Fecal Microbiota Transplantation from Patients with Autoimmune Encephalitis Modulates Immune Response and Relevant Behaviors in Mice

Background: The significance of the microbiota-gut-brain axis has been increasingly recognized as a major modulator of autoimmunity. However, little is known about the effects of the gut microbiome on immune function and behaviors in autoimmune encephalitis. In this study, we aim to take advantage of a large cohort of treatment naive anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis to rigorously characterise gut dysbiosis and investigated the roles of immune function and behaviors. Methods : We first conducted a cross-sectional study of 40 MSA treatment-naive patients and 54 matched healthy controls (HCs). Then fecal microbiota transplantation (FMT) from anti-NMDAR encephalitis patients to microbiota-depleted mice was performed to investigate the immune function and behaviors. Findings : Relative to HCs, anti-NMDAR encephalitis patients had a decreased microbiome alpha-diversity index, marked disturbances of gut microbial composition and intestinal permeability damage. Disturbed microbiota in anti-NMDAR encephalitis patients might be linked with different clinical characteristics. Imputed KEGG analysis revealed perturbations of functional modules in the gut microbiomes of anti-NMDAR encephalitis. Compared to HCs, microbiota-depleted mice receiving FMT from anti-NMDAR encephalitis patients had hypersensitivity and cognitive impairment. Furthermore, anti-NMDAR encephalitis FMT mice showed altered T cells in the spleen and inguinal lymph node with an increased Th17 cells. Interpretation: Our study presents a comprehensive gut microbiota landscape in anti-NMDAR encephalitis. It suggests that the anti-NMDAR encephalitis microbiome itself can influence neurologic, immune and behavioral function. The gut microbiota is a potential therapeutic target for anti-NMDAR encephalitis. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No. 81971141), the Israel Science Foundation and the National Natural Science Foundation of China joint programme (No. 813111290), the Natural Science Foundation of Guangdong Province (No. 2019A1515010201) and Tianhe District Technology Project (2018YT019). Declaration of Interests: All authors declare that there are no conflicts of interest. Ethics Approval Statement: This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval ID: [2018]02-363-01). The subjects or the guardians of patients with severe cognitive impairment provided written informed consent for research and publication. Animal protocols were performed using C57BL/6J wild-type (WT) female mice in accordance with guidelines for animal care, according to the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Bioethics Committee of South China Agricultural University (approval ID: 2019-D063).