Inflammatory Bowel Disease Conditions Research Articles

Effectiveness of the Specific Mobility Exercises on Pain Intensity and Quality of Life Among Stoma Patients: A Quasi-experimental Study.

An intestinal stoma is a surgically created artificial opening in the abdominal wall that helps the largeor small intestine end to divert the faecal matter for stoma patients with an underlying condition of inflammatory bowel disease and colorectal cancer.When a stoma is formed following surgery, one of the difficulties stoma patients confront has been identified as prolonged immobilization, which can eventually result in muscle inactivity that results due to their illness. Patients with stoma often experience an increase in pain and a decrease in quality of life. Patients can be mobilized and their muscles can be activated with the help of an early intervention calledspecific mobility exercises. The present study aimed to explore thespecific mobility exercises that reduce pain and improve quality of life among stoma patients. This quasi-experimental study involved 21 patients who underwent stoma surgery and were selected according to the inclusion and exclusion criteria. The experimental procedures were explained to all the patientsand their written informed consent was obtained. The patients performed specific mobility exercises for 30 minutes per day. Treatment was given for four weeks every day after three to four days of stoma surgery. The patient's pain and quality of life were assessed using the Numerical Pain Rating Scale and the Stoma-Quality of Life (QoL) Questionnaire andpre-test and post-test values were recorded before and after theexercises. The data were tabulated and evaluated. The findings suggest that specific mobility exercises following four weeks of intervention have a significant effect (p< 0.001) in reducing pain except inyoung adult stoma patients as they were found to be anxious and depressed, which was reflected in the findings as not statistically significant for pain on the NPRS (t(1) = 7, p > 0.001). However, it has been demonstrated that these specific mobility exercises have a significant effect (p< 0.001) in improving the quality of life among all stoma patients. The study evidenced that four weeks of specific mobility exercises in line with general medical treatment showed a significantreduction in pain and an improvement in quality of life among stoma patients. However, it should be noted that in the study, the majority of stoma patients were male and there were only a few patients with inflammatory bowel disease, which can limit the study findings. Future studies have to focus on equally distributing gender and conditions by emphasizing the importance of randomizing patients into the experimental and control groups and involving a combination of other exercises in rehabilitation for patients following stoma surgery.

P344 Diverting ileostomy in Inflammatory Bowel Disease's surgery: the real clinical cost analysis

Abstract Background A loop ileostomy does not prevent an anastomotic leak and it is not risk-free, but it can decrease the clinical impact of dehiscence. Inflammatory bowel disease condition is more complex than other benign situations candidated to colorectal surgery. The aim of our study was to assess the risk of complications related to the stoma presence and to identificate variables related with complications in a series of IBD’s patients undergoing various colorectal surgeries along with primary diverting stoma. Methods We conducted a retrospective study of patients who underwent sphincter-preserving elective surgery for IBD between January 2014 to December 2020 at IRCCS Sacro Cuore Don Calabria Hospital. Data were collected regarding baseline demographics, operative techniques and complications. Ileostomy-related complications were separated into three categories: complications related to stoma creation at the time of index surgery within 30 days; complications of having an ileostomy; complications of ileostomy closure. Results Fifty-six diverting loop ileostomies were performed and included in our study (table 1). Seventeen patients (30%) at index procedures had the following complications: 5 had anastomotic leak or pelvic abscess (8.9%), 3 had bowel obstruction (5.4%) and 7 (12.5%) bleeding requiring transfusion. Two patients had complications related to ileostomy creation: 1 had prolapse (1.8%) and 1 rotation with obstruction (1.8%). Seven patients (12.5%) required reoperation. Seven patients (12.5%) were readmitted within 30 days after index surgery for dehydratation. Twenty-four patients (42.1%) suffered during the same time from ileostomy management’s problems. Eighteen patients (32.1%) at stoma closure had the following complications: 6 had anastomotic leak or pelvic abscess (10.7%), 7 had SSI (12.5%), 5 had bowel obstruction (8.9%) and 2 bleeding requiring transfusions (3.6%). Nine patients (16%) required reoperation. At univariate analysis complications of ileostomy status are more frequent in male (p=0.01) and in patients who had ileostomy creation complications (p=0.04). Ileostomy closure complications are more common in male patients (p=0.005). Complications at the time of ileostomy creation were found at multivariate analysis statistically related to complications during ileostomy maintenance. Conclusion Ileostomy alone cannot mitigate the overall high rate of complications expected in IBD’s patients, also in consideration of potential problems stoma it-self related. Even if our study is retrospective and presents a small court, when resection is necessary despite patient's conditions we propose to resect without anastomosis at the time of index procedure and restore the bowel continuity only after patient's status optimization.

