Galectin-3 in the Gut-liver axis Regulates Autistic-like Behaviors by Mechanism Associated with Cerebral Shank-3+ cell Niches in BALB/c Mice

Abstract Galectin-3 stabilizes cell-cell junctions and regulates inflammatory pathways in the gut-liver axis. Galectin-3 knockout (Lgals3−/−) mice have atypical behaviors by obscure mechanisms. Given that BALB/c mice naturally develop low-sociability, stereotypies and restrict interest, they have been included as autism experimental model. Our major aims were to investigate whether galectin-3 in the gut-liver axis interferes with autistic-like behaviors analyzing BALB/c Lgals3−/− mice or under partial inhibition of galectin-3 oral intake of cow’s milk for 7 days. Behavioral patterns were assessed using a three-chambers test, open field, and self-grooming. Histological analysis and immunohistochemistry (Galectin-3, NOS-2, Iba-1, Ki-67, Dll-4, Shank-3, Synaptophysin and Drebrin) were performed in gut, liver, and/or brain. Lgals3−/− mice amplified stereotypies, social retraction and restrict interest associated with reduction of cerebral Shank-3+ cells. In Lgals3+/+ mice, cow’s milk intake also amplified atypical behaviors, reduced galectin-3 in enterocytes and Kupffer cells, and disturbed niches of intestinal KI67+ and Dll-4+ cells and hepatic NOS2+ cells. In the brain of milk-treated mice, Iba-1+ microglial cells and NOS2+ Purkinje cells were increased whereas Shank-3+ and Drebrin+Synaptophysin+ cells were reduced suggesting, for the first time, that galectin-3 interferes with autistic behavior. Perhaps, a perspective to new therapies in genetically predisposed individuals to atypical behaviors.