The usual suspects. Rett syndrome, which manifests as motor and cognitive regression, is also associated with gastrointestinal (GI) motility disorders. These can cause pain, constipation, or diarrhea, often leading to undernutrition if left unaddressed. Here, the authors found that GI muscles from Mecp2-KO mice, a model of the disease, were unable to sustain repetitive contractions. Acetylcholine, which contributes to GI motility, was significantly reduced in the GI muscle, together with its synthesizing enzyme and muscarinic receptor genes expression. These findings confirm cholinergic signaling as a key component of Rett syndrome, extending beyond the central nervous system to the enteric nervous system. (IB)

Scientific abstract: Background and aims: Rett syndrome (RTT) is a severe neurological disorder caused by pathogenic variants in the MECP2 gene associated with gastrointestinal (GI) motility disorders strongly impacting patients’ quality of life. Intestinal motility relies on coordinated neuronal activity in the enteric nervous system (ENS) where MECP2 is highly expressed. Here, we sought to determine whether cholinergic-mediated excitatory neuromuscular transmission could be affected in the ENS of a RTT mouse model and the functional consequences on intestinal motility. Methods: In this study, 55 days-old wild type (WT) and Mecp2-knock-out (KO) mice were used. After confirming the reduction in GI transit time in vivo, intestinal mechanical activity was assessed in vitro by evaluating contractile responses of small intestinal muscle to electrical field stimulation (EFS) of the enteric nervous system (ENS). The function of the cholinergic pathway was evaluated using gene expression, protein, and enzymatic activity quantifications of different factors of the acetylcholine (ACh) metabolism. Results: Our in vivo results confirm that the mouse models replicate the slowed GI transit previously identified in RTT patients and in the mouse model. In vitro, successive EFS lead to a progressive and rapid decrease in the amplitude of cholinergic contractions in Mecp2-KO mice contrary to WT mice. Levels of ACh are decreased in the ENS of Mecp2-KO mice (−47%, P-value<0.01) due to decreased activity of the synthesizing enzyme choline-acetyltransferase (−39%, P-value = 0.04). In addition to the deficit of ACh, we found that both nicotinic and muscarinic cholinergic receptors are also significantly impacted. Conclusion: This is the first report of a major dysfunction of the enteric cholinergic pathway in a mouse model of RTT supporting its direct involvement in GI disorders in this disease. We propose that the rhythmic GI contractions occurring during fed conditions may cause a rapid depletion of the stock of enteric ACh that could largely depress the propulsive efficiency of, or even suppress, peristalsis during digestion.

The authors: E Borloz, C de Combarieu, L Bourcin, MS Felix, C Fulachier, B Mazet & JC Roux

Published in 2026