S1P lyase inhibition increased tissue S1P levels, obliterated its gradient, induced lymphopenia, downregulated proinflammatory cytokines in the intestine, and ameliorated chronic ileitis. A, Tissue and plasma S1P levels in TNFΔARE mice treated with DOP or vehicle were measured using the LC-MS platform. B, Percentage of indicated lymphocyte subsets in the peripheral blood of TNFΔARE mice treated with DOP or vehicle for 2 weeks. C, mRNA transcripts of indicated proinflammatory cytokines relative to GAPDH in the ileum of 12-week-old TNFΔARE mice treated with DOP or vehicle control. D, Semiquantitative histopathological assessment of the effects of DOP treatment and vehicle on the severity of ileitis in TNFΔARE mice: active, chronic inflammation, villus distortion, and total inflammatory indices, respectively, as read by a gastrointestinal pathologist in a blinded fashion. Data are expressed as mean ± SEM; n ≥ 9 mice/group (***P < 0.001; **P < 0.01; *P < 0.05 by 2-tailed t test). E, Representative micrographs of the effects of DOP on intestinal architecture and inflammatory infiltrate (hematoxylin and eosin, 10× magnification).