Microbiota-Gut-Brain Axis Deficits in Neurodevelopmental Disorders

Objective: A strong link between neurodevelopmental disorders (NDD) and gastrointestinal (GI) tract dysfunction is increasingly appreciated despite the mechanisms involved still being poorly understood. Angelman Syndrome (AS) is a NDD caused by a mutation in the maternally inherited ubiquitin ligase E3A (UBE3A), leading to dysfunction in neurons within the central nervous system (CNS). Symptoms of AS include intellectual disability, developmental delays, gross and fine hypomobility, and 80% of patients suffer from GI dysfunction including acid reflux, vomiting, and constipation. Previously, we have identified alterations in the gut microbiome of multiple animal models of AS (rat, mouse, and pig), including increased colonization with microbes associated with constipation. We therefore hypothesized that deficits in the microbiota-gut-brain (MGB) axis caused GI symptoms in AS mice. Method: Adult (male/female) AS and littermate controls (WT) were used. Ussing chambers were used to assess permeability and ion transport within the duodenum, ileum and colon. Behavioral tests were performed to assess cognitive function (novel object recognition [NOR] task), anxiety-like behavior (light/dark [L/D] box), and locomotor activity (open field task [OFT]). qPCR was used to identify genes associated with ion transport, neuron signaling, and inflammation, and immunofluorescence was performed to assess neurons and microglia. Lastly, mass spectrometry was used to quantify fecal short-chain fatty acids (SCFA). Results: Ussing chamber studies revealed that AS mice had increased GI permeability within the ileum (FITC flux: 1500 [WT] vs 3,000 [AS] ng/mL/cm2/hr) coupled with, reduced ion transport in the colon (WT: 60 vs AS: 40 µA/cm2). qPCR indicated increased serotonin synthesis by enteric neurons via upregulated levels of tyrosine hydroxylase (Tph2) (colon: 2.5-fold expression and ileum: 3-fold expression in AS vs WT). GABA receptors (Gaba1a, Gaba1b, Gaba2a, and Gaba2b) were also upregulated in the ileum of AS mice. Additionally, the inflammatory cytokine IL-6 was elevated in the duodenum, ileum, and colon in AS mice. Behavioral deficits in AS mice, including decreased locomotive activity [OFT] and recognition memory (NOR task) were also seen, a finding that correlates to the hypomobility and intellectual disability seen AS patients. Within the CNS, increased microglia were seen by increase IBA1 expression by qPCR (1.7 fold expression in AS vs WT) and immunofluorescence (64% increase in AS) within the CA1 of the hippocampus of AS mice. Lastly, a decrease in beneficial SCFA (butyrate and isobutyrate) as well as decreased expression of enteric neuron specific free fatty acid receptor (FFAR)3 in the colon, suggests a potential pathway via which an altered microbiome, enteric neuron, and GI pathophysiology in AS may be linked. Conclusions: AS mice exhibit evidence of MGB axis deficits, likely regulated in part via enteric neuron dysfunction across the length of the GI tract. Whether or not therapeutic intervention through the gut microbiome and its metabolites can improve GI or CNS deficits seen in AS remains to be determined. Better understanding of GI deficits in NDD may provide important insights into behavioral impairments and provide novel therapeutic targets to treat patients. Funding: FAST-TRAC FT2022-007, 5T32MH112507-09 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.