Arbutin ameliorated depression by inhibiting neuroinflammation and modulating intestinal flora

Yu Cao; Kexuan Zhao; Yudi Zhao; Ying Ni; Zicheng Zhang; Xinyi Yuan; Jiamei Ning; Qinghua Song; Fan Zhao; Ling He; Tong Chen

doi:10.1016/j.phymed.2025.156944

Arbutin ameliorated depression by inhibiting neuroinflammation and modulating intestinal flora

Phytomedicine. 2025 Jun 6:145:156944. doi: 10.1016/j.phymed.2025.156944. Online ahead of print.

Authors

Yu Cao¹, Kexuan Zhao¹, Yudi Zhao¹, Ying Ni², Zicheng Zhang², Xinyi Yuan¹, Jiamei Ning³, Qinghua Song¹, Fan Zhao², Ling He⁴, Tong Chen⁵

Affiliations

¹ Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China.
² School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
⁴ Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China. Electronic address: hexyz@163.com.
⁵ Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China. Electronic address: chent1127@163.com.

PMID: 40554291
DOI: 10.1016/j.phymed.2025.156944

Abstract

Background: Arbutin (AR), a natural glycoside compound widely distributed in botanical sources, exerts neuroprotective properties. Nevertheless, the pharmacological effect of AR on depression and its underlying mechanism remain undefined.

Methods: The mice were induced by chronic unpredictable mild stress (CUMS) procedure 16S rRNA sequencing and metabolomic analyses were conducted. The in vitro neuroinflammatory model was established using lipopolysaccharide (LPS) stimulated BV2 microglia.

Results: The present study found that AR alleviated the depressive-like behaviors, inflammatory reaction, oxidative stress, restored neurotrophic factors and gut tight junction proteins. TLR4/NF-κB/IRAK1 signaling was involved in these alterations. 16S rRNA sequencing and metabolomics showed that AR enriched muribaculaceae and tryptophan metabolism. Muribaculum intestinale and AR ameliorated depressive-like behaviors, inflammation and 5-HT content, Tryptophan Hydroxylase 1 (TPH1) and Indoleamine 2,3-Dioxygenase 1 (IDO1) expressions, tryptophan metabolism and kynurenine route. The molecular docking and molecular dynamic suggested that AR might bind to TPH1 and IDO1.

Conclusion: In conclusion, AR alleviated depressive-like behavior in mice by reducing neuroinflammation, modulating gut microbiota, and TPH1/IDO1-mediated serotonin synthesis.

Keywords: Arbutin; Chronic unpredictable mild stress; Depression; Gut microbiota; Neuroinflammation.