Hypericin alleviates depression via the microbiota-gut-brain Axis: Role of Akkermansia muciniphila and glycerophospholipid metabolism

Oct 24, 2025European journal of pharmacology

Hypericin may reduce depression by affecting gut bacteria Akkermansia muciniphila and fat metabolism in the gut-brain system

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Abstract

Hypericin treatment significantly improved anxiety- and depression-like behaviors in a mouse model of chronic stress.

Hypericin reduced inflammation and histological damage in both the colon and hippocampus.
Alterations in the gut microbiota, specifically an increase in Akkermansia muciniphila, were observed after hypericin treatment.
Significant correlations were found between Akkermansia muciniphila abundance, changes in glycerophospholipid metabolites, and behavioral scores.
The sPLA2/LPCATs/LYPLA1 axis is involved in the modulation of glycerophospholipid metabolism by hypericin.
Depleting gut microbiota negated the behavioral improvements associated with hypericin treatment.

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BACKGROUND: Depression is one of the most severe mental disorders, affecting approximately 3.8 % of the global population. Chronic stress represents a major contributing factor, with the microbiota-gut-brain (MGB) axis playing a critical role in its pathophysiology.

PURPOSE OF THE STUDY: This study aimed to evaluate whether hypericin can ameliorate depression through MGB axis and its underlying mechanism.

MATERIALS AND METHODS: To evaluate the antidepressant potential of hypericin, a chronic restraint stress mouse model was established. Behavioral tests were conducted. Fecal 16S rRNA sequencing and serum untargeted metabolomics were performed to investigate alterations in gut microbiota and metabolic profiles, followed by integrative analysis. The glycerophospholipid signaling pathway was further examined in both colon and hippocampus. Finally, microbiota depletion experiments were carried out to validate the essential role of gut microbiota in mediating the antidepressant effects of hypericin.

RESULTS: Hypericin ameliorated anxiety- and depression-like behaviors, accompanied by reduced histological damage, inflammation, and dysregulated serotonin metabolism in both the colon and hippocampus. Furthermore, significant alterations in Akkermansia muciniphila (A. muciniphila) abundance and glycerophospholipid metabolites were observed after hypericin treatment, with strong correlations identified among A. muciniphila, differential glycerophospholipid metabolites, and behavioral scores. The sPLA2/LPCATs/LYPLA1 axis was further demonstrated to mediate hypericin's regulatory effects on glycerophospholipid metabolism in both tissues. Finally, microbiota depletion abolished the behavioral improvements induced by hypericin.

CONCLUSIONS: Together, our findings offer novel insights into the role of the MGB axis in mediating the antidepressant effects of hypericin, potentially through mechanisms involving the modulation of A. muciniphila and glycerophospholipid metabolism.