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Intergenerational effects of the microbiota on neurodevelopment: mechanisms and therapeutic perspectives

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Neurodevelopment is governed by precisely timed biological processes that are sensitive to environmental influences across generations. Among these, the gut microbiota (GM) has emerged as a key regulator of neurodevelopmental trajectories, not only within individuals but also through intergenerational transmission. This review highlights the emerging significance of the GM in shaping offspring brain and behavior, emphasizing its capacity to mediate maternal influences across generations. We first summarize the temporal and intergenerational effects of GM on host physiology and neurobehavioral outcomes. We then explore the mechanistic basis of neuro-microbial-immunometabolic interactions including epigenetic regulation, neurotransmitter modulation, neuroinflammation and intestinal barrier function in the context of the microbiota-gut-brain axis. Particular attention is given to how these mechanisms mediate the long-term impact of maternal states—such as stress, diet and inflammation—on offspring neurodevelopment. We further highlight the translational gap from animal models to humans and propose integrating multi-omics, computational modeling, and clinical approaches to define developmental windows and guide precision microbiota-based interventions for neurodevelopmental disorders. By elucidating how microbiota influence neurodevelopment across generations, this review aims to inform the development of novel microbial and pharmacological therapies to promote brain health from the maternal period through early offspring life.

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Fig. 1: Neuro-microbial-immunometabolic network in the intergenerational modulation of development.
Fig. 2: Microbial metabolites from the maternal microbiome contribute to fetal and neonatal immune development.
Fig. 3: Brain-gut-immunometabolic network in the intergenerational modulation of development.
Fig. 4: Mechanistic insights into gut microbiome-mediated DNA and RNA methylation.
Fig. 5: Strategies for maternal and infant gut microbiome interventions.

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Acknowledgements

This review was supported by Grants from the National Natural Science Foundation of China (32371213, 31900728), the Guangdong Basic and Applied Basic Research Foundation (2023A1515011743), the Shenzhen Science and Technology Program (JCYJ20250604183013017, KCXFZ20211020163549011, JCYJ20250604182920028), the Basic research of Shenzhen science and technology plan project (JCYJ20210324135211030), the Guangdong High-Level Hospital Construction Fund (LCYJ2022094), the Shenzhen Medical Research Funds (D2301002). The Figure 2 and Figure 4 were drawn by Figdraw.

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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

    Ruo-xi Wang, Xiao-yuan Jing, Zu-xin Chen & Xin-an Liu

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

    Ruo-xi Wang, Ali Afzal, Xiao-yuan Jing & Xin-an Liu

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

    Ali Afzal, Zu-xin Chen & Xin-an Liu

  4. Department of Neurology, University of Health and Rehabilitation Sciences Qingdao Central Hospital (Qingdao Central Medical Group), School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266000, China

    Yu Zhou

  5. Department of Neonatology, Shenzhen Children’s Hospital, Shenzhen, 518026, China

    Jin-xing Feng

  6. Shenzhen Key Lab of Drug addiction, Shenzhen Neher Neural Plasticity Lab, BCBDI, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Zu-xin Chen

  7. Neurology Department, Shenzhen Children’s Hospital, Shenzhen, 518026, China

    De-zhi Cao

Authors
  1. Ruo-xi Wang
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  2. Ali Afzal
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  3. Xiao-yuan Jing
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  4. Yu Zhou
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  5. Jin-xing Feng
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  6. Zu-xin Chen
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  7. De-zhi Cao
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  8. Xin-an Liu
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Contributions

XAL conceived and designed the project. RXW, AA, and XYJ prepared the manuscript. XAL, DZC, YZ, JXF, and ZXC reviewed and edited the manuscript. All authors approved the manuscript.

Corresponding authors

Correspondence to De-zhi Cao or Xin-an Liu.

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Wang, Rx., Afzal, A., Jing, Xy. et al. Intergenerational effects of the microbiota on neurodevelopment: mechanisms and therapeutic perspectives. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01693-6

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