Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice

Yuhua Chen; Junhui Chen; Hong Wei; Kai Gong; Jiao Meng; Tianlin Long; Jianfeng Guo; Jun Hong; Lingjian Yang; Junling Qiu; Kun Xiong; Zhanxiang Wang; Quanhua Xu

doi:10.3389/fimmu.2023.1172710

Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice

Front Immunol. 2023 May 23:14:1172710. doi: 10.3389/fimmu.2023.1172710. eCollection 2023.

Authors

Yuhua Chen^{1

2

3

4}, Junhui Chen¹, Hong Wei^{2

5}, Kai Gong⁴, Jiao Meng^{2

3}, Tianlin Long², Jianfeng Guo⁴, Jun Hong¹, Lingjian Yang⁶, Junling Qiu⁷, Kun Xiong^{1

8

9}, Zhanxiang Wang⁴, Quanhua Xu²

Affiliations

¹ Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
² Department of Neurosurgery, Bijie Traditional Chinese Medical Hospital, Bijie, Guizhou, China.
³ Department of Central Laboratory, Xi'an Peihua University, Xi'an, Shaanxi, China.
⁴ Xiamen Key Laboratory of Brain Center, Department of Neurosurgery, Trauma Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
⁵ Department of Rehabilitation Teaching and Research, Xi'an Siyuan University, Xi'an, China.
⁶ School of Chemistry & Chemical Engineering, Ankang University, Ankang, China.
⁷ Department of Cardiology, First Hospital of Northwestern University, Shannxi, China.
⁸ Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, Hainan, China.
⁹ Hunan Key Laboratory of Ophthalmology, Changsha, Hunan, China.

Abstract

Introduction: Gut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.

Objectives: This study investigated the association between PGAM5 and gut microbiota in mice with TBI.

Methods: The controlled cortical impact injury was established in mice with genetically-ablated Pgam5 (Pgam5^-/-) or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male Pgam5^-/- mice or Akkermansia muciniphila (A. muciniphila). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.

Results: Treated with antibiotics for suppressing gut microbiota in Pgam5^-/- mice partially relieved the role of Pgam5 deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. Pgam5 knockout exhibited an increased abundance of A. muciniphila in mice. FMT from male Pgam5^-/- mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and A. muciniphila was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, A. muciniphila treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.

Conclusion: Thus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with A. muciniphila-Nlrp3 contributing to peripheral effects.

Keywords: Akkermansia muciniphila; Nlrp3; Pgam5; TBI; gut-microbiota-brain axis; neuroprotection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Injuries, Traumatic* / metabolism
Brain Injuries, Traumatic* / therapy
Male
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Neuroinflammatory Diseases
Neuroprotection*
Phosphoglycerate Mutase
Verrucomicrobia / chemistry
Verrucomicrobia / metabolism

Substances

Phosphoglycerate Mutase
Nlrp3 protein, mouse
NLR Family, Pyrin Domain-Containing 3 Protein

Supplementary concepts

Akkermansia muciniphila

Grants and funding

This study was supported by the National Natural Science Foundation of China (No. 82072229, No. 81901270, No. 81971891, No. 82172196), Science and Technology Support Plan of Guizhou Province ([2023] general 088), the Central South University Research Innovation Project for Postgraduate Students (No. 2021zzts0312), Natural Science Basic Research Program of Shaanxi (No. 2018JM7141, 2019JQ-560, and 2023-JC-QN-0932), Scientific Research Program Funded by Shaanxi Provincial Education Department (No.19JK0016), Shaanxi Province Education Science Planning Project (SGH21Y0349), Key Laboratory of Emergency and Trauma (Hainan Medical University) of Ministry of Education (KLET-202108), and Special Research Project of Traditional Chinese Medicine Science and Technology of Guizhou (QZYY-2023-022 and QZYY-2023-025).