Ligilactobacillus salivarius enolase is an oxytocin-like systemic signal and it is reduced in children with autism spectrum disorder

Abstract Oxytocin (OT) is a peptide hormone promoting social interactions and reducing anxiety, both core behaviors altered in autism spectrum disorder (ASD)1. Current approaches to boost OT signaling in the brain have, however, had little success2. OT is carried in the blood by immunoglobulin G (IgG), suggesting a new therapeutic target for boosting OT, but its antigenic origin and capacity to influence central OT signaling are unknown3. Here we show that Ligilactobacillus salivarius (LS) 48 kDa enolase (ENO) displays a species-unique structural homology with OT underlying both its OT-like antigenic and ligand properties. While LS ENO was naturally present in human plasma, correlating between members of the same family, its levels were reduced in children of both sexes diagnosed with ASD, starting from the disorder’s onset. Using mice, we show that LS ENO was present in both plasma and brain, and that its levels were lower in BTBR mice, a model of ASD. We further show that LS ENO immunization induced OT-binding IgG, which enhanced OT stability in plasma, increased OT receptor activation, and facilitated OT entry into the brain. Accordingly, LS ENO-immunization boosted OT concentrations in the brain and improved social, repetitive and anxiety-like behavior in BTBR mice. Thus, LS ENO is an OT-like protein which enhances OT signaling and boosts brain OT levels via production of OT-carrier IgG. Reduced plasma levels of LS ENO may, hence, contribute to ASD pathophysiology.