Prenatal Poly I:C exposure affects tryptophan-kynurenine metabolism associated with intestinal microbiome in female
Lirong Yang1,2, Huiyu Chen2,3, Menglu Zeng2,3
1School of Public Health, Fujian Medical University, Fuzhou, China.
Insights
Maternal inflammation during pregnancy disrupts tryptophan metabolism and gut bacteria, leading to neurodevelopmental issues and behavioral problems in offspring. This highlights the gut-microbiota-tryptophan axis as a critical factor in these impairments.
Area of Science:
- Neuroscience
- Microbiology
- Developmental Biology
Background:
- Disrupted tryptophan (TRP) metabolism is increasingly linked to neurodevelopmental disorders (NDDs).
- Maternal inflammation during pregnancy is a risk factor for NDDs.
- Gut microbiota significantly influences TRP metabolic pathways.
Purpose of the Study:
- To investigate the association between TRP metabolite disturbance and neuropathological/behavioral abnormalities in offspring exposed to prenatal inflammation.
- To explore the role of gut microbiota in TRP metabolism and its impact on neurodevelopment.
Main Methods:
- Used juvenile female rats exposed prenatally to Poly I:C (an immune activator).
- Assessed behavior (anxiety, social interaction, spatial memory), neuroinflammation (microglial activation in PFC), and TRP-kynurenine (KYN) pathway activity.
- Analyzed gut microbial composition and intestinal TRP metabolism.
Main Results:
- Prenatal Poly I:C exposure caused anxiety, impaired social interaction, and spatial memory deficits.
- Observed sustained microglial activation, neuroinflammation in the PFC, and altered TRP-KYN pathway activity.
- Found gut microbiota dysbiosis, reduced microbial diversity, and altered TRP metabolism, correlating with behavioral issues.
Conclusions:
- Aberrant TRP metabolism linked to gut microbiota dysbiosis contributes to neuroinflammation and behavioral deficits after prenatal immune activation.
- The gut-microbiota-TRP axis is a key mechanism underlying neurodevelopmental impairments.
- Targeting this axis may offer therapeutic strategies for NDDs.
Background:
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.
Methods:
Juvenile female rats prenatally exposed to polyriboinosinic-polyribocytidylic acid (Poly I:C) were used to investigate the association between TRP metabolite disturbance and neuropathological/behavioral abnormalities. Behavioral tests assessed anxiety-like behavior, social interaction, and spatial memory. Immunohistochemical and gene expression analyses were performed on the prefrontal cortex (PFC) to evaluate microglial activation and neuroinflammation. TRP-kynurenine (KYN) pathway activity was measured in both PFC and peripheral circulation, along with intestinal TRP metabolism. Gut microbial composition was analyzed through diversity metrics and specific taxa identification.
Results:
Prenatal Poly I:C exposure induced anxiety-like behavior, impaired social interaction, and spatial memory deficits in offspring. The PFC showed sustained microglial activation and chronic neuroinflammation. TRP-KYN pathway activation was observed in both central and peripheral systems, accompanied by significant disruptions in intestinal TRP metabolism. Gut microbial analysis revealed reduced diversity and specific alterations in TRP-related taxa (Ruminococcus gauvreauii_group and Candidatus Saccharimonas). These microbial changes correlated with both intestinal TRP metabolic levels and behavioral abnormalities.
Conclusion:
Our findings demonstrate that aberrant TRP metabolism associated with gut microbiota dysbiosis contributes to neuroinflammation and behavioral deficits in offspring following prenatal immune activation, highlighting the gut-microbiota-TRP axis as a key mechanism in neurodevelopmental impairments.
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