• KSBNS 2024


Original Article

Exp Neurobiol 2023; 32(5): 313-327

Published online October 31, 2023

© The Korean Society for Brain and Neural Sciences

Lactobacillus reuteri ATG-F4 Alleviates Chronic Stress-induced Anhedonia by Modulating the Prefrontal Serotonergic System

Jiyun Lee1,2†, Eum-Ji Kim1†, Gun-Seok Park3†, Jeongseop Kim1,2, Tae-Eun Kim1,2, Yoo Jin Lee1, Juyi Park3, Jihee Kang3*, Ja Wook Koo1,2* and Tae-Yong Choi1*

1Emotion, Cognition, and Behavior Research Group, Korea Brain Research Institute (KBRI), Daegu 41062,
2Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988,
3AtoGen Co., Ltd., Daejeon 34015, Korea

Correspondence to: *To whom correspondence should be addressed.
Jihee Kang, TEL: 82-42-931-8255, FAX: 82-42-931-8257
Ja Wook Koo, TEL: 82-53-980-8430, FAX: 82-53-980-8399
Tae-Yong Choi, TEL: 82-53-980-8439, FAX: 82-53-980-8399
These authors contributed equally to this article.

Received: September 4, 2023; Revised: October 2, 2023; Accepted: October 12, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed in patients with major depressive disorder (MDD). Gut microbial changes by fecal microbiota transplantation or probiotics treatment reportedly modulates depressive symptoms. However, it remains unclear how gut dysbiosis contributes to mental dysfunction, and how correction of the gut microbiota alleviates neuropsychiatric disorders. Our previous study showed that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induced neurometabolic alterations in healthy mice. Here, we investigated whether F4 exerted therapeutic effects on depressive-like behavior by influencing the central nervous system. Using chronic unpredictable stress (CUS) to induce anhedonia, a key symptom of MDD, we found that chronic F4 consumption alleviated CUS-induced anhedonic behaviors, accompanied by biochemical changes in the gut, serum, and brain. Serum and brain metabolite concentrations involved in tryptophan metabolism were regulated by CUS and F4. F4 consumption reduced the elevated levels of serotonin (5-HT) in the brain observed in the CUS group. Additionally, the increased expression of Htr1a, a subtype of the 5-HT receptor, in the medial prefrontal cortex (mPFC) of stressed mice was restored to levels observed in stress-naïve mice following F4 supplementation. We further demonstrated the role of Htr1a using AAV-shRNA to downregulate Htr1a in the mPFC of CUS mice, effectively reversing CUS-induced anhedonic behavior. Together, our findings suggest F4 as a potential therapeutic approach for relieving some depressive symptoms and highlight the involvement of the tryptophan metabolism in mitigating CUS-induced depressive-like behaviors through the action of this bacterium.

Graphical Abstract

Keywords: Lactobacillus reuteri, Anhedonia, Prefrontal cortex, Serotonin