Ooi, C. Y. | Search bioRxiv

bioRxiv2025

Sodium Butyrate Rescues Neurodevelopmental Deficits Following Perinatal Methadone Exposure

Prenatal opioid exposure (POE) induces long-term neurodevelopmental, behavioral and cognitive deficits for which no targeted treatments are available. The mechanisms underlying POE deficits are poorly understood, but have been linked to a range of central, peripheral, and enteric nervous system changes. Emerging evidence indicates that maternal microbiota changes may also contribute to these long-term deficits in offspring. Here we test the efficacy of the short-chain fatty acid sodium butyrate (NaB) to mitigate POE-induced deficits in a rat model. Both methadone and sodium butyrate treatments altered dam microbiota composition and function: notably methadone disrupted dam gene expression of microbial enzymes critical for butyric acid production and reduced faecal butyric acid levels. In postnatal day 9 pups, methadone increased gut barrier permeability that was reversed with NaB, and enzymatic disruptions were observed in pups at postnatal day 21 that resolved in adulthood. POE induced anxiety-like behavior in adolescence, and adult deficits in working spatial memory and attentional processing that were partially rescued in rats that had received prenatal NaB. POE was associated with decreased myelination in the hippocampus, and this was partially reversed by NaB. Together these results highlight for the first time the link between the gut-brain axis in animal models of POE. Furthermore, they provide the first indication in a rat model of NaB as a simple yet effective treatment to significantly improve the outcomes of children born with POE.

animal behavior and cognition↗

bioRxiv2021

Molecular dynamics and theratyping in airway and gut organoids reveal R352Q-CFTR conductance defect

A significant challenge to making targeted CFTR modulator therapies accessible to all individuals with cystic fibrosis (CF) are many mutations in the CFTR gene that can cause CF, most of which remain uncharacterized. Here, we characterized the structural and functional defects of the rare CFTR mutation R352Q - with potential role contributing to intrapore chloride ion permeation - in patient-derived cell models of the airway and gut. CFTR function in differentiated nasal epithelial cultures and matched intestinal organoids was assessed using ion transport assay and forskolin-induced swelling (FIS) assay respectively. Two CFTR potentiators (VX-770, GLPG1837) and a corrector (VX-809) were tested. Data from R352Q-CFTR were compared to that of participants with mutations with known impact on CFTR function. R352Q-CFTR has residual CFTR function which was restored to functional CFTR activity by CFTR potentiators but not the corrector. Molecular dynamics (MD) simulations of R352Q-CFTR were carried out which indicated the presence of a chloride conductance defect, with little evidence supporting a gating defect. The combination approach of in vitro patient-derived cell models and in silico MD simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine.

molecular biology↗