Protective effect of 7-hydroxyl-1-methylindole-3-acetonitrile on the intestinal mucosal damage response to inflammation in mice with DSS-induced colitis

Ulcerative colitis (UC), a pathological condition of inflammatory bowel disease, is a chronic inflammatory disorder that involves an abnormal immune response and epithelial barrier dysfunction. Although we have previously reported the anti-inflammatory effects of 7-hydroxyl-1-methylindole-3-acetonitrile (7-HMIA), a synthesized analog of arvelexin on macrophages and paw edema, its anti-colitis effect and its mechanism are not known. In this study, colitis was induced in mice model by 4% (w/v) dextran sodium sulfate (DSS) solution in drinking water for 9 days. At the same time, from the first day of administering drinking water containing DSS, the animals were treated with 5-aminosalicylic acid (5-ASA), 75 mg/kg/day, orally) or 7-HMIA (10 or 20 mg/kg/day, intraperitoneally), depending on the experimental group, respectively. The studies were terminated on the tenth day of the experiment. Our data showed that 7-HMIA reduced the disease activity index and spleen/body weight (S/B) ratio, and improved the shortened colon length comparable to the effects of 5-ASA observed in the DSS-exposed mice. 7-HMIA, like 5-ASA, inhibited the histological damage, such as a thickened colonic muscle layer and shortened crypt length in the colon of the mice with DSS-induced colitis. 7-HMIA restored the tight junction-related proteins (occludin, claudin-1, and claudin-2) and epithelial-mesenchymal transition-mediated proteins (E-cadherin, N-cadherin, and vimentin) in the colon tissue of mice with DSS-induced colitis. Additionally, 7-HMIA (20 mg/kg/day) showed the inhibitory effects similar to that of 5-ASA on the myeloperoxidase activity, interleukin (IL)-6 production, and expression levels of inducible nitric oxide synthase (iNOS), and even showed greater inhibition of IL-1β production in the DSS-induced mice. Furthermore, the DSS-induced activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were effectively suppressed by 7-HMIA treatment like the effects of 5-ASA. Overall, our findings revealed that 7-HMIA decreased the severity of colitis by protecting the inflamed mucosal barrier by interfering with NF-κB and STAT3 activation.

Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease

Background and aimsBiological therapy for inflammatory bowel disease is efficient in many cases but not all. The underlying molecular mechanisms behind non-response to biological therapy in inflammatory bowel disease are poorly described. Therefore, we aimed to characterize the mucosal cytokine transcript profile in non-immunogenic, non-responder patients with adequate trough level.Material and methodsPatients with ulcerative colitis (UC) (n = 21) and Crohn’s disease (CD) (n = 12) with non-response to biological therapy (anti-tumor necrosis factor (TNF) or vedolizumab) were included. Reference groups were A: untreated patients with UC or CD at debut of disease who had severe 1-year outcome, B: patients with UC or CD treated to endoscopic remission with biological agents, and C: healthy normal controls. Mucosal transcripts of TNF, interleukin (IL)17 and IL23 were measured by reverse transcription real-time quantitative polymerase chain reaction.ResultsOf the non-responders, 2 out of 12 CD and 1 out of 21 UC patients needed surgery during follow-up. Of the remaining non-responding patients, 8 out of 10 CD and 12 out of 20 UC patients switched biologic treatment. The remaining 2 CD and 8 UC patients continued treatment with the same biological agent with the addition of steroids, immunomodulators (AZA/MTX) and /or local steroids/5ASA. Twelve (8 UC/4 CD) out of 20 IBD patients were still non-responders after changing biological therapy to either anti-TNF (2), vedolizumab (9) or ustekinumab (1).The transcripts of IL17, IL23 and TNF were significantly upregulated in the non-response group compared to normal controls and patients in remission. In UC, 24% of the non-responders had normal mucosal TNF transcript indicating a non-TNF mediated inflammation. No obvious differences in gene expression were observed between primary and secondary non-responders, nor between anti-TNF and vedolizumab non-responders.ConclusionsMucosal transcripts of IL17 and IL23 are highly associated with non-response to biological therapy, whereas some UC patients may also have a non-TNF mediated inflammatory pathway.

