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Review
. 2025 Jul 3:6:1626515.
doi: 10.3389/fpain.2025.1626515. eCollection 2025.

Gut microbiota-mediated pain sensitization: mechanisms and therapeutic implications

Minghe Zhao #  1   2 , Ling Zhang #  3 , Zhihui Liu  1
Affiliations
Review

Gut microbiota-mediated pain sensitization: mechanisms and therapeutic implications

Minghe Zhao et al. Front Pain Res (Lausanne). .

Abstract

Emerging evidence has illuminated the pivotal role of gut microbiota in modulating pain sensitivity through bidirectional gut-brain interactions. Current research demonstrates that gut microbial communities significantly influence pain perception by regulating both central and peripheral sensitization mechanisms across various pain modalities. This review synthesizes current knowledge on the mechanisms underlying gut microbiota-mediated pain sensitization, encompassing: (1) cross-talk within the microbiome-gut-brain axis, (2) regulatory effects of microbial metabolites on central and peripheral sensitization pathways, and (3) bioactive compounds derived from gut microbiota that participate in pain modulation. Furthermore, we systematically evaluate the therapeutic potential of microbiota-targeted interventions including probiotic supplementation, fecal microbiota transplantation, and dietary modifications in pain management. To advance this promising field, future investigations should prioritize three key directions: establishing causal relationships through rigorous verification, accelerating clinical translation of preclinical findings, and developing personalized microbial-based therapeutic strategies.

Keywords: GPR43; TLR2; gut microbiota; microbiome-gut-brain axis; neuroinflammation; pain; sensitization.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
GPR43 pathway. The schematic illustrates the molecular mechanism by which gut microbiota-derived short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, modulate neuroinflammatory signaling through the GPR43 pathway.
Figure 2
Figure 2
TLR2 pathway. This schematic delineates the molecular cascade triggered by enteric pathogens through Toll-like receptor 2 (TLR2)-mediated signaling, culminating in immune activation and inflammation.
Figure 3
Figure 3
Co-facilitation of pain sensitization. This schematic illustrates the dual modulation of excitatory and inhibitory synapses by inflammatory mediators, leading to drive pain hypersensitivity.
See this image and copyright information in PMC

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