Gut microbial butyrate influences pain through interconnected neuroimmune signaling, enteric nervous system-mediated gut–brain communication, intestinal and blood–brain barrier regulation, and neuronal plasticity, but its effects are highly context dependent. This Review integrates preclinical and clinical evidence across nociceptive, neuropathic, nociplastic, and cancer pain. We discuss translational limitations and potential approaches to improve treatment precision through microbiome- and host-informed patient stratification, optimization of butyrate exposure, and targeted delivery.
This work was supported by the National Natural Science Foundation of China (82171216), Zhejiang Province Compact yet High-performing Clinical Innovation Team (CXTD202502014), National Health Commission of the People’s Republic of China (WKJ-ZJ-2448), Zhejiang Provincial Program of Traditional Chinese Medicine Science and Technology (2024ZL170), “Xingyao Nanhu” Leading Talent Program of Jiaxing City (2022-XYNHCXTD-001), Zhejiang Provincial Clinical Key Specialties-Anesthesiology (2023-ZJZK-001), Zhejiang Provincial Natural Science Foundation of China (LMRY26H250003), The Peak Discipline Project of Jiaxing First Hospital (2026-JFGG-009 and 2026-JFGG-014) and Jiaxing Science and Technology Program Project (2025CGZ001). These authors contributed equally: Jie Fu, Kaiyu Shen. Department of Anesthesiology and Pain Research Center, The Affiliated Hospital of Jiaxing University, Jiaxing, China Jie Fu, Kaiyu Shen, Dianzun Liu, Huadong Ni & Xianli Liu Correspondence to Huadong Ni or Xianli Liu.
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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Fu, J., Shen, K., Liu, D. et al. Gut microbial butyrate in pain mechanisms and precision interventions. npj Biofilms Microbiomes (2026). https://doi.org/10.1038/s41522-026-01171-9 DOI: https://doi.org/10.1038/s41522-026-01171-9
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