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Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network

Molecular Psychiatry (2025)Cite this article

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Abstract

Psychosocial stress in women is a major public health concern, yet the intergenerational mechanisms linking maternal premating stress to offspring neuropsychiatric vulnerability remain incompletely understood. Here, female mice were exposed to chronic unpredictable mild stress (CUMS) prior to mating, and offspring were assessed for neurodevelopment, adult behavior, and multi-omics profiles. Premating stress induced neurodevelopmental delays and sexually dimorphic adult phenotypes: female offspring exhibited hyperactivity and social deficits, whereas male offspring displayed anxiety. Cerebellum cytokine levels were reduced in a sex-dependent manner. Maternal stress shifted offspring gut microbiota (GM) composition, with p_Proteobacteria as core taxa in females and p_Firmicutes in males, exhibiting sex-dependent and inverse shifts in microbial network connectivity. Male offspring showed marked metabolic alterations and enhanced maternal–offspring metabolic concordance. Integrated analyses of GM, metabolites, and cerebellum profiles identified sexually dimorphic network correlations, further supported by human data demonstrating maternal stress-induced, sex-dependent GM network remodeling. Lactoferrin (LF) intervention selectively rescued male anxiety but not female behavioral deficits, and in males specifically, reduced cerebellum pro-inflammatory cytokines, enhanced GM network connectivity, and enriched immune-related serum metabolic and cerebellum transcriptomic pathways. LF also suppressed Purkinje cell firing frequency in males and reinforced post-treatment connectivity across microbial, metabolic, and cerebellum transcriptional nodes. Collectively, these findings delineate a previously unrecognized sexually dimorphic neuro–microbiota–metabolic network underpinning intergenerational vulnerability and highlight microbiota-targeted modulation as a systems-level mechanistic framework for sex-specific prevention of maternal stress–associated neuropsychiatric disorders.

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Fig. 1: Neuropsychiatric behavior of adult offspring of chronic unpredictable mild stress (CUMS)-exposed maternal mice.
Fig. 2: Alterations on gut microbiota (GM) and analysis of GM interaction networks and blood metabolite levels in the offspring of maternal mice exposed to pre-mating CUMS.
Fig. 3: Community-level correlations between gut microbiota and differential offspring phenotypes.
Fig. 4: Lactoferrin (LF) treatment improves behavioral phenotypes in male and female mice with distinct deficits.
Fig. 5: Effects of LF treatment on GM composition, microbial interaction networks, and blood metabolites in male and female mice with distinct behavioral phenotypes.
Fig. 6: Effects of LF treatment on cerebellum gene expression, neuronal excitability, and neuro-immunometabolic networks in male and female mice with different behavioral phenotypes.

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Analyzed data and images reported in this paper will be shared by the corresponding authors upon request.

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Acknowledgements

This study was supported by Shenzhen Science and Technology Program (KCXFZ20211020163549011, JCYJ20250604183013017 to XAL); the “Nutrition and Care of Maternal & Child Research Fund Project” of Biostime Institute of Nutrition & Care (2020BINCMCF058 to XAL); the STI2030-Major Projects (2022ZD0207100 to ZXC); National Natural Science Foundation of China (NSFC) (32371213 to XAL, 32000710 to ZXC, U20A2016 to ZXC); the Shenzhen Medical Research Funds (D2301002 to XAL); the Outstanding Talents Training Fund in Shenzhen (to LPW); Beijing Life Science Academy (BLSA, 2024100CD0010 to ZXC); Shenzhen Key Basic Research Project (JCYJ20200109115641762 to ZXC), the Guangdong Basic and Applied Basic Research Foundation (2023A1515011743 to XAL); the Technology and Innovation Commission of Shenzhen (ZDSYS20190902093601675 to ZXC).

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Author notes

  1. These authors contributed equally: Xiaoyuan Jing, Zhibin Xu, Qixing Yang, Yan Jiang.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Xiaoyuan Jing, Zhibin Xu, Ruoxi Wang, Liping Wang, Zuxin Chen & Xin-an Liu

  2. Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Xiaoyuan Jing, Zhibin Xu, Qixing Yang, Jintao Wang, Ruoxi Wang, Liping Wang, Zuxin Chen & Xin-an Liu

  3. Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Qixing Yang, Jintao Wang & Zuxin Chen

  4. Department of Gynecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yan Jiang

  5. Department of Anesthesiology, Shenzhen Maternity & Child Healthcare Hospital, No.2004 Hongli Road, Shenzhen, 518028, China

    Yuantao Li & Rouxuan Zhou

  6. Biomedical Research Institute, Hubei University of Medicine, No. 30 South Renmin Road, Shiyan, 442000, China

    Yuantao Li

  7. University of Chinese Academy of Sciences, Beijing, 100049, China

    Liping Wang, Zuxin Chen & Xin-an Liu

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Contributions

XJ analyzed the data, visualized the figures, and drafted the original manuscript; XJ, ZX, QY, and YJ contributed to conducted experiments, data analysis, figures visualization and manuscript formatting; RW participated in the chronic unpredictable mild stress and behavioral experiments; YL and RZ participated in human sample information collection and neonatal faecal sampling; QY and JW performed the electrophysiological recording experiments; XL and ZC conceptualized the project framework and supervised the experimental execution; LW provided essential resources and analytic platforms and assisted with experimental execution; XL and ZC revised the manuscript.

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Correspondence to Liping Wang, Zuxin Chen or Xin-an Liu.

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Jing, X., Xu, Z., Yang, Q. et al. Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03378-2

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