Gastrointestinal (GI) distress is pervasive in autism spectrum disorders (ASDs). Foundations advocating for fourteen molecularly defined forms of ASD identify GI distress as an understudied symptom with negative impacts on quality of life.

ASD-linked GI symptoms include constipation, reflux and abdominal pain, all of which could be explained by gut-intrinsic abnormalities that alter GI motility. GI motility is known to be regulated by enteroendocrine cells (EECs), chemosensory cells residing in the gut epithelium that are responsive to nutrients and microbial metabolites. EECs then signal to the enteric nervous system (ENS) to modulate digestive reflexes and GI motility.

The current study focuses on four SFARI-curated zebrafish ASD models (shank3, syngap1, nrxn1 and cntnap2) to test the central hypothesis that GI phenotypes in multiple diverse genetic subtypes of ASD are caused by gut-intrinsic mechanisms. The proposed studies establish a new collaboration between Julia Dallman and John Rawls (Duke University), who have highly complementary expertise.

Published and preliminary work from the Dallman lab has shown that shank3 and syngap1 zebrafish mutant models both have GI dysmotility¹. Both models also have reduced numbers of serotonin-producing (5HT+) EECs. Strikingly, the Rawls lab has preliminary evidence showing enrichment of several ASD risk genes in zebrafish EECs, including shank3, nrxn1 and cntnap2. New transgenic lines generated by the Rawls lab enable in vivo imaging of nutrient/microbial sensing in EECs² and the ENS³ and optogenetic activation of EECs³. Dallman and Rawls plan to use these tools to test the working hypothesis that ASD genes expressed in the gut epithelium are required for the development of 5HT+ EECs which normally promote intestinal motility. However, not all ASD risk genes are expressed in EECs (e.g., syngap1 is enriched in the ENS but not EECs). Collectively, these data suggest that ASD risk genes play important but, as yet, completely unknown functional roles in the gut.

Ultimately, findings from these studies will answer the question of whether gut motility defects are a unifying theme in ASD genetic models and open a new field of EEC-ENS research for ASD that could suggest treatment strategies for managing GI distress in humans.

1. James D.M. et al. Mol. Autism 10, 3 (2019) PubMed
2. Ye L. et al. Elife 8, e48479 (2019) PubMed
3. Ye L. et al. Cell Host Microbe 29, 179-196 (2021) PubMed