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Background Tricyclic antidepressants (TCAs) have efficacy in treating irritable bowel syndrome (IBS). Some clinicians use TCAs to treat residual symptoms in inflammatory bowel disease (IBD) patients already on decisive IBD therapy or with quiescent inflammation, although this strategy has not been formally studied. Goals The aim of this study was to examine the efficacy of TCA therapy in IBD patients with residual symptoms, despite controlled inflammation, in a retrospective cohort study. Study Inclusion required initiation of TCA for persistent gastrointestinal symptoms. IBD patients had inactive or mildly active disease with persistent symptoms despite adequate IBD therapy as determined by their physician. Symptom response was compared with IBS patients. Established Likert scales were used to score baseline symptom severity (0=no symptoms, 3=severe symptoms) and TCA response (0=no improvement; 3=complete satisfaction). Results Eighty-one IBD [41.3±1.7 y, 56F; 58 Crohn's disease/23 ulcerative colitis (UC)] and 77 IBS (46.2±1.7 y, 60F) patients were initiated on a TCA therapy. Baseline symptom scores (IBD, 2.06±0.03; IBS, 2.12±0.04; P=0.15) and symptom response to TCA therapy (IBD, 1.46±0.09; IBS, 1.30±0.09; P=0.2) were similar in both the groups. At least moderate improvement (Likert score ≥2) on TCA was achieved by comparable proportions of patients (59.3% IBD vs. 46% IBS; P=0.09). Within IBD, response was better with UC than Crohn's disease (1.86±0.13 vs. 1.26±0.11, respectively, P=0.003). Conclusions In a clinical practice setting, TCA use led to moderate improvement of residual gastrointestinal symptoms in IBD patients for whom escalation of IBD therapy was not planned. UC patients demonstrated higher therapeutic success. IBD symptom responses were similar to IBS patients.

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are primarily derived from graft-versus-leukemia (GvL) that is mediated by mature T cells in donor grafts. Unfortunately, graft-versus-host disease (GvHD) results from immune reactions of these same donor T cells against host tissues and organs after allo-HSCT. Due to this strong association between GvHD and the beneficial GvL, our lab and others have been working on developing effective therapeutic strategies to selectively prevent and treat GvHD without abrogating GvL. Recently we have reported that pharmacologic inhibition of Janus kinases 1/2 (JAK1/JAK2) prevents GvHD by blocking IFNGR and IL6R signaling. Although baricitinib (BARI) and ruxolitinib (RUX) are both JAK1/JAK2 inhibitors with similar potency, BARI was found to be superior to RUX in prevention of GvHD in our mouse models of allo-HSCT. One of our proposed mechanistic pathways by which BARI prevents GvHD is via a robust increase in regulatory T cells (Tregs) which play a pivotal role in controlling GvHD. Since the proliferation and survival of Tregs are mediated through the IL2-JAK1/JAK3-STAT5 signaling pathway and that RUX is a more JAK3 inhibitor, we hypothesized that sparing JAK3 by BARI is critical for this increase of Tregs. To test this hypothesis, we administered BARI to allo-HSCT recipient mice with or without JAK3-specific inhibitor and monitored them for GvHD signs. The mice treated with BARI and iJAK3 had significantly lower Tregs and overall survival rates compared to the mice treated with BARI alone. This data suggests that BARI prevents GvHD by retaining JAK3, thereby increasing Tregs. We have also previously reported that BARI treats established GvHD. However, the mechanisms by which BARI reverses ongoing GvHD remain unclear. Consequently, we hypothesized that BARI not only modulates immune cell functions as we previously reported, but also promotes restoration of GvHD damaged tissues. To test our hypothesis, we delayed the administration of BARI until mice developed clinically apparent GvHD and treated them starting on days 10, 17, or 24 after allo-HSCT. Despite this latency, the day 10 group showed significantly better overall survival (p Since the gastrointestinal (GI) tract is the one of most frequently diagnosed and severely damaged GvHD target organs, we tested the possible mechanistic pathways by which BARI reverses GvHD in the GI tract. We found that Paneth cells and intestinal stem cells which are both involved in maintaining the intestinal barrier integrity are substantially increased in day 10 (p Figure Disclosures DiPersio: Karyopharm Therapeutics: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline Rx: Research Funding, Speakers Bureau; NeoImmune Tech: Research Funding. Choi:Daewoong Pharmaceuticals Co., Ltd: Consultancy.

