2. Academic Validation
  3. Microbiota alterations leading to amino acid deficiency contribute to depression in children and adolescents

Microbiota alterations leading to amino acid deficiency contribute to depression in children and adolescents

  • Microbiome. 2025 May 19;13(1):128. doi: 10.1186/s40168-025-02122-w.
Teng Teng # 1,  Fang Huang # 1 2,  Ming Xu # 3 4,  Xuemei Li # 1,  Lige Zhang 1,  Bangmin Yin 1,  Yuping Cai 5,  Fei Chen 1,  Luman Zhang 1,  Jushuang Zhang 2,  Aoyi Geng 2,  Chengzhi Chen 6 7,  Xiaofei Yu 8,  Jing Sui 3,  Zheng-Jiang Zhu 5,  Kai Guo 9 10,  Chenhong Zhang 11,  Xinyu Zhou 12
Affiliations

Affiliations

  • 1 Department of Psychiatry, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China.
  • 2 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China.
  • 3 State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China.
  • 4 China Mobile Research Institute, Beijing, 100032, China.
  • 5 Interdisciplinary Research Center On Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 6 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, China.
  • 7 Research Center for Environment and Human Health, School of Public Health, Chongqing, 400016, China.
  • 8 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China.
  • 9 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China. kaiguo@med.umich.edu.
  • 10 Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA. kaiguo@med.umich.edu.
  • 11 State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China. zhangchenghong@situ.edu.cn.
  • 12 Department of Psychiatry, Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China. zhouxinyu@cqmu.edu.cn.
  • # Contributed equally.
PMID: 40390033 DOI: 10.1186/s40168-025-02122-w
Abstract

Background: Major depressive disorder (MDD) in children and adolescents is a growing global public health concern. Metabolic alterations in the microbiota-gut-brain (MGB) axis have been implicated in MDD pathophysiology, but their specific role in pediatric populations remains unclear.

Results: We conducted a multi-omics study on 256 MDD patients and 307 healthy controls in children and adolescents, integrating plasma metabolomics, fecal metagenomics, and resting-state functional magnetic resonance imaging (rs-fMRI) of the brain. KEGG enrichment analysis of 360 differential expressed metabolites (DEMs) indicated significant plasma amino acid (AA) metabolism deficiencies (p-value < 0.0001). We identified 58 MDD-enriched and 46 MDD-depleted strains, as well as 6 altered modules in amino acid metabolism in fecal metagenomics. Procrustes analysis revealed the association between the altered gut microbiome and circulating AA metabolism (p-value = 0.001, M2 = 0.932). Causal analyses suggested that plasma AAs might mediate the impact of altered gut microbiota on depressive and anxious symptoms. Additionally, rs-fMRI revealed that connectivity deficits in the frontal lobe are associated with depression and 22 DEMs in AA metabolism. Furthermore, transplantation of fecal microbiota from MDD patients to adolescent rats induced depressive-like behaviors and 14 Amino acids deficiency in the prefrontal cortex (PFC). Moreover, the dietary lysine restriction increased depression susceptibility in adolescent rats by reducing the expression of excitatory amino acid transporters in the PFC.

Conclusions: Our findings highlight that gut microbiota alterations contribute to AAs deficiency, particularly lysine, which plays a crucial role in MDD pathogenesis in children and adolescents. Targeting AA metabolism may offer novel therapeutic strategies for pediatric depression. Video Abstract.

Keywords

Amino acid; Children and adolescents; Depression; Glutaminergic synapse; MGB axis; Microbiota.

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