Explainable Machine Learning for Longitudinal Multi-Omic Microbiome

Over the years, research studies have shown there is a key connection between the microbial community in the gut, genes, and immune system. Understanding this association may help discover the cause of complex chronic idiopathic disorders such as inflammatory bowel disease. Even though important efforts have been put into the field, the functions, dynamics, and causation of dysbiosis state performed by the microbial community remains unclear. Machine learning models can help elucidate important connections and relationships between microbes in the human host. Our study aims to extend the current knowledge of associations between the human microbiome and health and disease through the application of dynamic Bayesian networks to describe the temporal variation of the gut microbiota and dynamic relationships between taxonomic entities and clinical variables. We develop a set of preprocessing steps to clean, filter, select, integrate, and model informative metagenomics, metatranscriptomics, and metabolomics longitudinal data from the Human Microbiome Project. This study accomplishes novel network models with satisfactory predictive performance (accuracy = 0.648) for each inflammatory bowel disease state, validating Bayesian networks as a framework for developing interpretable models to help understand the basic ways the different biological entities (taxa, genes, metabolites) interact with each other in a given environment (human gut) over time. These findings can serve as a starting point to advance the discovery of novel therapeutic approaches and new biomarkers for precision medicine.

POS1017 GUSELKUMAB PROVIDES CONTINUED IMPROVEMENT IN KEY DOMAINS OF PSORIATIC ARTHRITIS THROUGH 2 YEARS

BackgroundRecent guidelines from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommend that psoriatic arthritis (PsA) therapy achieve lowest possible disease activity across 6 key domains and related conditions. 1 In the DISCOVER-1&amp;2 trials, guselkumab (GUS) significantly improved signs and symptoms of PsA at Week (W) 24.ObjectivesEvaluate GUS efficacy through W100 of DISCOVER-2 by GRAPPA-recommended PsA domains (peripheral arthritis, skin, dactylitis, enthesitis, axial disease [nails not evaluated]) and related conditions of inflammatory bowel disease (IBD) and uveitis.MethodsEnrolled adults had active PsA, were naïve to biologics/JAK inhibitors, and had ≥5 swollen and ≥5 tender joints and CRP ≥0.6 mg/dL. Randomized (1:1:1) patients (pts) received GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then every 8 weeks (Q8W); or placebo (PBO) with crossover to GUS 100 mg Q4W at W24. Outcomes selected aligned with GRAPPA-recommended domains/conditions: overall disease activity (Psoriatic Arthritis Disease Activity Score [PASDAS], Minimal Disease Activity [MDA]), peripheral arthritis (changes in Disease Activity Index for Psoriatic Arthritis [DAPSA] and clinical DAPSA [cDAPSA]), skin (Psoriasis Area and Severity Index [PASI], Investigator’s Global Assessment of psoriasis [IGA]), dactylitis (Dactylitis Severity Score [DSS]), enthesitis (Leeds Enthesitis Index [LEI]), axial disease (spinal pain) and IBD/uveitis (adverse events [AEs]). Among 493 GUS-randomized pts, change from baseline (BL) through W100 in continuous outcomes were analyzed by Repeated Measures Generalized Linear Mixed Effects Models adjusting for respective BL score and GUS regimen. Achievement of therapeutic endpoints was summarized by descriptive statistics using nonresponder imputation (NRI) for missing categorical data.Results~90% of GUS-randomized pts completed treatment at W100. For continuous outcomes, improvements over time in key PsA domains extended through W100 of GUS (Figure 1). Therapeutic endpoint response rates also increased incrementally through W100 (Table 1). Mean improvements and response rates were consistent across key domains with no significant difference between GUS regimens. For related conditions, 1 GUS pt had IBD and 4 had uveitis at BL and none had AE of exacerbation through W100. No pt developed IBD through W100 (vs 1 PBO pt through W24); 1 GUS pt had AE of iridocyclitis through W100 (vs 1 PBO pt through W24).Table 1.Number (%) of GUS-randomized Pts (N=493) Achieving Therapeutic Endpoints Over Time (NRI)*WeekQ4WQ8W81624521008162452100MDA*8 (3)33 (14)47 (19)83 (34)93 (38)9 (4)42 (17)63 (25)77 (31)100 (40)DAPSA43 (18)61 (25)88 (36)125 (51)151 (62)43 (17)79 (32)97 (39)130 (52)147 (59) ≤14’; ≤45 (2)12 (5)21 (9)39 (16)52 (21)3 (1)15 (6)23 (9)46 (19)60 (24)cDAPSA41 (17)58 (24)89 (36)125 (51)150 (61)44 (18)75 (30)95 (38)131 (53)147 (60) ≤13* ≤35 (2)13 (5)29 (12)44 (18)59 (24)4 (2)19 (8)25 (10)53 (21)65 (26)PASDAS ≤3.225 (10)44 (18)58 (24)105 (43)126 (51)28 (11)56 (23)76 (31)106 (43)122 (49) ≤1.94 (2)11 (4)22 (9)36 (15)51 (21)2 (1)16 (6)23 (9)52 (21)58 (23)Skin PASI75†-137 (74)146 (79)160 (87)152 (83)-129 (73)139 (79)151 (86)144 (82) PASI90†-100 (54)114 (62)142 (77)136 (74)-97 (55)121 (69)131 (74)123 (70) PASI100†-62 (34)83 (45)106 (58)109 (59)-48 (27)80 (46)93 (53)94 (53) IGA 0/1 Response‡-122 (66)127 (69)147 (80)140 (76)-110 (62)124 (70)131 (74)126 (72)Enthesitis resolution§45 (27)66 (40)71 (43)93 (56)102 (61)50 (32)75 (48)87 (55)97 (62)110 (70)Dactylitis resolution§39 (32)64 (53)80 (66)90 (74)87 (72)34 (31)51 (46)66 (60)86 (77)92 (83)*Repeated Measures Generalized Linear Mixed Effects Models; excludes pts who achieved endpoint at BL.†Pts with BL IGA≥2 and BSA≥3%.‡IGA skin response = score of 0 or 1 and ≥2 grade improvement from BL.§Among pts with domain at BL.ConclusionIn DISCOVER-2 bio-naïve PsA pts, both GUS regimens provided continued improvements in key GRAPPA-recommended domains of PsA through up to 2 years of treatment.

