Mucosal
inflammation is accompanied by an alteration in
5-HT. Intestinal
5-HT synthesis is catalyzed by
tryptophan hydroxylase 1 (Tph1) and we have shown that mice deficient in this rate-limiting
enzyme have reduced severity of intestinal
inflammation in models of chemical-induced experimental
colitis. Here, we investigated the effect of blocking peripheral
5-HT synthesis in generation of intestinal
inflammation by a using peripheral Tph inhibitor,
telotristat etiprate (
LX1606), in models of intestinal
inflammation.
LX1606 was given orally either prophylactically or therapeutically to mice with
dextran sulfate sodium (DSS)-induced
colitis or with
infection with Trichuris muris. Severity of intestinal
inflammation was measured by assessment of disease activity scores, histological damage, and MPO and inflammatory
cytokine levels.
LX1606 significantly reduced intestinal
5-HT levels and delayed onset and severity of DSS-induced acute and chronic
colitis. This was associated with decreased MPO and proinflammatory
cytokine levels compared with vehicle-treated controls. In the
infection-induced
inflammation model, treatment with
LX1606 enhanced worm expulsion as well as increased
IL-10 production and goblet cell numbers. LX1606-treated mice had significantly lower MPO and IL-1β levels compared with controls postinfection. Our results demonstrate that peripheral
5-HT plays an important role in intestinal
inflammation and in the generation of immune responses. Pharmacological reduction of peripheral
5-HT may serve as a potential strategy for modulating various intestinal inflammatory disorders.