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Background: The recent regulatory approval of ustekinumab which targets IL-12/IL-23 and clinical data from several anti-IL-23 monoclonal antibodies, MEDI2070, BI655066 and LY3074828, support IL-23 as a therapeutic target for the treatment of inflammatory bowel disease (IBD). We are developing an oral peptide, PTG-200, that would act locally in the gastrointestinal (GI) tissues to block the IL-23 signaling pathway by selectively binding to the IL-23 receptor (IL-23R). In this study, we sought to evaluate the efficacy and associated disease-related and mechanism-specific pharmacodynamic (PD) biomarkers of oral PTG-200 in a preclinical model of IBD.Methods: Acute colitis was induced in Sprague-Dawley rats by a single intra-rectal instillation of TNBS followed by efficacy analysis at day seven. PD biomarkers were examined using enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), or immunohistochemistry (IHC) analysis of colon, feces, or serum samples obtained from colitic rats treated with oral PTG-200.Results: In the TNBS-induced colitis model, oral treatment with PTG-200 resulted in significant dose-dependent improvement in animal body weight, reduction in the colon weight-to-length ratio, and normalization of the macroscopic and histopathological changes in the colon. In the colons of treated animals, the levels of MPO which is an indicator of neutrophil infiltration, the levels of IL-17A and IL-22 which are cytokines downstream of IL-23 signaling, and the levels of pStat3 which is a transcription factor whose phosphorylation status is known to be regulated by IL-23, were significantly reduced and correlated to dose titration of PTG-200. In the feces collected from the colons of treated animals, the levels of MPO and lipocalin 2 (LCN2), which is a neutrophil anti-bacterial protein over-expressed in the inflamed colonic epithelium, were significantly downregulated. LCN2 was also found to be significantly decreased in the serum.Conclusions: Blockade of IL-23R-mediated signaling by oral treatment with PTG-200 significantly improved disease outcomes in a TNBS-induced rat model of IBD through specific inhibition of the IL-23 pathway. Moreover, we identified additional inflammatory markers from feces as well as a non-invasive marker for colitic activity in the serum, that were responsive to PTG-200 treatment. Finally, we showed that responses from these biomarkers tracked with effects of PTG-200 on disease parameters. These data support the potential value of the profiled PD biomarkers in translating preclinical efficacy to clinical proof-of-concept for PTG-200, a potential first-in-class oral peptide therapeutic targeting IL-23R for the treatment of IBD.