgements

We thank the staff at Monash Animal Research Facilities, Monash Micromon, Monash Micro Imaging and Monash Histology Platform, which are managed by Monash University. The bioinformatics data was analyzed using the Isaac Newton high-performance computing system at Central Queensland University. We wish to acknowledge the help from J. Bell that was provided for all aspects of the high-performance computing. We thank E.A. Palombo (Swinburne University of Technology) for providing a streptomycin-resistant derivative of the E. coli strain ATCC700927 (EDL933), designated DLL206. The work was supported by the Australia Research Council (ARC) (D.S. and C.H.Y.W.), the Australian National Heart Foundation (NHF) (C.H.Y.W.) and the Australian National Health and Medical Research Council (NHMRC) (C.H.Y.W.).

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Authors

Contributions

C.H.Y.W. conceived, designed and performed most of the experiments, and prepared the manuscript; D.S. and R.J.M. performed all of the microbiota sequencing and relevant bioinformatics analyses; L.J.M. assisted in tissue harvesting and was instrumental in organizing experiments that involved GF mice; M.D.P. and K.N. performed gut motility and immunohistochemistry analyses on ileum tissue; Y.N.S. and D.L. performed the ddPCR; K.E.M. and D.L. sourced the DLL206 strain for the E. coli colonization experiment and performed the bacteriological analysis after gavage; A.V. and M.D.H. provided clinical data for the individuals in the Stroke Unit who had acquired infections after having a stroke; and all authors read and critically reviewed the manuscript.

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Correspondence to Connie H Y Wong.

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The authors declare no competing financial interests.

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Stanley, D., Mason, L., Mackin, K. et al. Translocation and dissemination of commensal bacteria in post-stroke infection. Nat Med 22, 1277–1284 (2016). https://doi.org/10.1038/nm.4194

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