Recent evidence implicates the gut microbiome in peripheral hypersensitivity in chronic opioid use models, and in chemotherapeutic-induced hypersensitivity in mice. An important constituent of the commensal microbiome are bacterial species that ferment fibers through complex enzymatic pathways and produce short chain fatty acids, acetate, propionate, and butyrate. Butyrate is known to improve the integrity of the epithelium and enhance antimicrobial peptides thus preventing colonization by pathogenic bacteria, as well as having an established role in reducing inflammation through the inhibition of histone deacetylase. Based on this, we hypothesized that sodium butyrate can relieve peripheral hypersensitivity as well as reduce primary nociceptor hyperexcitability in experimental models of peripheral hypersensitivity. We used both paclitaxel (PAC) and morphine (MOR) animal models, which were organized into the following treatment groups: PAC (8mg/kg i.p q.d, total 4 injections) ± Sodium Butyrate (10mg/kg i.p b.i.d), MOR (escalating from 20mg/kg i.p b.i.d on day 1 to 80mg/kg i.p b.i.d on day 4) ± Sodium Butyrate (10mg/kg i.p b.i.d). PAC animals were assessed for peripheral cold hypersensitivity using an acetone evaporation assay. MOR-treated animals were assayed using a hot-plate test for opioid-induced hyperalgesia. Primary nociceptors from L4-S1 dorsal root ganglia were collected from these mice for whole-cell patch clamp electrophysiological recordings to assess for enhanced excitability. PAC-treated mice developed significant cold hypersensitivity 7 days post PAC, when compared with vehicle (average time engaging stimulated paw 2.0s vs 8.6s respectively). Butyrate ameliorated this paclitaxel-induced hypersensitivity (average time reduced to 2.5s). Similarly, MOR induced thermal hypersensitivity (Hot-plate latency of 14.8s vs 28.16s saline), which was also reversed by sodium butyrate (Hot-plate latency of 24.84s). Whole-cell patch clamp recordings revealed that PAC and MOR-treated neurons fired a greater number of regenerating action potentials compared to respective controls (PAC: 4 vs 2; MOR: 3.8 vs 2.1), indicating enhanced excitability. In-vivo butyrate treatment attenuated this enhanced excitability. Hysteresis plots of hyperexcitable cells revealed a depolarizing shift in the membrane potential of regenerating action potentials. Sodium butyrate treatment recovered this shift in membrane potential within the repetitive action potentials. Therefore, similar to the in-vivo peripheral hypersensitivity, butyrate reversed enhanced excitability of PAC and MOR-treated DRG neurons. These findings demonstrate that the short chain fatty acid, butyrate, a major metabolite of the gut microbiome plays an important role in preventing the development of drug-induced peripheral hypersensitivity.