Abstract Introduction Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor expressed in the gastrointestinal tract, with high expression levels in the intestinal epithelium. Previously we have shown that FXR agonists with sustained activity decreased colitis in multiple chronic IBD models (i.e. Adoptive transfer colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis). Because FXR agonists are dosed orally and do not have systemic immunosuppressive properties, they represent a novel and differentiated therapeutic approach for IBD. MET642 is an optimized, potent non-bile acid FXR agonist with sustained FXR activation. In this study, we examined the efficacy of MET642 in therapeutic treatment mode in adoptive T-cell transfer model. Methods Colitis was induced by transplanting CD4+CD45RBhi T-cells to recipient C.B-17 SCID mice. Body weights were monitored throughout study duration. Staring 21 days after T-cell transfer, mice were treated with vehicle (n=10), MET642 (0.1, 0.3 or 1 mg/kg p.o., daily, n=10), or anti-IL-12p40 (neutralizing both IL-12 and IL-23, 0.5mg/mouse, i.p., weekly, n=5) for 4 weeks. Terminal endpoints included colon weight to length ratio (W/L), colon histopathology and gene expression. Histopathology scores were determined for inflammation, erosion, gland loss and hyperplasia, each with a score of 0–5, and cumulative sum score of 0–20. Results CD4+CD45RBhi T-cell transfer led to a significant reduction in body weight and increase in colon W/L ratio; both were reversed by MET642 and anti-IL-12p40. All dose levels of MET642 significantly improved the histopathology sum score relative to vehicle treatment, with maximal efficacy reached at 0.3mg/kg. Similar to anti-IL-12p40, MET642 showed improvements across all individual histopathology endpoints. Gene expression analysis suggests FXR activation increases anti-microbial activity, improves gut barrier and transporter function, and suppresses inflammation. Conclusion MET642, an oral once daily FXR agonist, significantly improved colitis in the adoptive T-cell transfer model. Activation of FXR by MET642 potentially promotes pathways of gut anti-microbial function, barrier function, and suppression of inflammation. These findings support further development of MET642 as a novel oral therapeutic for treating IBD.

modification of ultrasound elastography, is feasible and accurate for non-invasively quantifying bowel fibrosis in patients with CD.Prior studies implied that bowel fibrosis could influence therapeutic response of anti-TNF treatment.The aim of this study was to investigate a) the feasibility of SWE in predicting response to infliximab, and b) the change of bowel ultrasound findings during induction and post-induction in patients with CD.Methods: Patients with ileal/ileocolonic CD starting infliximab treatment were prospectively enrolled.Bowel ultrasound including SWE were performed at baseline (week 0), week 2, week 6 and week 14.The differences in bowel wall thickness, bowel wall Doppler signal (Limberg socre) and SWE value between the response group and the non-response group were analyzed.The response was defined by clinical activity index change combined with colonoscopy at week 14.Results: Eighteen patients were enrolled including 12 with response and 6 with non-response to IFX at week 14.A significant reduction of bowel thickness (P=0.030) and Doppler signal (P=0.049) was observed at week 14 in response group compared with nonresponse group.No significant change of SWE value at weeks 0, 2, 6 and 14 was observed in neither response group nor non-response group.The mean SWE value of disease bowel wall was higher in non-response group than that in the response group at baseline (13.0KPa±3.1KPavs 24.7KPa±10.8KPa,P=0.045).However, no difference in bowel thickness (6.7mm±2.1mmvs 8.0mm±2.1mm,P=0.229) and Doppler signal(3.1±0.9 vs 3.3±1.0,P= 0.735) was found between the two groups at baseline.Conclusions: This pilot study suggested that baseline SWE value may predict early efficacy of infliximab treatment in patients with CD.Intestinal wall thickness and blood flow signal change on bowel ultrasound could be used as indicators of infliximab response at week 14. Sa1736

Introduction: Sacral nerve stimulation (SNS) was reported to improve TNBS-induced colitis in rats.However, the routes of action need to be investigated.Our aim of this study was to investigate if SNS anti-inflammatory effect is mediated by the local sacral splanchnic nerves efferent-colon and/or the spinal cord-brain stem-vagal efferent-colon pathway.Methods: SNS electrodes were implanted unilaterally at S3 sacral nerve of rats to investigate the routes of action of SNS.The sacral and vagal nerves were cut in distinct locations at the same time of electrode implantation.Rats were subjected to 1-Bilateral truncal vagotomy 2-Proximal-Sacrotomy (proximal to the implanted electrodes), 3-Mid-Sacrotomy (middle to the implanted electrodes), 4-Distal-Sacrotomy (distal to the implanted electrodes) and 5-Splenic neurectomy.Rats were administrated with TNBS intra-rectally.Five days after TNBS-induced colitis, rats were divided into different groups and subjected to different treatment for 10 days as follows: Sham-SNS (control group with no stimulation), SNS, Vagotomy, Vagotomy+SNS, Distal-Sacrotomy, Distal-Sacrotomy+SNS, Mid-Sacrotomy, Mid-Sacrotomy+SNS, Proximal-Sacrotomy, Proximal-Sacrotomy+SNS, Splenic-Neurectomy, Splenic-Neurectomy+SNS and another control group with rectal injection of saline and without any treatment.SNS was performed 1 hours daily.The autonomic function was assessed by spectral analysis of heart rate variability (HRV) derived from the electrocardiogram.Results: 1) SNS and Distal-Sacrotomy+SNS, Splenic Neurectomy+SNS but not Vagotomy+SNS significantly decreased the DAI and MPO activity compared with sham-SNS.However, the anti-inflammatory effects of SNS group were more potent than Distal-Sacrotomy+SNS and Splenic Neurectomy+SNS.2) Spectral analysis of HRV showed a decrease in vagal activity (HF) following TNBS treatment; however, SNS was able to normalize the vagal activity in both Distal-Sacrotomy+SNS and Splenic-Neurectomy+SNS groups.3) SNS significantly increase Acetyl choline in colon tissues in both Distal-Sacrotomy+SNS, and Splenic-Neurectomy+SNS but not the Vagotomy and Vagotomy+SNS groups.4) SNS elevated anti-inflammatory cytokines (IL-2, IL-10) and decreased pro-inflammatory cytokines (IL-17A, TNF a) in SNS and Distal-Sacrotomy+SNS groups in comparison with Sham-SNS.5) SNS effectively increased the number of c-fos positive cells in NTS area in SNS group than sham-SNS.This demonstrated that the spinal cord-brain stem-vagal efferent-colon pathway is actively involved in antiinflammatory pathway.Conclusion: SNS exerts an anti-inflammatory effect on TNBSinduced colitis by enhancing vagal activity mediated via the spinal cord-brain stem-vagal efferent-colon pathway.