Background & Aims Inflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice. Methods We generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn’s disease. Results Histologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn’s disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5. Conclusions In mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn’s disease patients. We propose that IDO1 contributes to intestinal homeostasis.

Several gastrointestinal diseases including the inflammatory bowel diseases (IBDs) and malignancy are associated with elevated expression of indoleamine 2,3 dioxygenase-1 (IDO1). IDO1 initiates tryptophan catabolism along a pathway that generates several bioactive kynurenine-based metabolites. Promotion of T-cell-mediated tolerance and antimicrobial effects are among the variety of functions attributed to IDO1 activity. Recent advances addressing the diverse implications of gut-associated IDO1 expression are herein reviewed.In active IBD, IDO1 is highly expressed both in the cells of the lamina propria and epithelium. Experimental models demonstrate that IDO1 promotes gut immune homeostasis by limiting inflammatory responses and protecting the epithelium. In human colon cancer, high expression of IDO1 by the neoplastic epithelium correlates with poor prognosis. The serum kynurenine : tryptophan ratio is elevated in both active Crohn's disease and in colon cancer, suggesting this measurement may prove useful as a disease biomarker. IDO1 inhibitors have moved to clinical trials providing new hope as immunotherapy for advanced malignancy.IDO1 activity significantly shapes gastrointestinal disease pathophysiology and severity. Measures of IDO1 activity may be useful as a disease biomarker. Manipulation of IDO1 activity has great potential as a treatment for both inflammatory and malignancy associated gastrointestinal disease.

Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals. Likewise, using CRISPR/Cas9 engineering, a functional group O line (HT-29-A(-/-)) was generated from a parent group A HT-29 line. CT stimulated robust cAMP responses in HT-29-A(-/-) cells relative to HT-29 cells. These findings provide a direct molecular link between blood group O expression and differential cellular responses to CT, recapitulating clinical and epidemiologic observations.

The enteric microbiota contribute to gastrointestinal health, and their disruption has been associated with many disease states. Some patients consume probiotic products in attempts to manipulate the intestinal microbiota for health benefit. It is important for gastroenterologists to improve their understanding of the mechanisms of probiotics and the evidence that support their use in practice. Clinical trials have assessed the therapeutic effects of probiotic agents for several disorders, including antibiotic- or Clostridium difficile-associated diarrhea, irritable bowel syndrome, and the inflammatory bowel diseases. Although probiotic research is a rapidly evolving field, there are sufficient data to justify a trial of probiotics for treatment or prevention of some of these conditions. However, the capacity of probiotics to modify disease symptoms is likely to be modest and varies among probiotic strains-not all probiotics are right for all diseases. The current review provides condition-specific rationale for using probiotic therapy and literature-based recommendations.

