Epidemiological studies show that subsets of adult and pediatric IBS patients have prior exposures to psychological or inflammatory stress. We investigated the cellular mechanisms of colonic smooth muscle dysfunction in adult rats subjected to neonatal inflammation. Ten-day old male rat pups received 2,4,6-Trinitrobenzene sulfonic acid to induce colonic inflammation. Colonic circular smooth muscle strips were obtained 6 to 8 weeks later. We found that only about half of the neonate pups subjected to inflammatory insult showed a significant increase in expression of the pore-forming α_1C-subunit of Ca_v1.2b channels in adult life. These were the same rats in whom Vip mRNA increased in the colon muscularis externae. Additional experiments showed reduced interaction of histone deacetylase (HDAC) 3 with α_1C1b promoter that increased the acetylation of histone H3 lysine 9 (H3K9) in the core promoter region. VIP-treatment of naïve muscularis externae swiftly recruited CREB binding protein (CBP) to the α_1C1b promoter and dissociated HDAC3 from this region to initiate transcription. The CBP interaction with the α_1C1b promoter was transient, but the dissociation of HDAC3 persisted to sustain H3K9 hyperacetylation and increase in transcription. Intraperitoneal treatment of adult naïve rats with butyrate mimicked the effects of neonatal colon inflammation. We conclude neonatal inflammation upregulates VIP in the colon muscularis externae, which modulates epigenetic events at the α_1C1b promoter to activate α_1C1b gene transcription. Inflammatory insult in early-life may be one of the etiologies of smooth muscle dysfunction in adult life, which contribute to the altered motility function in diarrhea-predominant IBS patients.