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  • Gut Microbiome–Neural Crosstalk in Cancer: Emerging Implications for Perineural Invasion and Metastatic Progression

  • Zahra seifi,1,* Delnia Khadiry,2
    1. Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
    2. Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran


  • Introduction: Perineural invasion (PNI), defined as the infiltration of cancer cells into or around peripheral nerves, is an important feature of aggressive tumor behavior and is associated with recurrence and poor prognosis in several malignancies, including colorectal, pancreatic, gastric, and head and neck cancers. Although tumor–nerve interactions have increasingly been recognized as an important component of the tumor microenvironment, the potential contribution of the gut microbiome to cancer–nerve crosstalk remains poorly understood. Emerging evidence suggests that microbial communities and their metabolites may influence tumor behavior through immune, metabolic, and neuroactive pathways, raising the possibility of a microbiome–immune–neural axis in cancer progression.
  • Methods: A narrative literature review was conducted to investigate the emerging relationship between the gut microbiome, neural signaling, PNI, and cancer progression. Relevant studies were identified through searches of PubMed, Scopus, and Web of Science using combinations of the keywords gut microbiome, microbiota, cancer, perineural invasion, tumor–nerve interaction, neuroimmune signaling, neural invasion, metastasis, and tumor microenvironment. Particular attention was given to recent human studies investigating microbial signatures associated with PNI and to experimental evidence describing microbiome-mediated immune, metabolic, and neural mechanisms. Findings were thematically synthesized according to microbial composition, microbial metabolites, immune regulation, neural signaling, and potential implications for tumor invasion and metastasis.
  • Results: Recent clinical evidence provides an initial link between gut microbial composition and tumor neural invasion. In a 2025 study of patients with colorectal cancer, stool microbiome profiling identified 35 differentially abundant bacterial taxa between patients with and without PNI, despite no significant differences in overall alpha or beta diversity. Several taxa belonging to Ruminococcaceae, Lachnospiraceae, Peptostreptococcaceae, and related bacterial groups were associated with the PNI phenotype. Functional analyses further identified differences in pathways related to O-glycan and glycosphingolipid biosynthesis and neuroactive ligand–receptor interactions. Microbial differences were also associated with tumor immune-cell infiltration, immune checkpoints, chemokines, and chemokine receptors. However, these findings represent associations rather than evidence of causality and require validation in larger, independent cohorts. Several mechanisms may connect microbial alterations to neural invasion. Microbial metabolites, including short-chain fatty acids, secondary bile acids, indole derivatives, and other bioactive molecules, can influence epithelial integrity, systemic immunity, inflammation, and neuronal signaling. Microbiome-induced immune remodeling may alter the inflammatory environment surrounding peripheral nerves and facilitate tumor–nerve interactions. Conversely, tumor-derived neurotransmitters, neuropeptides, and inflammatory mediators can modify local immunity, angiogenesis, extracellular matrix remodeling, and cancer-cell migration. Such bidirectional communication may create a permissive microenvironment for PNI and potentially contribute to subsequent metastatic dissemination. The microbiome–neural axis may therefore represent an additional layer connecting distant microbial ecosystems with the local tumor microenvironment. Importantly, fecal microbiome studies alone cannot determine whether microbial alterations precede PNI or arise as a consequence of tumor progression. Future investigations integrating longitudinal metagenomics, metabolomics, spatial microbiome profiling, tumor transcriptomics, and functional neural–tumor models are needed to establish causality.
  • Conclusion: The emerging microbiome–immune–neural axis provides a novel framework for understanding PNI and cancer progression. Although current evidence remains preliminary, integrating microbial signatures with neural and tumor-microenvironmental features may reveal new biomarkers and therapeutic targets for cancers characterized by neural invasion and metastatic behavior.
  • Keywords: Gut microbiome; Perineural invasion; Cancer; Tumor–nerve interaction

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