Persistence of Gut Microbiota Dysbiosis and Chronic Systemic Inflammation After Cerebral Infarction in Cynomolgus Monkeys

Yonghong Chen; Jiahui Liang; Fubing Ouyang; Xinran Chen; Tao Lu; Zimu Jiang; Jianle Li; Yuefeng Li; Jinsheng Zeng

doi:10.3389/fneur.2019.00661

Persistence of Gut Microbiota Dysbiosis and Chronic Systemic Inflammation After Cerebral Infarction in Cynomolgus Monkeys

Front Neurol. 2019 Jun 28:10:661. doi: 10.3389/fneur.2019.00661. eCollection 2019.

Authors

Yonghong Chen¹, Jiahui Liang¹, Fubing Ouyang¹, Xinran Chen¹, Tao Lu², Zimu Jiang¹, Jianle Li¹, Yuefeng Li³, Jinsheng Zeng¹

Affiliations

¹ Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Neurology, Liuzhou Worker's Hospital, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.
³ Guangdong Landau Biotechnology Co., Ltd., Guangzhou, China.

Abstract

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-1.5 m, MCAO-6 m, and MCAO-12 m 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-α), interferon (IFN)-γ, 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-α, IFN-γ, and IL-6 were significantly increased after cerebral infarction (P < 0.05). Additionally, the increases in plasma LPS, TNF-α, IFN-γ, 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.

Keywords: cerebral infarction; cynomolgus monkey; gut microbiota; intestinal mucosal damage; middle cerebral artery occlusion; short-chain fatty acids; systemic inflammation.