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Detection of the role of intestinal flora and tryptophan metabolism involved in antidepressant-like actions of crocetin based on a multi-omics approach

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Abstract

Rationale

Depression is a serious mood disorder, and crocetin has a variety of pharmacological activities, including antidepressant effect. The alterations of intestinal flora have a significant correlation with depression, and crocetin can alter the composition of intestinal flora in mice with depression-like behaviors.

Objective

This study investigated the underlying antidepressant mechanisms of crocetin through multi-omics coupled with biochemical technique validation.

Methods

Chronic unpredictable stress (CUMS) was used to induce mice model of depression to evaluate the antidepressant effect of crocetin through behavioral tests, and the metagenomic and metabolomic were used to explore the potential mechanisms involved. In order to verify its underlying mechanism, western blot (WB), Elisa, immune histological and HPLC techniques were used to detect the level of inflammatory cytokines and the level of metabolites/proteins related to tryptophan metabolism in crocetin-treated mice.

Results

Crocetin ameliorated depression-like behaviors and increased mobility in depressive mice induced by CUMS. Metagenomic results showed that crocetin regulated the structure of intestinal flora, as well as significantly regulated the function gene related to derangements in energy metabolism and amino acid metabolism in mice with depression-like behaviors. Metabolomic results showed that the tryptophan metabolism, arginine metabolism and arachidonic acid metabolism played an essential role in exerting antidepressant-like effect of crocetin. According to multi-omics approaches and validation results, tryptophan metabolism and inflammation were identified and validated as valuable biological processes involved in the antidepressant effects of crocetin. Crocetin regulated the tryptophan metabolism in mice with depression-like behaviors, including increased aryl hydrocarbon receptor (AhR) expression, reduced indoleamine 2,3-dioxygenase 1 (IDO1) and serotonin transporter (SERT) expression in the hippocampus, elevated the content of 5-HT, kynurenic acid in serum and 5-HT, tryptophan in hippocampus. In addition, crocetin also attenuated inflammation in mice with depression-like behaviors, which presented with reducing the production of inflammatory cytokines in serum and colon. Meanwhile, crocetin up-regulated the expression of zonula occludens 1 (ZO-1) and occludin in ileum and colon to repair the intestinal barrier for preventing inflammation transfer.

Conclusion

Our findings clarify that crocetin exerted antidepressant effects through its anti-inflammation, repairment of intestinal barrier, modulatory on the intestinal flora and metabolic disorders, which further regulated tryptophan metabolism and impacted mitogen-activated protein kinase (MAPK) signaling pathway to enhance neural plasticity, thereby protect neural.

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Funding

This study was financially supported by the National Natural Science Foundation of China (grant number 81703688), the key research and development project of Zhejiang Province (grant number 2022C03050), key projects of international scientific and technological innovation cooperation between governments (grant number 2017YFE0130100), Zhejiang Provincial Natural Science Foundation of China under Grant (grant number LQ22H280014) and Taizhou Social Development Science and Technology Program (grant number 21ywb80).

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  1. Susu Lin and Qiaoqiao Li have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, People’s Republic of China

    Susu Lin, Qiaoqiao Li, Zijin Xu, Ziwei Chen, Yi Tao, Suhong Chen & Ping Wang

  2. The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing University, Jiaxing, 314001, People’s Republic of China

    Susu Lin

  3. Institute of Natural Medicine and Health Products, School of Advanced Study, Taizhou University, Taizhou, 318000, People’s Republic of China

    Yingpeng Tong & Ting Wang

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Contributions

SL: writing—original draft, performed the experiment, revised the manuscript, data curation. QL: performed the animal experiment, data curation. ZX: prepared the crocetin, performed the experiment, formal analysis. ZC: performed the experiments, analyzed the data. YT: writing—review and editing, provided professional assistance in manuscript drafting. YT: writing—review and editing, provided professional assistance in manuscript drafting. TW: performed the experiment. SC: supervision, writing—review and editing. PW: writing—review editing, conceived the studies, supervision, all authors reviewed the manuscript.

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Correspondence to Suhong Chen or Ping Wang.

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Lin, S., Li, Q., Xu, Z. et al. Detection of the role of intestinal flora and tryptophan metabolism involved in antidepressant-like actions of crocetin based on a multi-omics approach. Psychopharmacology 239, 3657–3677 (2022). https://doi.org/10.1007/s00213-022-06239-w

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