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Gut-Derived Exosomes Mediate Memory Impairment After Intestinal Ischemia/Reperfusion via Activating Microglia

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Abstract

Intestinal ischemia/reperfusion is a grave condition with high morbidity and mortality in perioperative and critical care settings and causes multiple organ injuries beyond the intestine, including brain injury. Exosomes act as intercellular communication carriers by the transmission of their cargo to recipient cells. Here, we investigate whether exosomes derived from the intestine contribute to brain injury after intestinal ischemia/reperfusion via interacting with microglia in the brain. Intestinal ischemia/reperfusion was established in male C57/BL mice by clamping the superior mesenteric artery for 30 min followed by reperfusion. The sham surgery including laparotomy and isolation of the superior mesenteric artery without occlusion was performed as control. Male C57 mouse was intracerebral ventricular injected with intestinal exosomes from mice of intestinal ischemia/reperfusion or sham surgery. Primary microglia were cocultured with intestinal exosomes; HT-22 cells were treated with intestinal exosomes or microglia conditioned media. Intestinal ischemia/reperfusion-induced microglial activation, neuronal loss, synaptic stability decline, and cognitive deficit. Intracerebral ventricular injection of intestinal exosomes from intestinal ischemia/reperfusion mice causes microglial activation, neuronal loss, synaptic stability decline, and cognitive impairment. Microglia can incorporate intestinal exosomes both in vivo and in vitro. Microglia activated by intestinal exosomes increases neuron apoptotic rate and decreases synaptic stability. This study indicates that intestinal exosomes mediate memory impairment after intestinal ischemia/reperfusion via activating microglia. Inhibiting exosome secretion or suppressing microglial activation can be a therapeutic target to prevent memorial impairment after intestinal ischemia/reperfusion.

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Data Availability

The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.

Abbreviations

I/R:

ischemia/reperfusion

DMEM:

Dulbecco’s Modified Eagle Medium

FBS:

fetal bovine serum

CNS:

central nervous system

Iba-1:

ionized calcium-binding adaptor molecule1

ICV:

intracerebroventricular

SEM:

standard error of the mean

TNFα:

tumor necrosis factor-α

IL-1β:

interleukin-1β

IL-6:

interleukin-6

LPS:

lipopolysaccharide

PBS:

phosphate buffer solution

NeuN:

neuronal nuclei

PSD95:

postsynaptic density 95

CA1:

central amygdala 1

EpCAM:

epithelial cell adhesion molecule

POCD:

postoperative cognitive dysfunction

MAPK:

mitogen-activated protein kinase;

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Acknowledgements

The authors thank Prof. Zhiji Han from Sun Yat-sen University for his generous help in the preparation of the manuscript.

Funding

This work was supported by grants from National Natural Science Foundation, Beijing, China (81671955 to Ke-Xuan Liu), Key Program of National Natural Science Foundation, Beijing, China (81730058 to Ke-Xuan Liu).

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  1. Xiao-Dong Chen and Jin Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Xiao-Dong Chen, Jin Zhao, Xiao Yang, Bo-Wei Zhou, Zhengzheng Yan, Wei-Feng Liu, Cai Li & Ke-Xuan Liu

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  1. Xiao-Dong Chen
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Contributions

(1) Study conception/design: XD Chen, KX Liu, C Li

(2) Conduct of experiments: XD Chen, J Zhao, X Yang, BW Zhou

(3) Data analysis: J Zhao, Z Yan, WF Liu, C Li

(4) Drafting of paper: XD Chen

(5) Editing/revision of paper: C Li, KX Liu

(6) Reading and approval of the final version of the paper: all authors

Corresponding authors

Correspondence to Cai Li or Ke-Xuan Liu.

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All animal experimental protocols were approved by the Experimental Animal Ethisc Committee of Southern Medical University.

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Supplementary Information

Figure S1.

Intestinal exosomes are CD45 negative. SP: spleen, EV1: exosomes from the normal intestine, EV2: exosomes from ischemic/reperfused intestine. (PNG 763 kb)

High Resolution Image (TIF 58 kb)

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Chen, XD., Zhao, J., Yang, X. et al. Gut-Derived Exosomes Mediate Memory Impairment After Intestinal Ischemia/Reperfusion via Activating Microglia. Mol Neurobiol 58, 4828–4841 (2021). https://doi.org/10.1007/s12035-021-02444-4

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