Disruption of tryptophan metabolism by high-fat diet-triggered maternal immune activation promotes social behavioral deficits in male mice

Penghao Sun, Mengli Wang, Xuejun Chai (), Yong-Xin Liu, Luqi Li, Wei Zheng, Shulin Chen, Xiaoyan Zhu () and Shanting Zhao ()
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Penghao Sun: Northwest A&F University
Mengli Wang: Northwest A&F University
Xuejun Chai: Xi’an Medical University
Yong-Xin Liu: Chinese Academy of Agricultural Sciences
Luqi Li: Northwest A&F University
Wei Zheng: Northwest A&F University
Shulin Chen: Northwest A&F University
Xiaoyan Zhu: Northwest A&F University
Shanting Zhao: Northwest A&F University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Diet-related maternal obesity has been implicated in neurodevelopmental disorders in progeny. Although the precise mechanisms and effective interventions remain uncertain, our research elucidates some of these complexities. We established that a prenatal high-fat diet triggered maternal immune activation (MIA), marked by elevated serum lipopolysaccharide levels and inflammatory-cytokine overproduction, which dysregulated the maternal tryptophan metabolism promoting the accumulation of neurotoxic kynurenine metabolites in the embryonic brain. Interventions aimed at mitigating MIA or blocking the kynurenine pathway effectively rescued the male mice social performance. Furthermore, excessive kynurenine metabolites initiated oxidative stress response causing neuronal migration deficits in the fetal neocortex, an effect that was mitigated by administering the glutathione synthesis precursor N-Acetylcysteine, underscoring the central role of maternal immune-metabolic homeostasis in male mice behavioral outcomes. Collectively, our study accentuated the profound influence of maternal diet-induced immuno-metabolic dysregulation on fetal brain development and provided the preventive strategies for addressing neurodevelopmental disorders.

Date: 2025
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DOI: 10.1038/s41467-025-57414-4

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