IMPACT OF GUT-MICROBIOTA-DERIVED INDOLE COMPOUNDS ON EARLY BRAIN DEVELOPMENT IN MICE

A better understanding of the gut microbiota’s role in neonatal central nervous system development may inform prevention of behavioral disorders. Indole and indole-3-lactic acid (ILA), key microbial tryptophan metabolites, may modulate neurodevelopment via the microbiota-gut-brain axis. Nevertheless, their functional impact on the developing brain remains unknown. Thus, we investigated their effects on behavior and brain maturation in mice from postnatal day 12 (D12) to 45 (D45) and assessed indole-induced activation of vagal and brain circuits at D36.
To test whether these metabolites influence brain maturation and behavior, we colonized germ-free mice within 24h after birth with indole-producing Escherichia coli together with either ILA-producing Bifidobacterium longum or its mutant unable to produce ILA. Behavioral assays assessing anxiety, memory and locomotion were conducted from D6 to D45, and brain development was evaluated using neuronal morphology and immunohistochemical markers at D12 and D45. In a separate experiment, indole-responsive circuits were mapped using FosTRAP activity-dependent labeling.
Unexpectedly, absence of ILA reduced anxiety at D21 and D45 and enhanced object recognition selectively in female mice. In contrast, it was associated with decreased hippocampal arborization and shorter neuronal extensions at D45 in both sexes. Indole administration activated vagal sensory neurons in the nodose ganglia, implicating the vagus nerve as a conduit for gut-derived signals to the brain.
Together, our findings reveal that indolic compounds shape neurodevelopment in a sex- and region-specific manner, and identify a potential vagal pathway linking microbial-metabolites to brain circuits maturation. Therefore, targeting microbial-metabolites offer novel strategies to modulate early-life brain development.