Tryptophan-related Gut Microbes are Linked with Neural and Behavioral Autism Phenotypes

Converging evidence implicates brain activity differences in interoceptive and emotion-related brain regions (e.g., insula) in the pathophysiology of autism spectrum disorder (ASD). Given that regions such as the insula are heavily modulated by serotonin, and gut microbes influence central serotonin levels by regulating the availability of its precursor, tryptophan via microbial metabolism, studies exploring associations between such gut microbes and brain regions are much needed. However, studies integrating neural, gut microbiome, and behavioral data in humans are rare. Such studies are necessary to better understand the neurobiology of ASD from a systems perspective and develop novel treatment strategies. In 53 ASD (42 Male, Mage = 12.05 years) and 53 neurotypical (NT) (30 Male, Mage = 11.82 years) youth we tested the hypotheses that gut species involved in tryptophan metabolism: 1) significantly differ in relative abundance between ASD and NT children; 2) are associated with activity in interoceptive and emotion regulating brain regions during functional neuroimaging tasks; and 3) are linked to ASD symptoms. In addition, we tested the exploratory hypothesis that functional brain activity mediates relationships between gut bacteria and behavior. Autistic youth had significantly greater relative abundances of species of Blautia, Clostridium, Ruminococcus , and Streptococcus , which were significantly associated with distinct neural activity patterns in interoceptive and emotion-related brain regions. Activity in the right mid-insula during physical disgust processing was a significant mediator of the relationship between Lactococcus lactis and restricted and repetitive behaviors. These results support the hypothesis that differences in the relative abundance of several gut microbes involved in the metabolism of tryptophan are related to known ASD brain alterations and symptomatology. These findings highlight the potential for targeting the gut microbiome to influence neural activity and behavioral outcomes in ASD, offering a promising avenue for novel intervention strategies.