Association of Aberrant Promoter Methylation Changes in the Suppressor of Cytokine Signaling 3 (SOCS3) Gene with Susceptibility to Crohn's Disease.

Background:Growing evidence supports that changes in the methylation state of Inflammatory Bowel Disease (IBD)-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We supposed that alterations in DNA methylation status at promoter region within the suppressor of cytokine signaling 3 (SOCS3) gene in intestinal tissues may be involved in the susceptibility to Crohn's Disease (CD).Methods:DNA methylation status in the promoter region of the human SOCS3 gene of intestinal tissues from 15 patients with CD and 15 age- and sex-matched healthy controls were profiled using the real-time Quantitative Multiplex Methylation Specific PCR (QM-MSP) assay.Results:Based on methylation assay data profiling, we found that patients with CD showed a higher degree of methylation of the SOCS3 gene promoter region than did the healthy controls (unmethylated DNA in CD vs. healthy controls; 0.00048±0.0011 vs. 0.07±0.142, p<0.000).Conclusion:The data presented here demonstrate that aberrant methylation of the CpG islands within promoter regions of SOCS3 gene in colonic mucosa of CD was associated with mucosal inflammatory status, providing insights into the involvement of methylation could contribute to the initiation of the inflammatory process and development of CD.

Advances in Understanding Early-Onset Colorectal Cancer.

Since the 1990s, the incidence of early-onset colorectal cancer (at <50 years of age) in the US has increased by more than 50%; similar increases have also been observed internationally. These increases are found particularly among individuals born during and after the 1960s, raising the possibility that the increased rates of early-onset colorectal cancer are attributable to changes in risk-factor patterns throughout successive generations. The reasons for these alarming epidemiologic patterns for early-onset colorectal cancer worldwide are only recently being investigated and major gaps in our knowledge remain. In the current issue of this journal, Arif and colleagues differentiated characteristics and outcomes of early-onset colorectal cancer in patients with the predisposing conditions of inflammatory bowel disease or hereditary genetic syndromes, compared with patients who have sporadic disease. Also, in this issue, Schumacher and colleagues investigated risk factors for early-onset colorectal adenocarcinoma in a nested case-control study among Kaiser Permanente Southern California (KPSC) health plan members. The research presented on characteristics and outcomes points to the importance of sporadic disease in the rise of early-onset colorectal cancer, while the research presented on risk factors points to the importance of obesity as a potential explanatory factor for this rise.See related articles by Arif et al., p. 1785 and by Schumacher et al., p. 1792.

