The Role of the Microbiota-Gut-Brain Axis in Schizophrenia: An Immunological Perspective

Bowei Su¹Yao Li²Le-Ying Yang³Hai-Xia Yang¹Wen-Hao Wang¹Huiwen Ren^1,4亚男 包¹Jia-Yi Lao⁵Zhi-Lin Luan^1,4*

• ¹Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
• ²Department of Neuroregulation Center，Southwest Rehabilitation Hospital, Chengdu, China
• ³School of Education, University of New South Wales, Sydney, Australia
• ⁴Dalian Key Laboratory for Nuclear Receptors in Major Metabolic Diseases, Dalian, China
• ⁵Dalian Medical University, Dalian, China

Schizophrenia(SZ) is a severe neuropsychiatric disorder arising from complex interactions between genetic susceptibility and environmental factors. There is growing evidence that immune dysregulation and neuroinflammation are central to its pathogenesis, with the microbiota-gut-brain (MGB) axis playing a critical role. This review synthesizes clinical and preclinical findings to elucidate the relationship between gut microbiota dysbiosis and aberrant inflammatory signaling in the periphery and central nervous system in schizophrenia. We detail how alterations in gut microbiota metabolites,following dysbiosis disrupt blood-brain barrier (BBB) integrity and exacerbate neuroinflammation, ultimately leading to the neuropathology of SZ. The review further explores how gut dysbiosis activates innate immune pathways, including the complement system (e.g., C4) and Toll-like receptors (e.g., TLR4), and examines the bidirectional relationship between cytokine imbalances and gut microbiota. A key focus is placed on the dysregulation of the kynurenine pathway of tryptophan metabolism, which mechanistically links immune activation to neurotransmitter imbalances. Collectively, these findings demonstrate that gut microbiota dysbiosis contributes to the pathophysiology of schizophrenia through multifaceted immune-neuro-endocrine pathways, highlighting the MGB axis as a promising target for novel therapeutic strategies.