Abstract
Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota–brain–immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
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Data availability
The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive [80] in National Genomics Data Center [81], China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA: CRA014210, CRA014216) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa.
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Acknowledgements
This work was supported by grants from the Shanghai Science and Technology Committee (20XD1423100, 23QA1408300), the National Natural Science Foundation of China (82230045, 82071518, 32271066), the Shanghai Municipal Education Commission (2021-01-07-00-02-E0086), and the Xuhui District Artificial Intelligence Medical Hospital Cooperation Project (2021-005).
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ZW, YDZ, and DDS designed the experiments. YDZ and DDS conducted behavioral, molecular and histological assays with the help of BBL, YL, and SZ. DDS performed electrophysiological recording. JG and LJL assisted in patient recruitment and fecal sample collection. YDZ and DDS performed subsequent bioinformatics analysis of transcriptomic and metabolomics data. YDZ wrote the paper and drafted the manuscript, and DDS revised it. ZW supervised the experiments and reviewed the paper.
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Zhang, YD., Shi, DD., Liao, BB. et al. Human microbiota from drug-naive patients with obsessive-compulsive disorder drives behavioral symptoms and neuroinflammation via succinic acid in mice. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02424-9
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DOI: https://doi.org/10.1038/s41380-024-02424-9