Exploring how microbiome signatures change across inflammatory bowel disease conditions and disease locations

Understanding the variables that influence microbiome studies is critical for successful translational research. Inflammatory bowel disease (IBD) is a complex group of diseases that can present at multiple locations within the Gastrointestinal tract. Here, using the FAMISHED study cohort, we aimed to investigate the relationship between IBD condition, IBD disease location, and the microbiome. Signatures of the microbiome, including measures of diversity, taxonomy, and functionality, all significantly differed across the three different IBD conditions, Crohn’s disease (CD), ulcerative colitis (UC), and microscopic colitis (MC). Notably, when stratifying by disease location, patients with CD in the terminal ileum were more similar to healthy controls than patients with CD in the small bowel or colon, however no differences were observed at different disease locations across patients with UC. Change in taxonomic composition resulted in changes in function, with CD at each disease location, UC and MC all having unique functional dysbioses. CD patients in particular had deficiencies in Short-Chain Fatty Acid (SCFA) pathways. Our results demonstrate the complex relationship between IBD and the microbiome and highlight the need for consistent strategies for the stratification of clinical cohorts and downstream analysis to ensure results across microbiome studies and clinical trials are comparable.

Validity and Reliability of the 8-Item Inventory of Dimensions of Emerging Adulthood in a Sample of Inflammatory Bowel Disease Patients.

The purpose was to examine the 8-item Inventory of Dimensions of Emerging Adulthood (IDEA-8) among 61 emerging adults (ages 18-29) with the chronic condition of inflammatory bowel disease (IBD). An online continence sample of participants' ages 18-29 years with a self-reported diagnosis of IBD completed a questionnaire including IDEA-8, demographic, and clinical characteristics. The exploratory factor analysis identified a three-factor structure. The three subscales had acceptable internal consistency (α = .74-.86). Two factors (identity exploration/feeling in-between and instability) were associated with demographics. The factors were not associated with clinical characteristics. Developmental features of emerging adults, as measured by the IDEA-8 for those with IBD, may retain conceptual consistency with healthy adults, but demonstrate a restructuring in factor analysis.

OP39 Treatment of ulcerative colitis With AMT-101, a novel oral interleukin-10 immunomodulatory fusion biologic that traffics across the intestinal epithelium

Abstract Background While different chronic inflammatory diseases can be correlated with distinct pro-inflammatory cytokines, interleukin-10 (IL-10) represents a central anti-inflammatory cytokine capable of modulating many pro-inflammatory signals. Previous clinical efforts to capture the benefit of IL-10 in suppressing the pro-inflammatory state in inflammatory bowel disease (IBD) patients have been limited by dose-limiting systemic side effects. Methods We have designed a chimaera of human IL-10 genetically fused to a non-toxic and poorly immunogenic fragment of the cholix exotoxin, termed AMT-101, that demonstrated rapid receptor-mediated transcytosis in vitro and in vivo and could activate phospho-STAT3 in cells within the lamina propria following luminal administration (data not shown). Mice with oxazolone-induced colitis were dosed by oral gavage with AMT-101 daily for 12 days, at which time colon tissue and serum were examined for hallmarks of inflammation. Enteric-coated capsules were used to deliver either 1 or 5 mg of AMT-101 to the distal ileum of cynomolgus monkeys; serum was collected to examine PK and PD outcomes in this non-inflamed model. Results Histological changes of colonic tissue associated with oxazolone-induced colitis was blocked by the oral gavage of AMT-101. Increases in serum levels of pro-inflammatory cytokines IL-1b, IL-6, and IL-17A were blunted by AMT-101 treatment. Remarkably, endogenous IL-10 increased in this model in an attempt to correct inflammation, but this was also decreased by the delivery of AMT-101. Cynomolgus monkeys dosed orally with AMT-101 capsules showed very low serum levels compared with those observed after IV injection of 0.5 mg/kg AMT-101. Strikingly, serum levels of IL-1 receptor antagonist (IL-1RA) as an anti-inflammatory PD marker were increased to a greater extent following oral capsule dosing compared with IV administration. Conclusion These studies provide strong pre-clinical evidence that AMT-101 can effectively reach the intestinal lamina propria to delivery biologically-active IL-10 following transcytosis across the intestinal epithelium. Importantly, the gut-selective nature of the responses observed suggests AMT-101 may alleviate the previous issues of dose-limiting side effects observed with systemic administration of IL-10 and point to the intestinal lamina propria as a critical site of IL-10’s immunomodulatory actions. AMT-101 has advanced to the clinic and is currently being evaluated in a Phase1b trial in patients with active ulcerative colitis.

