Loss of autism-candidate CHD8 perturbs neural crest development and intestinal homeostatic balance.

Scientists studied zebrafish with mutations in a gene called CHD8 that's linked to autism and gut problems. They found that this gene affects the development of nerve cells that control the gut, leading to reduced serotonin (a chemical messenger) and inflammation in the intestine. The gut lining was also thinner with immune system changes. This research helps explain why children with certain autism-related gene changes often have digestive issues.

This zebrafish study investigated gastrointestinal mechanisms in CHD8 mutations, which are associated with autism. Loss of CHD8 reduced vagal neural crest cells emigrating from the neural tube and altered their migration. Complete intestinal colonization still occurred, but with decreased serotonin-producing cells and serotonergic neurons, suggesting intestinal hyposerotonemia. Transcriptomic analyses revealed altered serotonin and acetylcholine signaling pathways.

CHD8 mutants showed thinner intestinal epithelium, neutrophil accumulation, decreased goblet cells and eosinophils. Single-cell sequencing demonstrated global immune balance disruption with altered inflammatory interleukins and immune cell cluster changes. The study proposes a developmental link between CHD8, neural crest development, intestinal homeostasis, and autism-associated gastrointestinal complaints.

Provides mechanistic insights into CHD8-related gastrointestinal symptoms in autism. May inform targeted treatments addressing serotonin deficiency, intestinal inflammation, and immune dysfunction. Could guide development of biomarkers for GI complications in CHD8 mutations.

Zebrafish model may not fully translate to humans. Sample size not reported. Single study findings require replication. Mechanisms identified are correlational rather than definitively causal.

Individuals with mutations inpresent with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutivemutant zebrafish model, we found that the loss ofleads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence ofFurthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination ofmutants revealed a thinner intestinal epithelium accompanied by an accumulation of neutrophils and the decreased numbers of goblet cells and eosinophils.

Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with a perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between, NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.