Andriantsitohaina, R. | Search bioRxiv

bioRxiv2026

Fecal extracellular vesicles from adults with autism spectrum disorder affect mouse behavior and gut motility by targeting the neuronal nitrergic pathway

Beside behavioral symptoms, many patients with autism spectrum disorder (ASD) present gastrointestinal disorders and gut microbiota dysbiosis. In order to better understand the mechanisms underlying microbiota-gut-brain interactions in ASD, we isolated fecal extracellular vesicles (EVs), as a source of microbiota-derived EVs, from control individuals (f-EV-CTL) and patients with ASD (f-EV-ASD) to study in mice their impact on brain and gut. The f-EV-ASD induced hypersocial and anxiolytic-like behavior, and reduced gastrointestinal transit time compared to mice treated with f-EV-CTL. In the colon, f-EV-ASD altered motility through the enteric neuronal nitric oxide (NO)-sensitive component. f-EV-ASD potentiated NO signaling and disrupted intracellular calcium dynamics in enteric neurons. This effect was mediated by butyrate and valerate through FFAR3 receptor. Our findings establish fecal EVs as critical mediators of microbiota-host communication, linking microbial metabolites to altered behavior and gut function and identifying a potential mechanism underlying ASD pathophysiology.

physiology↗

bioRxiv2025

The Mutated p.H222P A-type Lamins Drive Loxl2-Mediated Extracellular Matrix Remodeling in Both Patient-Derived Cardiomyocytes and Mouse Models of Dilated Cardiomyopathy

LMNA cardiomyopathy, caused by mutations in the LMNA gene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derived LMNA p.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and a LmnaH222P/H222P mouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed that LMNA p.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark of LMNA cardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in both LMNA p.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac function in vivo. Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function in LMNA cardiomyopathy.

pathology↗