Role of gut microbiota and IL-17 function in the pathogenesis of RAB39B X-Intellectual Disability and Autism Spectrum Disorder

WILLE-BILLE, ARANZA; LAURA, COGROSSI; ZUMMO, FRANCESCA; MANCINI, NICASIO; BELLONE, MATTEO; D'ADAMO, PATRIZIA

Milan

Congreso; MICROBIOTAMI; 2023

University of Milan-Bicocca

Emerging evidence suggest that RAB39B is implicated in several biological processes leading to pre- and/or post-synaptic neuronal terminal dysfunction. RAB39B is a small monomeric GTPase that regulates intracellular vesicular trafficking of GluA2/GluA3 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), allowing its expression on the neuronal cell surface. Down regulation and/or deletion of Rab39b alters the conformation of the AMPAR, causing synaptic impairment, which is at the base of cognitive dysfunction in RAB39B-related disorders, such as autism spectrum disorder (ASD) and intellectual disability (ID). ASD and ID patients are characterized by gut dysbiosis. Importantly, IL-17A, whose production is modulated by the gut microbiota, affects neuronal functions and cognitive behaviors with implications in the clinical ASD manifestation. Our preliminary results showed gut dysbiosis in Rab39b KO mouse model. Based on these premises, we hypothesized that gut dysbiosis in human and mice affect the ASD and ID impact clinical manifestations by modulating IL-17 production.Thus, sixty-day old male mice were isolated and treated with wide-spectrum antibiotic or vehicle. At the end of the treatment, mice were subjected to several behavioral tests, including three-chambers sociability test, spontaneous alternation and trace fear conditioning tasks. Stool samples were collected for microbiota analysis, and immunological characterization was conducted in the intestinal Peyer’s patches (PPs) and spleen of mice.We found different microbiota composition in untreated Rab39b KO mice and wild-type (WT), which correlated with reduced representation of IL-17-producing cells in the PPs but not in the spleen of Rb39b KO mice. Features of ASD and ID were only documented in Rab39b KO mice. After antibiotic treatment, the percentage of intestinal IL-17-producing cells dropped ti values comparable to Rab39KO mice. Behavioral tests are ongoing in treated animals.Our preliminary results confirm dysbiosis in Rab39b KO mice that appears to correlate with reduced frequency of IL-17-producing cells in the PPs. A correlation between gut microbiota, IL-17 and behavioral dysfunction might open the path to novel therapeutic approaches in ADS and ID.