Gut microbiota and brain-resident CD4+ T cells shape behavioral outcomes in autism spectrum disorder
John Chulhoon Park, Min-A Sim, Changhon Lee, Hye-Eun Park, Juhun Lee, Seung Yeon Choi, Seohyun Byun, Haeun Ko, Haena Lee, S. Kim, Jun-Hee Noh, Gaeun Park, Solji Lee, Tae-Kyung Kim, Sin‐Hyeog Im
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by alterations in social, repetitive, and anxiety-like behaviors. While emerging evidence suggest a gut-brain etiology in ASD, the underlying mechanisms remain unclear. To dissect this axis, we developed a germ-free BTBR mouse model for ASD. The absence of gut microbiota in male mice ameliorates ASD-associated behaviors and reduces populations of inflammatory brain-resident T cells. Additionally, CD4+ T cell depletion mitigates neuroinflammation and ASD behaviors, suggesting a gut-immune-brain axis. We identify several microbial and metabolic regulators of ASD, particularly those relevant to the glutamate/GABA ratio and 3-hydroxyglutaric acid. Using an in silico metabolite prediction model, we propose Limosilactobacillus reuteri IMB015 (IMB015) to be a probiotic candidate. Administration of IMB015 reduces the glutamate/GABA ratio and neuroinflammation, resulting in improved behaviors. Here we report a gut-immune-brain axis in which the gut microbiota and its metabolites can modulate brain-resident immune cells and ASD-associated behaviors. Using a germ-free BTBR mouse model of ASD-like behaviors, here the researchers demonstrated that the absence of gut microbiota significantly reduced social deficits, repetitive behaviors, and neuroinflammation.