Neurodevelopmental disorders, including autism spectrum disorders, have been increasingly associated with prenatal environmental factors. One emerging contributor is maternal immune activation (MIA) which is often triggered by infection or metabolic stress during pregnancy. Building on previous findings showing the importance of tryptophan (TRP) metabolism during pregnancy (See 2023 August highlight), this new preclinical study explores how a high-fat maternal diet (HFD) can initiate MIA, disrupt TRP metabolism and lead to behavioral deficits in male offspring.
In this study, Sun et al., show that HFD during pregnancy activates immune pathways involving TLR4 and IL-17a, leading to increased placental and fetal expression of IDO1. This mechanism shifts TRP metabolism away from serotonin and toward the kynurenine pathway. This metabolic change is linked to a reduced social behavior in male offspring. Surprisingly, these effects were reversed through specific interventions such as blockade of IL-17a, inhibition of IDO1, or antioxidant treatment with N-acetylcysteine. All these interventions, when administered during pregnancy, were able to rescue normal social behavior in the offspring.
Interestingly, the study reported these effects predominantly in male offspring, but did not explore the mechanisms underlying this sex-specific difference in TRP metabolism. This highlights a need for further research on sex-related metabolic pathways during neurodevelopment. These findings strengthen the importance of TRP metabolism as an essential interface between maternal health and fetal brain development. They also provide mechanistic insight into how both dietary and immune factors converge into TRP pathways to influence neurodevelopment. By identifying specific immune and metabolic mediators, such as IL-17a and IDO1, this research highlights potential therapeutic targets to prevent long-term neurodevelopmental consequences. Framed within the broader context of the mother-baby dyad, these findings contribute to the growing field of immunometabolic research and metabolic reprogramming during pregnancy. As scientists continue to explore the complex interplay between TRP metabolism, immunity, and the brain-mind-body system – including the gut-brain axis – this study underscores the potential of targeting these pathways to prevent long-term effects and protect future generations.