Human-derived fecal microbiota transplantation alleviates social deficits of the BTBR mouse model of autism through a potential mechanism involving vitamin B 6 metabolism

Author:

Zheng Lifeng12ORCID,Jiao Yinming3ORCID,Zhong Haolin1ORCID,Tan Yan2,Yin Yiming2,Liu Yanhong2,Liu Ding2,Wu Manli2,Wang Guoyun3,Huang Jinqun2,Wang Ping4,Qin Meirong4,Wang Mingbang56ORCID,Xiao Yang7ORCID,Lv Tiying8,Luo Yangzi9,Hu Han2ORCID,Hou Sheng-Tao1ORCID,Kui Ling3ORCID

Affiliation:

1. Brain Research Centre and Department of Neuroscience, Southern University of Science and Technology, Shenzhen, China

2. Xbiome Co. Ltd., Shenzhen, China

3. Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China

4. Shenzhen Institute for Drug Control, Shenzhen, China

5. Microbiome Therapy Center, South China Hospital, Medical School, Shenzhen University, Shenzhen, China

6. Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children’s Hospital of Fudan University, National Center for Children’s Health, Shanghai, China

7. Department of Hematology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China

8. Guangzhou University of Chinese Medicine, Guangzhou, China

9. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

Abstract

ABSTRACT Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficiencies and stereotypic behaviors influenced by hereditary and/or environmental risk factors. There are currently no approved medications for treating the core symptoms of ASD. Human fecal microbiota transplantation (FMT) has emerged as a potential intervention to improve autistic symptoms, but the underlying mechanisms are not fully understood. In this study, we evaluated the effects of human-derived FMT on behavioral and multi-omics profiles of the BTBR mice, an established model for ASD. FMT effectively alleviated the social deficits in the BTBR mice and normalized their distinct plasma metabolic profile, notably reducing the elevated long-chain acylcarnitines. Integrative analysis linked these phenotypic changes to specific Bacteroides species and vitamin B 6 metabolism. Indeed, vitamin B 6 supplementation improved the social behaviors in BTBR mice. Collectively, these findings shed new light on the interplay between FMT and vitamin B 6 metabolism and revealed a potential mechanism underlying the therapeutic role of FMT in ASD. IMPORTANCE Accumulating evidence supports the beneficial effects of human fecal microbiota transplantation (FMT) on symptoms associated with autism spectrum disorder (ASD). However, the precise mechanism by which FMT induces a shift in the microbiota and leads to symptom improvement remains incompletely understood. This study integrated data from colon-content metagenomics, colon-content metabolomics, and plasma metabolomics to investigate the effects of FMT treatment on the BTBR mouse model for ASD. The analysis linked the amelioration of social deficits following FMT treatment to the restoration of mitochondrial function and the modulation of vitamin B 6 metabolism. Bacterial species and compounds with beneficial roles in vitamin B 6 metabolism and mitochondrial function may further contribute to improving FMT products and designing novel therapies for ASD treatment.

Funder

The Sanming Project of Medicine in Shenzhen Nanshan

Major Program of Shenzhen Nanshan

MOST | National Natural Science Foundation of China

the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions

Shenzhen Medical Research Fund

Publisher

American Society for Microbiology

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