AI Summary
This article discusses the role of the ELP1 gene in familial dysautonomia (FD) and its impact on the enteric nervous system (ENS) and gut epithelium. It states that ELP1 is essential for the normal development and maintenance of the ENS and for gut epithelium homeostasis. The study found that FD patients and mouse models exhibit dysbiotic gut microbiome, altered metabolome, and reduced intestinal motility. Additionally, ELP1 is crucial for regulating both neuronal and non-neuronal cells in the ENS and for target innervation in the mucosa and intestinal smooth muscle. It also highlights the importance of neurons in maintaining gastrointestinal epithelial barrier function.
Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient’s gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis.