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

Wu, Jo-Ting and Sun, Chia-Ling and Lai, Tzu-Ting and Liou, Chia-Wei and Lin, Yuan-Yuan and Xue, Jia-Ying and Wang, Hong-Wen and Chai, Laura Min Xuan and Lee, Yen-Jung and Chen, Shiou-Lan and Chang, Alice Y. W. and Hung, Jia-Horung and Hsu, Cheng-Chih and Wu, Wei-Li (2022) Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice. Neuropharmacology, 214 . Art. No. 109140. ISSN 0028-3908. doi:10.1016/j.neuropharm.2022.109140.

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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.

Item Type:Article
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URLURL TypeDescription data Information
Lai, Tzu-Ting0000-0003-2620-0062
Liou, Chia-Wei0000-0002-9003-4065
Wu, Wei-Li0000-0003-2610-1881
Additional Information:© 2022 Published by Elsevier. Received 8 December 2021, Revised 5 May 2022, Accepted 14 May 2022, Available online 22 May 2022. We thank Prof. Chen-Chih Hsu's laboratory in Department of Chemistry at National Taiwan University and BIOTOOLS Co., Ltd. for the feces and brain SCFA measurements; Dr. Yen-Jung Lee and Center for Research Resources and Development of Kaohsiung Medical University for the serum SCFA measurement; the staff in the Laboratory Animal Center, National Cheng Kung University (NCKU) for caring of animals. This work was supported by the scholarship from Prof. Kun-Yen Huang Education Fund of CHENG-HSING Medical Foundation in Taiwan to T.-T.L. and C.-W.L.; the scholarship Pilot Program of Ministry of Science and Technology (MOST) to Subsidize Universities and Colleges to Cultivate Outstanding Doctoral Students at NCKU (MOST 110-2926-I-006-001-MY4) to T.-T.L.; the funds from the MOST in Taiwan: Undergraduate Research MOST 108-2813-C-006-130-B to J.-Y.X.; MOST 110-2636-M-002-014- to C.-C.H.; MOST 107-2320-B-006-072-MY3; 109-2314-B-006-046; 110-2314-B-006-114; 110-2320-B-006-018-MY3 to W.-LW.; Ministry of Health and Welfare of Taiwan (MOHW110-TDU-B-211-124003) to J.-H.H.; Ditmanson Medical Foundation Chia-yi Christian Hospital in Taiwan (CYC109002) to W.-L.W; National Cheng Kung University Hospital (NCKUH-11102004) to J.-H.H. and W.-L.W.; and the Higher Education Sprout Project, Ministry of Education to the Headquarters of University Advancement at National Cheng Kung Universtiy, Taiwan. CRediT authorship contribution statement: Jo-Ting Wu: Methodology, Investigation, Validation, Formal analysis, Data curation, Visualization, Writing – original draft. Chia-Ling Sun: Resources, Supervision, Funding acquisition. Tzu-Ting Lai: Methodology, Investigation, Validation, Formal analysis. Chia-Wei Liou: Validation, Formal analysis. Yuan-Yuan Lin: Validation, Formal analysis. Jia-Ying Xue: Validation. Hong-Wen Wang: Formal analysis. Laura Min Xuan Chai: Investigation, Formal analysis. Yen-Jung Lee: Investigation, Formal analysis. Shiou-Lan Chen: Supervision. Alice Y.W. Chang: Supervision. Jia-Horung Hung: Supervision, Funding acquisition. Cheng-Chih Hsu: Supervision, Funding acquisition. Wei-Li Wu: Conceptualization, Methodology, Investigation, Formal analysis, Data curation, Visualization, Writing – original draft, Writing – review & editing, Supervision, Project administration, Funding acquisition. All authors declare no conflicts of interest related to this work.
Funding AgencyGrant Number
Ministry of Science and Technology (Taipei)MOST 110-2926-I-006-001-MY4
Ministry of Science and Technology (Taipei)MOST 108-2813-C-006-130-B
Ministry of Science and Technology (Taipei)MOST 110-2636-M-002-014
Ministry of Science and Technology (Taipei)MOST 107-2320-B-006-072-MY3
Ministry of Science and Technology (Taipei)109-2314-B-006-046
Ministry of Science and Technology (Taipei)110-2314-B-006-114
Ministry of Science and Technology (Taipei)110-2320-B-006-018-MY3
Ministry of Health and Welfare (Taipei)MOHW110-TDU-B-211-124003
Ditmanson Medical FoundationCYC109002
National Cheng Kung University HospitalNCKUH-11102004
Ministry of Education (Taipei)UNSPECIFIED
Subject Keywords:Gut microbiota; Short-chain fatty acids; Antibiotic cocktail; Innate anxiety; Aversive stimulus; Vagus nerve; Subdiaphragmatic vagotomy
Record Number:CaltechAUTHORS:20220523-165177000
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Official Citation: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, Oral short-chain fatty acids administration regulates innate anxiety in adult microbiome-depleted mice, Neuropharmacology, Volume 214, 2022, 109140, ISSN 0028-3908, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114883
Deposited By: George Porter
Deposited On:23 May 2022 20:39
Last Modified:27 Jun 2022 14:28

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