The gut–brain axis (GBA) represents a sophisticated bidirectional communication network that integrates neural, immune, endocrine, and metabolic pathways to govern brain function and systemic homeostasis. At its core lies the gut microbiota, a diverse community of microorganisms whose composition and metabolic activity exert profound effects on the central nervous system (CNS). This study was published in the Chinese Medical Journal on February 03, 2026. Neural communication is primarily mediated by the vagus nerve and enteric nervous system (ENS): the vagus nerve transmits sensory signals from gut microbes and their metabolites—such as short-chain fatty acids (SCFAs) and neurotransmitters like serotonin—to the brainstem, while the ENS independently produces over 90% of the body’s serotonin and 50% of dopamine, directly influencing mood and cognition. Immune pathways involve gut-associated lymphoid tissue (GALT), where dysbiosis triggers systemic inflammation, impairs intestinal barrier integrity (“leaky gut”), and facilitates peripheral immune cell infiltration into the CNS via a compromised blood–brain barrier (BBB), exacerbating neuroinflammation. Endocrinologically, the hypothalamic-pituitary-adrenal (HPA) axis serves as a key mediator, with gut microbes modulating stress responses by regulating corticosterone release and gut-derived hormones like ghrelin and glucagon-like peptide-1 (GLP-1), which cross the BBB to influence brain function.
Microbial metabolites are pivotal mediators of GBA crosstalk, with SCFAs, tryptophan derivatives, and bile acids standing out as key signaling molecules. SCFAs—produced by bacterial fermentation of dietary fiber—cross the BBB to modulate neuroinflammation, neurotransmission, and neurogenesis: butyrate, for instance, exhibits neuroprotective and antidepressant-like effects by inhibiting histone deacetylases (HDACs) and reducing neuroinflammation in animal models. Tryptophan metabolism, shaped by gut microbiota, yields neuroactive compounds like kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic), with dysregulation linked to depression and schizophrenia. Bile acids, modified by gut microbes, influence neurotransmitter production and neuroplasticity, with altered profiles associated with Alzheimer’s disease (AD) and cognitive impairment. These metabolites highlight the direct biochemical link between gut microbiota and brain health, underscoring their role as central regulators of neural function.
Dysregulation of the GBA—particularly gut microbiota imbalance (dysbiosis)—is a common thread in major neuropsychiatric and neurodegenerative disorders. In major depressive disorder (MDD), clinical studies consistently report reduced microbial diversity, enrichment of pro-inflammatory taxa, and depleted SCFA-producing bacteria, with SCFAs mediating epigenetic changes that alter synaptic plasticity. AD involves bacterial amyloids (e.g., E. coli curli fibers) cross-seeding with host amyloid-beta, promoting protein aggregation and chronic neuroinflammation. Parkinson’s disease (PD) follows a “gut-first” model, where α-synuclein aggregates originate in the gut and spread to the brain via the vagus nerve, amplified by microbial dysbiosis and neuroinflammation. These disorders share core pathways of disrupted neurotransmission, impaired BBB integrity, and chronic neuroinflammation, all driven by aberrant GBA signaling.
Therapeutic strategies targeting the GBA have shown promising potential for neurological disorders. Probiotics (e.g., Lactobacillus rhamnosus , Bifidobacterium longum ) and prebiotics (e.g., dietary fiber) modulate microbial composition to enhance SCFA production and reduce inflammation, improving mood in MDD and cognitive function in mild cognitive impairment. Fecal microbiota transplantation (FMT) restores microbial balance, alleviating gastrointestinal and autonomic symptoms in PD patients, though motor effects vary across trials. Dietary interventions, such as the Mediterranean diet rich in polyphenols and fermented foods, support beneficial microbiota, while non-invasive bioelectronic approaches like transcutaneous auricular vagus nerve stimulation (taVNS) target neural pathways to reduce inflammation and improve depressive symptoms. Collectively, these interventions leverage the GBA’s plasticity to mitigate disease progression.
Despite significant advances, critical gaps remain in translating preclinical findings to clinical practice. Inconsistent outcomes across trials, lack of standardized microbiome analysis methods, and the observational nature of many human studies hinder definitive causal links between dysbiosis and brain disease. Future research must prioritize function-centric microbiome studies, leveraging multi-omics approaches to decode microbial-metabolic signatures. Precision therapeutics—including CRISPR-edited probiotics and tailored dietary plans—hold promise for personalized medicine, while large-scale longitudinal studies will identify critical windows for microbiome modulation. Bridging these gaps will unlock the GBA’s full therapeutic potential, offering novel avenues for treating currently untreatable neurological disorders.
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Reference
DOI: 10.1097/CM9.0000000000003920
About Oluwatayo Israel Olasunkanmi from Chongqing Medical University
The first author, Oluwatayo Israel Olasunkanmi, is a postdoctoral fellow at the First Affiliated Hospital of Chongqing Medical University. Under the guidance of Professors Peng Zheng and Zhong Zhaohua, he mainly studies the molecular mechanism of the gut–brain axis in depression and the development of new antiviral drugs. As the first author, the applicant has published 4 SCI papers, and as a co-author, 4 SCI papers, including Translational Psychiatry (IF = 6.22), Antimicrobial Agents and Chemotherapy (IF = 4.9), Frontiers in Microbiology (IF = 5.2), Journal of Virus eradication (IF = 5.5), and Virus (IF = 4.7), etc.
About Professor Peng Zheng from Chongqing Medical University
The corresponding author, Peng Zheng, is a Professor, Chief Physician, Researcher, Director of Neurology at The First Affiliated Hospital of Chongqing Medical University, and doctoral supervisor. His research focuses on basic and clinical translation of neuroimmunology and neuropsychology. He has published 25 SCI papers (10 with IF>10), been cited over 1,300 times, and is listed in Stanford’s Global Top 2% Scientists and Elsevier’s China Highly Cited Researchers.
Funding information
This work was supported by the National Key Research and Development Program of China (Nos. STI2030-Major Projects 2021ZD0202400, STI2030-Major Projects 2021ZD0200600), Natural Science Foundation Project of China (Nos. 82171523, 82471545, 82401784, 32400850, 82401523, 82201688, and 82171526), National Reserve Talent Project in the Health and Wellness Sector of Chongqing (Nos. HBRC202410, HBRC202417), CQMU Program for Youth Innovation in Future Medicine, Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJZD-K202400404), Chinese Institutes for Medical Research (No. CX23YQ02, Beijing), and Beijing Natural Science Foundation (No. J230011).
Chinese Medical Journal
Literature review
Not applicable
Gut–brain axis in health and brain disease
3-Feb-2026