Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice

Jo-Ting Wu; Chia-Ling Sun; Tzu-Ting Lai; Chia-Wei Liou; Yuan-Yuan Lin; Jia-Ying Xue; Hong-Wen Wang; Laura Min Xuan Chai; Yen-Jung Lee; Shiou-Lan Chen; Alice Y W Chang; Jia-Horung Hung; Cheng-Chih Hsu; Wei-Li Wu

doi:10.1016/j.neuropharm.2022.109140

Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice

Neuropharmacology. 2022 Aug 15:214:109140. doi: 10.1016/j.neuropharm.2022.109140. Epub 2022 May 22.

Authors

Affiliations

¹ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
² Department of Psychiatry, Ditmanson Medical Foundation Chia-yi Christian Hospital, Chiayi, 60002, Taiwan.
³ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
⁴ Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
⁵ Center for Research Resources and Development, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan.
⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807378, Taiwan.
⁷ Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
⁸ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA. Electronic address: [email protected].

PMID: 35613660
DOI: 10.1016/j.neuropharm.2022.109140

Abstract

Anxiety is characterized by feelings of tension and worry even in the absence of threatening stimulus. Pathological condition of anxiety elicits defensive behavior and aversive reaction ultimately impacting individuals and society. The gut microbiota has been shown to contribute to the modulation of anxiety-like behavior in rodents through the gut-brain axis. Several studies observed that germ-free (GF) and the broad spectrum of antibiotic cocktail (ABX)-treated rodents display lowered anxiety-like behavior. We speculate that gut microbial short-chain fatty acids (SCFA) modulate the innate anxiety response. Herein, we administered SCFA in the drinking water in adult mice treated with ABX to deplete the microbiota and tested their anxiety-like behavior. To further augment the innate fear response, we enhanced the aversive stimulus of the anxiety-like behavior tests. Strikingly, we found that the anxiety-like behavior in ABX mice was not altered when enhanced aversive stimulus, while control and ABX mice supplemented with SCFA displayed increased anxiety-like behavior. Vagus nerve serves as a promising signaling pathway in the gut-brain axis. We determined the role of vagus nerve by subdiaphragmatic vagotomy (SDV) in ABX mice supplemented with SCFA. We found that the restored anxiety-like behavior in ABX mice by SCFA was unaffected by SDV. These findings suggest that gut microbiota can regulate anxiety-like behavior through their fermentation products SCFA.

Keywords: Antibiotic cocktail; Aversive stimulus; Gut microbiota; Innate anxiety; Short-chain fatty acids; Subdiaphragmatic vagotomy; Vagus nerve.

Publication types

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

MeSH terms

Animals
Anxiety / drug therapy
Anxiety Disorders
Fatty Acids, Volatile / metabolism
Gastrointestinal Microbiome*
Mice
Mice, Inbred C57BL
Microbiota*

Substances

Fatty Acids, Volatile