The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis

Wang, Zhen; Ma, Xiaoying; Shi, Weibo; Zhu, Weihao; Feng, Xiaowei; Xin, Hongjian; Zhang, Yifan; Cong, Bin; Li, Yingmin

doi:10.3390/ijms26041698

Open AccessArticle

The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis

by

Zhen Wang

^†,

Xiaoying Ma

^†,

Weibo Shi

,

Weihao Zhu

,

Xiaowei Feng

,

Hongjian Xin

,

Yifan Zhang

,

Bin Cong

^* and

Yingmin Li

^*

Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(4), 1698; https://doi.org/10.3390/ijms26041698

Submission received: 21 January 2025 / Revised: 11 February 2025 / Accepted: 13 February 2025 / Published: 17 February 2025

(This article belongs to the Section Molecular Microbiology)

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Abstract

Stress has been implicated in the onset of mental disorders such as depression, with the prefrontal cortex (PFC) playing a crucial role. However, the underlying mechanisms remain to be fully elucidated. Metabolites secreted by intestinal flora can enter the bloodstream and exert regulatory effects on the body. Consequently, this study aims to investigate the molecular mechanisms by which gut flora influences ferroptosis in PFC neurons, thereby affecting depression-like behavioral changes in mice subjected to acute stress. Initially, we established a mouse model of acute restraint stress (3-day duration) and verified that stress-induced ferroptosis of PFC neurons contributed to depression-like behavioral alterations in mice, as evidenced by morphological, behavioral, and molecular biology assessments. Subsequently, through fecal microbiota transplantation (FMT) experiments, we established a significant correlation between gut microbiota and ferroptosis of PFC neurons in acute stress-exposed mice. 16S rDNA sequencing identified butyric acid-producing bacteria, specifically g_Butyricimonas and its primary metabolite, butyric acid, as critical regulators of ferroptosis in PFC neurons in acutely stressed mice. Furthermore, the intervention of butyrate demonstrated its potential to ameliorate damage to the intestinal and blood–brain barriers in these mice. This intervention also mitigated depression-like behaviors induced by ferroptosis of PFC neurons by alleviating systemic inflammatory responses. The findings of this study indicate that acute stress-induced ferroptosis of PFC neurons plays a critical role in depression-like behavioral changes in mice. Additionally, the gut microbiota metabolite butyrate can modulate ferroptosis and depression-like behavioral changes through the gut–brain axis.

Keywords: acute stress; prefrontal cortex; ferroptosis; gut–brain axis; butyrate

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MDPI and ACS Style

Wang, Z.; Ma, X.; Shi, W.; Zhu, W.; Feng, X.; Xin, H.; Zhang, Y.; Cong, B.; Li, Y. The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis. Int. J. Mol. Sci. 2025, 26, 1698. https://doi.org/10.3390/ijms26041698

AMA Style

Wang Z, Ma X, Shi W, Zhu W, Feng X, Xin H, Zhang Y, Cong B, Li Y. The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis. International Journal of Molecular Sciences. 2025; 26(4):1698. https://doi.org/10.3390/ijms26041698

Chicago/Turabian Style

Wang, Zhen, Xiaoying Ma, Weibo Shi, Weihao Zhu, Xiaowei Feng, Hongjian Xin, Yifan Zhang, Bin Cong, and Yingmin Li. 2025. "The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis" International Journal of Molecular Sciences 26, no. 4: 1698. https://doi.org/10.3390/ijms26041698

APA Style

Wang, Z., Ma, X., Shi, W., Zhu, W., Feng, X., Xin, H., Zhang, Y., Cong, B., & Li, Y. (2025). The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis. International Journal of Molecular Sciences, 26(4), 1698. https://doi.org/10.3390/ijms26041698

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The Gut Microbiota Metabolite Butyrate Modulates Acute Stress-Induced Ferroptosis in the Prefrontal Cortex via the Gut–Brain Axis

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