Dextran sulfate sodium (DSS) induces experimental colitis and promotes colitis-associated cancer in rodents. In practice we observe potent inhibition of real-time quantitative PCR (qPCR) using cDNA from DSS-exposed mouse tissues, which complicates gene expression analysis. Here we characterize DSS inhibition of qPCR in a wide array of murine tissues following ingestion of DSS. We examine different approaches to RNA purification prior to cDNA synthesis in order to optimize cDNA amplification and gene expression analysis. We find that poly-A purification of DSS-exposed RNA allows cDNA synthesis and permits reliable and cost-effective mRNA quantification for gene expression analysis in DSS-exposed tissue.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the major curative immunotherapy for hematologic malignancies. The therapeutic benefits of allo-HSCT are primarily derived from an anti-leukemia effect or graft-versus-leukemia (GvL) that is mediated by mature T cells in donor grafts. Unfortunately, these T cells could react against recipient tissues resulting in graft-versus-host disease (GvHD), a life-threatening complication post allo-HSCT. Due to this strong association between GvL and GvHD, developing a more effective therapeutic strategy to selectively suppress GvHD while preserving or enhancing the GvL effects remains a fundamental yet unmet medical need. We have previously published that co-blockade of interferon gamma receptor (IFNGR) and interleukin-6 receptor (IL6R) results in a complete prevention of GvHD (Choi et al., Leukemia, 2018). Moreover, in vivo administration of baricitinib, an inhibitor of Janus kinases 1 and 2 (JAK1/JAK2) which are downstream of IFNGR and IL6R, also prevents GvHD while preserving GvL in our preclinical murine model. The possible mechanistic pathways by which baricitinib mitigates GvHD include robust upregulation of regulatory T cells (Tregs), inhibition of GvHD-inducing Th1/Th2 cell differentiation, an altered T cell trafficking away from GvHD organs, and reduction of antigen presenting cells' allo-reactivity. Given the potent modulatory effect of baricitinib on GvHD and GvL, we next sought to determine the minimum duration of baricitinib treatment for the complete prevention of GvHD. Since we have found that baricitinib significantly increases Tregs during the first two weeks of the treatment, we hypothesized that two weeks of baricitinib administration is sufficient to completely prevent GvHD. We performed allo-HSCT in which B6 (H-2b) T cell-depleted bone marrow cells (5x106) along with pan T cells (5x105) were intravenously injected into lethally irradiated Balb/c mice (H-2d). Baricitinib was subcutaneously administered to the recipient mice once a day (5 days/week) for a period of one, two, three, or four weeks following allo-HSCT. Overall survival rates, clinical GvHD scores, complete blood counts, immunophenotyping of blood cells and histopathological scores were assessed to determine whether the GvHD was prevented. We have found that two to four-week treatment groups demonstrate significantly better overall survival rates, blood count recovery and histopathological scores than vehicle control or the one-week treatment groups, while no such significant differences were observed among the other groups (Fig. A). All of these data suggest that two weeks of baricitinib treatment is sufficient for complete prevention of GvHD. Lastly, we have previously reported that baricitinib reverses established GvHD (Choi et al., Leukemia, 2018) and we have recently found that both JAK1/JAK2 inhibitors, ruxolitinib and baricitinib, significantly enhance human intestinal organoid growth in vitro (Fig. B). Of note, the intestines are frequently diagnosed and severely damaged GvHD target organs in both human patients and our mouse models of GvHD. Thus, we hypothesized that baricitinib not only modulates immune cell functions as described above, but also promotes restoration of tissues damaged by GvHD. To test this hypothesis, we delayed baricitinib administration until mice developed clinically apparent GvHD and administered baricitinib starting on days 10, 17, or 31 after allo-HSCT for a period of two weeks. Despite this latency, the day 10 group showed 100% overall survival rate (5% in control, p In conclusion, our studies demonstrate that baricitinib-induced blockade of IFNGR and IL6R represents a promising therapeutic strategy for both prevention and treatment of GvHD while preserving GvL. Molecular mechanisms underlying baricitinib-mediated reversal of established GvHD are being currently investigated and will be presented. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

The chronic inflammatory bowel diseases are characterized by aberrant innate and adaptive immune responses to commensal luminal bacteria. In both human inflammatory bowel disease and in experimental models of colitis, there is an increased expression of the enzyme IDO. IDO expression has the capacity to exert antimicrobial effects and dampen adaptive immune responses. In the murine trinitrobenzene sulfonic acid model of colitis, inhibition of this enzyme leads to worsened disease severity, suggesting that IDO acts as a natural break in limiting colitis. In this investigation, we show that induction of IDO-1 by a TLR-9 agonist, immunostimulatory (ISS) DNA, critically contributes to its colitis limiting capacities. ISS DNA induces intestinal expression of IDO-1 but not the recently described paralog enzyme IDO-2. This induction occurred in both epithelial cells and in subsets of CD11c+ and CD11b+ cells of the lamina propria, which also increase after ISS-oligodeoxynucleotide. Signaling required for intestinal IDO-1 induction involves IFN-dependent pathways, as IDO-1 was not induced in STAT-1 knockout mice. Using both the trinitrobenzene sulfonic acid and dextran sodium sulfate models of colitis, we show the importance of IDO-1s induction in limiting colitis severity. The clinical parameters and histological correlates of colitis in these models were improved by administration of the TLR-9 agonist; however, when the function of IDO is inhibited, the colitis limiting effects of ISS-oligodeoxynucleotide were abrogated. These findings support the possibility that targeted induction of IDO-1 is an approach deserving further investigation as a therapeutic strategy for diseases of intestinal inflammation.