Altered Gut Motility in Mice Lacking Neuropilin 2 in Smooth Muscle

Introduction/ObjectivesProfound changes in gut motility and colonic smooth muscle contraction are observed in inflammatory bowel disease states such as colitis. However, the mechanisms that contribute to altered motility and contractility under these circumstances are incompletely defined. Recent data from our group have identified the smooth muscle of the gastrointestinal tract as a major site of expression of neuropilin 2 (Nrp2) in vivo. Nrp2 and the related molecule neuropilin 1 are 130–140 kDa transmembrane receptors for the class 3 semaphorin (SEMA3) family of axonal guidance regulators and for members of the vascular endothelial growth factor (VEGF) family that regulate angiogenesis. Based on recent data from our group implicating Nrp2 as a novel regulator of bladder smooth muscle contractility, the objective of this study was to determine the functional significance of Nrp2 in gastrointestinal smooth muscle.MethodsTwo mouse models were used to explore a role for Nrp2 in gastrointestinal motility: (i) SM22alpha‐Cre; Nrp2 fl/fl mice to enable inducible smooth muscle‐specific deletion of Nrp2 in vivo under controlled conditions and (ii) wild type Balb/c mice exposed to dextran sodium sulfate (DSS) to evoke acute colitis. Gut tissues were subjected to isometric tension testing to characterize contractility. Gut transit was evaluated by charcoal meal assay. Nrp2 levels were assessed by immunohistochemical staining and immunoblot analysis of tissues and of primary colonic smooth muscle cells exposed to inflammatory cytokines.ResultsSmooth muscle‐specific deletion of Nrp2 led to an increase in force generation of colonic rings, upon exposure to electrical field stimulation or treatment with the cholinergic agonist, carbachol. Nrp2 deletion also led to elevated gut transit as assessed by charcoal meal assay. In response to colitis, Nrp2 levels were found to decrease in the distal colon, in parallel with elevated contractility of distal colon rings. In addition, treatment of primary human colonic smooth muscle cells with IL‐4, representative of the TH2 inflammatory milieu associated with DSS colitis, decreased Nrp2 levels while treatment with TNF‐a, characteristic of the TH1 response in colitis increased Nrp2 levels.ConclusionsThese observations suggest that dynamic alterations in Nrp2 under conditions of inflammation may underlie altered contractility of intestinal smooth muscle, resulting in dysmotility. Moreover, these findings suggest that Nrp2 may represent a novel therapeutic target for restoration of normal gut motility.Support or Funding InformationHarvard Digestive Diseases Center P&amp;F Grant (RMA); R01 DK104641 (RMA, DRB, MPS)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fecal calprotectin is significantly linked to azathioprine metabolite concentrations in Crohn's disease.

The value of therapeutic drug monitoring during azathioprine (AZA) therapy with respect to clinical outcomes has been convincingly demonstrated in recent meta-analyses. However, the association between AZA metabolites and the mucosal state in inflammatory bowel disease is largely unclear. We investigated the association between AZA's active metabolite 6-thioguanine nucleotides (6-TGN) and fecal calprotectin (FC) as a well-validated surrogate marker of mucosal inflammation in patients with Crohn's disease (CD) on AZA monotherapy. Of 443 6-TGN measurements, 140 values from 88 patients with CD on AZA monotherapy visiting the inflammatory bowel disease outpatient clinic between 2009 and 2016 were retrospectively analyzed. In a subcohort with serial 6-TGN measurements, longitudinal FC measurements in patients with versus without intervention (dose increase, allopurinol, and education) were assessed. In patients with 6-TGN concentrations within a predefined range (250-450 pmol/8×10 red blood cells), FC was significantly lower (median: 119.5 vs. 327.2 mg/kg, P=0.003), and hemoglobin as well as serum protein concentrations were significantly higher than in patients with 6-TGN outside of this range. C-reactive protein and transferrin saturation were not different. In the longitudinal cohort, 6-TGN increased in the intervention group, but only a minority reached the defined range; no significant change in FC was observed. This study is the first to show that in patients with CD receiving AZA monotherapy, 6-TGN concentrations within a defined range (250-450 pmol/8×10 red blood cells) are associated with significantly lower FC. A treat-to-target concept directed by 6-TGN to reach mucosal healing may thus be a promising approach (DRKS00013246).

