Journal
FRONTIERS IN NEUROLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fneur.2019.00661
Keywords
gut microbiota; short-chain fatty acids; intestinal mucosal damage; systemic inflammation; cerebral infarction; middle cerebral artery occlusion; cynomolgus monkey
Categories
Funding
- National Key R&D Program of China [2017YFC1307500]
- Natural Science Foundation of China [81571107, 81771137, 81801059]
- Scientific and Technical Project of Guangdong Province [2017A030303011]
- Sun Yat-sen University Clinical Research 5010 Program [2018001]
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases [2017B030314103]
- Southern China International Cooperation Base for Early Intervention and Functional Rehabilitation of Neurological Diseases [2015B050501003]
- Guangdong Provincial Engineering Center for Major Neurological Disease Treatment
- Guangdong Provincial Translational Medicine Innovation Platform for Diagnosis and Treatment of Major Neurological Disease
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Background: The bidirectional interaction between the gut and brain after stroke through the immune-mediated pathway has been studied. However, the long-term effects of gut microbiota and systemic immune homeostasis after cerebral ischemia remain unclear. We examined long-term changes in the gut microbiota and systemic inflammatory cytokines after cerebral infarction in cynomolgus monkeys. Methods: Twelve monkeys underwent successful distal M1 segment of the left middle cerebral artery occlusion (MCAO) and were randomly and equally assigned to the MCAO-1.5m, MCAO-6m, and MCAO-12m groups, which were sacrificed 1.5, 6, and 12 months after cerebral infarction induction, respectively. Four monkeys that underwent a sham operation were sacrificed 12 months later. The gut microbiota and short-chain fatty acids (SCFAs) were analyzed by 16S rDNA sequencing and gas chromatography mass spectrometry, respectively. Histological examinations of the transverse colon were performed. Plasma D-lactate, zonulin, lipopolysaccharide (LPS), tumor necrosis factor (TNF-alpha), interferon (IFN)-gamma, and interleukin (IL)-6 were detected by immunoassay kits. Results: The levels of the Bacteroidetes phylum and Prevotella genus were significantly increased, while the Firmicutes phylum as well as the Faecalibacterium, Oscillospira, and Lactobacillus genera were decreased after cerebral infarction. Gut-originating SCFAs were significantly decreased 6 and 12 months after cerebral infarction (P < 0.05). We observed intestinal mucosal damage, evaluated by Chiu's score. Plasma D-lactate, zonulin, LPS, TNF-alpha, IFN-gamma, and IL-6 were significantly increased after cerebral infarction (P < 0.05). Additionally, the increases in plasma LPS, TNF-alpha, IFN-gamma, and IL-6 after cerebral infarction coincided with overgrowth of the Bacteroidetes phylum (P < 0.001). Conclusion: Cerebral infarction induces persistent host gut microbiota dysbiosis, intestinal mucosal damage, and chronic systemic inflammation in cynomolgus monkeys.
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