Background and aims: Vedolizumab inhibits leucocyte vascular adhesion and migration into the gastrointestinal tract through α4β7 integrin blockade. This agent became available in mid-2014 for the treatment of moderate to severe Crohn’s disease (CD) and UC (UC). The aim of this study was to assess the patterns of use, effectiveness and safety of vedolizumab in an inflammatory bowel disease (IBD) clinical practice. Methods: Patients beginning vedolizumab were enrolled with informed consent. A prospective cohort was followed with laboratory, disease activity and quality-of-life assessments made during infusion visits up to week 14. Duration of vedolizumab use, mucosal healing and safety were analysed retrospectively for all patients not captured in the prospective component of this study. Results: One hundred and two patients started vedolizumab, with 51 patients (30 CD, 21 UC) followed prospectively. The CD patients exhibited a significant decrease in Crohn’s Disease Activity Index ( p = 0.04) and Harvey–Bradshaw index ( p < 0.01) by week 14. The UC patients demonstrated improved partial Mayo scores at weeks 6 ( p < 0.01) and 14 ( p < 0.001). Ninety percent of all CD and UC patients remained on vedolizumab up to week 14. IBD-related quality of life was improved by week 6 in CD and UC cohorts ( p = 0.02 and p < 0.01 respectively). Colectomy for lack of response and systemic histoplamosis were notable reasons for early discontinuation of vedolizumab, which was otherwise well tolerated. Conclusions: Vedolizumab was efficacious and a high percentage of patients continued this therapy beyond induction dosing. Observed safety signals may be attributed to the refractory IBD disease state of this early-adopting clinical cohort.

In the course of obtaining nutrients from the environment to sustain life, the gastrointestinal (GI) tract encounters a myriad diversity of foreign antigens, microbiota, and environmental toxins. To maintain homeostasis in this setting, the GI mucosal immune system employs a multitude of techniques to distinguish the helpful from harmful. Recent studies reveal amino acid metabolism pathways as an integral mechanism to maintaining homeostasis at the mucosal interface. Tryptophan metabolism along the kynurenine pathway in particular is now recognized as an important feature of both GI inflammation and malignancy. Indoleamine 2,3 dioxygenase (IDO1), the most prevalent of the tryptophan catabolizing enzymes, is expressed widely across tissues and cell types within the GI tract. This chapter will address the current knowledge of kynurenine pathway functions in the diseased GI tract and highlight the potential benefits of exploiting this pathway for therapeutic purposes.

STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Johanna L. Chan, Houston, TX Matthew A. Ciorba, St. Louis, MO Massimo Colombo, Milan, Italy Gregory A. Cote, Charleston, SC Evan S. Dellon, Chapel Hill, NC Alex Ford, Leeds, United Kingdom Lauren B. Gerson, San Francisco, CA David S. Goldberg, Philadelphia, PA Samir Gupta, San Diego, CA Reena Khanna, London, Ontario, Canada W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Uma Mahadevan, San Francisco, CA Baha Moshiree, Miami, FL Swati G. Patel, Aurora, CO Laurent Peyrin-Biroulet, Vandoeuvre-les-Nancy, France Jesus Rivera-Nieves, San Diego, CA Sameer Saini, Ann Arbor, MI Ekihiro Seki, Los Angeles, CA Amit Singal, Dallas, TX Ryan W. Stidham, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Sachin Wani, Aurora, CO Alastair J. M. Watson, Norwich, United Kingdom Yana Zavros, Cincinnati, OH