Gastrointestinal Spice Sensors and Their Functions

Capsaicin is a constituent of chili pepper, and induces the burning sensation on the tongue. The site of action for capsaicin has been discovered as transient receptor potential vanilloid receptor subtype 1 (TRPV1) that resides on the membranes of pain- and heat-sensing primary afferent nerves. The immunohistochemical study on the stomach revealed that nerve fibers expressing TRPV1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers. High numbers of TRPV1-immunoreactive axons were observed in the rectum and distal colon. Therefore, capsaicin stimulates TRPV1 not only on the tongue but also in the gut. In this review, the mechanism of gastrointestinal mucosal defense enhanced by capsaicin was summarized. TRPV1 plays a protective role in gastrointestinal mucosal defensive mechanism. Hypersensitivity of afferent fibers occurs during gastrointestinal inflammation. Abnormalities of primary afferent nerve fibers are strongly associated with the visceral hypersensitive state in inflammatory bowel disease (IBD). The alteration of TRPV1 channels in mucosa contributes to the visceral hypersensitivity in colitis model mice. TRPV1-expressing neurons in the gut are thought to be extrinsic sensory afferent neurons that operate to maintain gastrointestinal functions under physiological and inflammatory states.

P854 Quantitative microbiome profiling changes the described dysbiotic state in inflammatory bowel disease

P854 Quantitative microbiome profiling changes the described dysbiotic state in inflammatory bowel disease

IRON INFUSION THERAPY WITH FERRIC CARBOXYMALTOSE (FCM) IN CHILDREN LESS THAN 14 YEARS OLD

Aim To prospectively assess iron infusion therapy with ferric carboxymaltose (FCM) in children less than 14 years old. Methods All children with confirmed iron-deficiency less than fourteen years old who received an FCM-infusion at a dose of 15 mg/kg (max 20 mg/kg) were included in the study. The use of FMC is licensed for use in adults and children older than 14 years. Data was taken from a database system registered as a service evaluation tool with the local hospital. Data on forty two children (from Jul 2011 to Mar 2014) younger than 14 years was recorded out of which 36 had an underlying condition of inflammatory bowel disease (IBD), two patients with short-bowel syndrome started on parenteral nutrition, and four patients with anaemia due to other clinical causes. One these patients had Down9s syndrome. All patients (19 girls, 23 boys) aged between 1–13 years of age at the time of the first dose, (mean 9 years of age; 8 children were less than 5 years old) received the infusion in an outpatient clinic setting. Mean weight was 30.5 kg (range 7 kg to 50 kg). Ten patients received at least one more course of FCM half to one year later, during the reported period. The result for haemoglobin, serum ferritin and iron of the first treatment course was documented from routine blood samples at one to six months following the infusion. Results There was an improvement in blood indices: mean haemoglobin rise of 3 g/L (range pre 3.7–12.8, post 9.3–14.7 g/L), mean serum ferritin rise 72 microgram/L (range pre 0.5–106, post 4.6–273 microgram/L) and mean serum iron rise of 6.7 micromol/L (range pre: 1.1–11.5, post: 2.1–22.8 micromol/L). No early or late adverse reactions have been reported on any of the patients. Conclusion The results suggest that the use of intravenous iron in its formulation as FCM seems to be a safe treatment in young children with iron-deficiency. A clinical trial may be needed to evaluate an efficient dosing regimen of FCM in children less than 14 years of age with different medical backgrounds.

Immunohistochemical analysis of altered serotonin signaling and transient receptor potential vanilloid 1 channels in experimental colitis mice

Primary afferent nerve fibers are highly associated with visceral hypersensitivity state of inflammatory bowel disease. Hypersensitivity of afferent fibers occurs during inflammation, and therefore to gain insight into the alteration of receptors and channels, we examined receptors such as 5-HT receptors and transient receptor potential vanilloid type 1 (TRPV1), which are expressed in primary afferent neurons. The current study was designed to investigate the time-dependent dynamic changes of 5-HT3 receptors, 5-HT4 receptors, TRPV1 channels, and 5-HT regulatory factors in DSS-induced colitis model mice. Colitis was induced by 3% dextran sulfate sodium (DSS) solution given as drinking water in C57BL/6J mice. Immunohistochemical analysis and visceromotor responses to colorectal distension were measured during induction of DSS colitis (day 0, 4 and 7). Progress of the inflammation led to down regulation of serotonin transporter immunoreactivities with concomitant increases in 5-HT and tryptophan hydroxylase-1 positive cell numbers. TRPV1-expressing nerve fibers gradually increased during DSS treatment. Abundant non-neuronal TRPV1-immunopositive cell like structure was observed on day 7 of DSS treatment, but not on day 4. The number of 5-HT3 receptor-expressing nerve fibers increased in mucosa on day 7. On the other hand, 5-HT4 receptor-expressing nerve fibers decreased on day 7. TRPV1 antagonist and 5-HT3 receptor antagonist attenuated the visceral hyperalgesia to control level in the DSS-induced colitis model. We made the novel observations of increased neuronal/non-neuronal TRPV1 channel and 5-HT3 receptor expression, and decreased 5-HT4 receptor expression in mucosa. Moreover, we show that a correlation existed between the mucosal changes and visceral hypersensitivity in experimental colitis.

