Prenatal Poly I:C exposure affects tryptophan-kynurenine metabolism associated with intestinal microbiome in female juvenile rats

Lirong Yang¹Huiyu Chen²Menglu Zeng²Yanfang Lu²Chen Xu²Zhenju Cao²Fuchun Zhong²Xinyu Yang¹Anying Shen¹Yueqing Su²Chao Deng³Hua Cao^2*

• ¹Fujian Medical University Public Health School, Fuzhou, China
• ²Fujian Maternity and Child Health Hospital, Fuzhou, China
• ³University of Wollongong School of Medical Indigenous and Health Sciences, Wollongong, Australia

Emerging evidence suggests that disrupted tryptophan (TRP) metabolism may contribute to an increased risk of neurodevelopmental disorders (NDDs) in the context of maternal inflammation, with gut microbiota playing a pivotal role in regulating TRP metabolic pathways. In this study, we demonstrated an association of the disturbance of TRP metabolites with neuropathological and behavioral abnormalities in juvenile female rats prenatally exposed to polyriboinosinic-polyribocytidylic acid (Poly I:C). Behavioral assessments revealed heightened anxiety-like behavior, impaired social interaction, and deficits in spatial memory in Poly I:C-exposed offspring. Immunohistochemical and gene expression analysis of the prefrontal cortex (PFC) showed sustained microglial activation and long-term neuroinflammation. Concurrently, activation of the TRP-kynurenine (KYN) pathway was observed in both the PFC and peripheral circulation, accompanied by pronounced disturbances in intestinal TRP metabolism. Notably, alterations in gut microbial composition, including reduced microbial diversity and changes in key taxa such as Ruminococcus gauvreauii_group and Candidatus Saccharimonas – both implicated in TRP metabolism – were detected. These microbial shifts correlated with intestinal TRP metabolite levels and behavioral deficits. Together, our findings provide novel evidence that aberrant TRP metabolism, associated with gut microbiota dysbiosis, contributes to neuroinflammation and behavioral abnormalities in offspring following prenatal immune activation.