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, Seung Won Kim, Jaegyun Noh, Geon Park, Solji Lee, Tae-Kyung Kim () and Sin-Hyeog Im ()
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John Chulhoon Park: Pohang University of Science and Technology
Min-A Sim: Pohang University of Science and Technology
Changhon Lee: Pohang University of Science and Technology
Hye-Eun Park: Pohang University of Science and Technology
Juhun Lee: ImmunoBiome Inc
Seung Yeon Choi: ImmunoBiome Inc
Seohyun Byun: Pohang University of Science and Technology
Haeun Ko: Pohang University of Science and Technology
Haena Lee: Pohang University of Science and Technology
Seung Won Kim: Pohang University of Science and Technology
Jaegyun Noh: Pohang University of Science and Technology
Geon Park: Pohang University of Science and Technology
Solji Lee: ImmunoBiome Inc
Tae-Kyung Kim: Pohang University of Science and Technology
Sin-Hyeog Im: Pohang University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61544-0

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