Gut microbial GABAergic signaling improves stress-associated innate immunity to respiratory viral infection

Yanan Gao; Zihao Liang; Bingyong Mao; Xudong Zheng; Jinjun Shan; Cuiyuan Jin; Shijia Liu; Narasaiah Kolliputi; Yugen Chen; Feng Xu; Liyun Shi

doi:10.1016/j.jare.2023.06.008

Gut microbial GABAergic signaling improves stress-associated innate immunity to respiratory viral infection

J Adv Res. 2023 Jun 22:S2090-1232(23)00171-6. doi: 10.1016/j.jare.2023.06.008. Online ahead of print.

Authors

Yanan Gao¹, Zihao Liang¹, Bingyong Mao², Xudong Zheng¹, Jinjun Shan³, Cuiyuan Jin⁴, Shijia Liu⁵, Narasaiah Kolliputi⁶, Yugen Chen⁵, Feng Xu⁷, Liyun Shi⁸

Affiliations

¹ Department of Immunology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
² School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
³ Medical Metabolomics Center, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁴ Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, China.
⁵ Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
⁶ Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
⁷ Department of Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: xufeng99@zju.edu.cn.
⁸ Institute of Translational Medicine, Zhejiang Shuren University, Hangzhou, Zhejiang 310015, China. Electronic address: shi_liyun@njucm.edu.cn.

Abstract

Introduction: Epidemiological evidences reveal that populations with psychological stress have an increased likelihood of respiratory viral infection involving influenza A virus (IAV) and SARS-CoV-2.

Objectives: This study aims to explore the potential correlation between psychological stress and increased susceptibility to respiratory viral infections and how this may contribute to a more severe disease progression.

Methods: A chronic restraint stress (CRS) mouse model was used to infect IAV and estimate lung inflammation. Alveolar macrophages (AMs) were observed in the numbers, function and metabolic-epigenetic properties. To confirm the central importance of the gut microbiome in stress-exacerbated viral pneumonia, mice were conducted through microbiome depletion and gut microbiome transplantation.

Results: Stress exposure induced a decline in Lactobacillaceae abundance and hence γ-aminobutyric acid (GABA) level in mice. Microbial-derived GABA was released in the peripheral and sensed by AMs via GABA_AR, leading to enhanced mitochondrial metabolism and α-ketoglutarate (αKG) generation. The metabolic intermediator in turn served as the cofactor for the epigenetic regulator Tet2 to catalyze DNA hydroxymethylation and promoted the PPARγ-centered gene program underpinning survival, self-renewing, and immunoregulation of AMs. Thus, we uncover an unappreciated GABA/Tet2/PPARγ regulatory circuitry initiated by the gut microbiome to instruct distant immune cells through a metabolic-epigenetic program. Accordingly, reconstitution with GABA-producing probiotics, adoptive transferring of GABA-conditioned AMs, or resumption of pulmonary αKG level remarkably improved AMs homeostasis and alleviated severe pneumonia in stressed mice.

Conclusion: Together, our study identifies microbiome-derived tonic signaling tuned by psychological stress to imprint resident immune cells and defensive response in the lungs. Further studies are warranted to translate these findings, basically from murine models, into the individuals with psychiatric stress during respiratory viral infection.

Keywords: Alveolar macrophages; GABA; Gut microbiome; Psychological stress; Respiratory viral infection.