Serotonin Has a Key Role in Pathogenesis of Experimental Colitis

Background & Aims

Mucosal changes in inflammatory bowel disease are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells as well as alteration in serotonin (5-hydroxytryptamine [5-HT])–producing enterochromaffin cells. We investigated the role of 5-HT in colonic inflammation in mice.

Methods

Colitis was induced with dextran sulfate sodium or dinitrobenzene sulfonic acid in tryptophan hydroxylase 1–deficient (TPH1^−/−) mice, which have markedly reduced 5-HT in the gastrointestinal tract, and in mice given the 5-HT synthesis inhibitor parachlorophenylalanine.

Results

Delayed onset, decreased severity of clinical disease, and significantly lower macroscopic and histologic damage scores were observed in TPH1^−/− mice, compared with wild-type mice, and in mice given parachlorophenylalanine after induction of colitis by dextran sulfate sodium. This was associated with down-regulation of macrophage infiltration and production of proinflammatory cytokines. 5-HT stimulated production of proinflammatory cytokines from macrophages collected from the peritoneal cavity of wild-type mice; this process was inhibited by a nuclear factor κB inhibitor, indicating a critical role for nuclear factor κB signaling in 5-HT–mediated activation of immune cells. Restoration of 5-HT levels in TPH1^−/− mice by the 5-HT precursor 5-hydroxytryptophan increased the severity of DSS-induced colitis. We also observed significant reduction in severity of colitis in TPH1^−/− mice after induction of dinitrobenzene sulfonic acid–induced colitis.

Conclusions

5-HT is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of gastrointestinal inflammation and could lead to new therapeutic strategies for inflammatory disorders.

Abbreviations used in this paper: CRP, C-reactive protein, DAI, disease activity index, DNBS, dinitrobenzene sulfonic acid, DSS, dextran sulfate sodium, EC, enterochromaffin, 5-HT, 5-hydroxytryptamine, 5-HTP, 5-hydroxytryptophan, IL, interleukin, LPS, lipopolysaccharide, MPO, myeloperoxidase, NF-κB, nuclear factor κB, PCPA, parachlorophenylalanine, SERT, serotonin reuptake transporter, TNBS, trinitrobenzene sulfonic acid, TNF, tumor necrosis factor, TPH, tryptophan hydroxylase