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Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells

Abstract

Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17–positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17+ γδ T cells on ischemic injury.

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Figure 1: Alteration of intestinal microbiota protects from MCAO-induced brain injury.
Figure 2: Increased Treg cells and reduced IL-17+ γδ T cells in the small intestine of ACSens mice.
Figure 3: Accumulation of IL-17+ γδ T cells at the meninges is associated with increased infarct size.
Figure 4: Migration of intestinal T cells to the meninges after ischemic brain injury.
Figure 5: Neuroprotection conferred by intestinal dysbiosis requires a reduction in intestinal IL-17+ γδ T cells.
Figure 6: DCs from ACSens mice originate in the intestine, induce Treg cells and downregulate IL-17+ γδ T cells in vitro.

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Acknowledgements

J.A. is the recipient of the Finbar and Marianne Kenny Research Scholarship. Parts of the study were supported by the US National Institutes of Health (NIH) grants NS081179 (J.A.) and NS34179 (C.I. and J.A.), the Feil Family Foundation (C.I.) and the Swiss National Science Foundation for Grants in Biology and Medicine (P3SMP3 148367; C.B.). We thank A.-K. Hadjantonakis (Memorial Sloan Kettering Cancer Center) for helpful discussions on the use of the KikGR33 mice.

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C.B. and D.B. contributed to study design, performed and/or contributed critically to all experiments and analyzed data. In some experiments, C.B. and D.B. were assisted by J.M., M.M., G.S. and G.R. G.F. performed EB extravasation experiments. E.G.P. and S.C. developed and provided the ACRes mouse model. L.L. performed r16S sequencing, and together with E.G.P., analyzed taxonomic data. C.I. contributed to study design. J.A. formulated the original hypothesis, designed the study, analyzed data and wrote the manuscript together with C.B., D.B. and C.I. All authors read and approved the manuscript.

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Correspondence to Josef Anrather.

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Benakis, C., Brea, D., Caballero, S. et al. Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat Med 22, 516–523 (2016). https://doi.org/10.1038/nm.4068

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