In vivo evaluation of inflammatory bowel disease with the aid of μPET and the translocator protein 18 kDa radioligand [18F]DPA-714.

PurposeThe purpose of the study was to validate [18F]DPA-714, a translocator protein (TSPO) 18 kDa radioligand, as a probe to non-invasively quantify the inflammatory state in inflammatory bowel disease (IBD) animal models.ProceduresQuantitative positron emission tomography (PET) imaging of intestinal inflammation was conducted with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) a glucose metabolism surrogate marker and [18F]DPA-714 a ligand of the 18 kDa TSPO, on two IBD models. The first model was induced using dextran sodium sulfate (DSS), creating global inflammation in the colon. The second model was induced by rectally administering trinitrobenzenesulfonic acid (TNBS), creating local and acute inflammation.ResultsThe level of inflammation was analyzed using PET imaging on days 7 and 8. The analysis obtained with [18F]DPA-714, yielded a significant difference between the DSS treated (0.50 ± 0.17%ID/cc) and non-treated rats (0.35 ± 0.15%ID/cc). [18F]FDG on the other hand did not yield a significant difference. We did observe a mean glucose consumption in the colon increase from 0.40 ± 0.11 %ID/cc to 0.54 ± 0.17 %ID/cc. In the TNBS model, the uptake level of [18 F]DPA-714 increased significantly from 0.46 ± 0.23%ID/cc for the non-treated group, to 1.30 ± 0.62%ID/cc for those treated. PET signal was correlated with increased TSPO expression at cellular level.ConclusionsResults indicate that [18F]DPA-714 is suitable for studying inflammation in IBD models. [18F]DPA-714 could be a good molecular probe to non-invasively evaluate the level and localization of inflammation. Moreover, in vivo imaging using this TSPO ligand is potentially a powerful tool to stage and certainly to follow the evolution and therapeutic efficiency at molecular level within this disease family.

The effect of cigarette smoking on the clinical course of inflammatory bowel disease.

IntroductionCigarette smoking is considered an important risk factor for developing Crohn's disease (CD), contributing to a more severe course of the disease. Conversely, smoking is believed to have a beneficial effect on the course of ulcerative colitis (UC), a second major condition of inflammatory bowel disease (IBD).AimTo investigate the effect of tobacco use on the clinical course of IBD.Material and methodsA group of 95 adults with IBD were enrolled to the study. Demographic and clinical data of patients as well as their smoking status were analysed based on their medical history. Values were considered significant when p ≤ 0.05.ResultsCurrent smokers constituted the majority of CD patients. They tended to develop a more severe course of the disease, compared to former smokers and non-smokers. Current smokers suffered a moderate-to-severe form of the disease and required immunosuppressive therapy more frequently. They were also hospitalised and underwent surgeries more frequently than patients from other investigated subgroups. The study failed, however, to fully confirm the beneficial effect of smoking on the clinical outcome of UC. The investigated non-smokers and former smokers suffered a more severe disease, but the analysis did not find any statistical differences in the frequencies of hospitalisations nor immunosuppressant usage among the investigated subgroups.ConclusionsThe study confirmed a detrimental effect of smoking on the outcome of CD, but failed to fully confirm its beneficial effect on UC.

Bile acids differentially impact on platelet activation

Platelets are well-established mediators of inflammatory responses throughout the body. Increased platelet activity occurs in the intestinal mucosa in conditions of Inflammatory Bowel Disease (IBD), where it may contribute to the mucosal fibrosis associated with these diseases. The bile acids, ursodeoxycholic acid (UDCA), deoxycholic acid (DCA) and tauroursodeoxycholic acid (TUDCA) were shown to regulate inflammatory responses in the intestine. The aim of this study is to analyse the impact of these bile acids on platelet activation.