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Published August 15, 2022 | Supplemental Material
Journal Article Open

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

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.

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.

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Additional details

Created:
August 22, 2023
Modified:
October 24, 2023