High Perceived Stress is Associated With Increased Risk of Ulcerative Colitis Clinical Flares.

BACKGROUND & AIMS: Although perceived stress (PS) has been associated with symptomatic flares in inflammatory bowel disease, clinical and physiological measures associated with perceived stress and flare are not known. The aim of this study was to identify physiological factors associated with perceived stress in ulcerative colitis (UC) subjects, and their relationship with flare. METHODS: Patients with UC in clinical remission (Simple Colitis Clinical Activity Index [SCCAI] score <5) underwent clinical and behavioral assessments, morning salivary cortisol measurements, autonomic nervous system activity testing (heart rate variability, electrodermal activity) at baseline with patient-reported SCCAI every 2 weeks over 1 to 2 years and fecal calprotectin at time of flare. Clinical flares (SCCAI ≥5) and biochemical flares (SCCAI ≥5 with fecal calprotectin ≥250 µg/g) were evaluated. RESULTS: One hundred ten patients with UC were enrolled, with mean follow-up of 65.6 weeks. Patients with UC with higher and lower PS were determined. Although the high PS group had 3.6 times higher odds of a clinical flare than the low PS group, no significant differences in biochemical flares were observed between the low and high PS groups. The high vs low PS group differed in tonic sympathetic arousal as indexed by significantly greater baseline electrodermal activity (4.3 vs 3.4 microsiemens; P = .026) in the high PS group, but not in terms of heart rate variability and morning cortisol levels. Increased fecal calprotectin was associated with cardioautonomic measures, suggesting lower parasympathetic activity. CONCLUSIONS: Increased PS assessed at baseline is associated with tonic sympathetic arousal and greater odds of clinical flares in patients with UC.

Anorectal Function with High-Resolution Anorectal Manometry in Active Ulcerative Colitis and after Remission: A Pilot Study.

BACKGROUND: Ulcerative colitis may impair anorectal function, causing disabling symptoms such as incontinence and/or increase in the stool frequency, urgency and tenesmus. Data on anorectal function in these patients evaluated by conventional anorectal manometry are conflicting. OBJECTIVES: The aim of this prospective study was to assess by means of high resolution anorectal manometry the anorectal function in patients with mild-to-moderate ulcerative colitis at presentation and after remission. Anorectal function of ulcerative colitis patients was compared to that observed in healthy volunteers. METHODS: 20 patients with mild to moderate left-sided ulcerative colitis or proctitis and 20 healthy volunteers were prospectively enrolled. All ulcerative colitis patients underwent high resolution anorectal manometry before treatment and after clinical remission. RESULTS: Ulcerative colitis patients showed similar values for anal sphincter function as healthy volunteers, whereas rectal threshold volume for the first sensation, desire to defecate, urgency to defecate and maximum discomfort were significantly lower than in healthy volunteers (p<0.05). Rectal compliance was significantly lower in ulcerative colitis than in healthy volunteers (p<0.05). After remission, rectal threshold volumes, as well as rectal compliance, significantly increased. An inverse linear correlation was found between regression of urgency and stool frequency and rectal compliance (r=0.811; p<0.05). CONCLUSION: Ulcerative colitis patients show altered rectal function, with increased rectal sensitivity and lower compliance, compared to controls. This altered function is restored after successful treatment of the underlying inflammatory process. Finally high resolution anorectal manometry provides useful information on anorectal functionality and, in our opinion, should be preferred over conventional manometry.

Body Composition Changes and Related Factors in Patients with Ulcerative Colitis: A Retrospective Single-Center Study in China.

BACKGROUND This study retrospectively explored body composition changes and related factors in patients with ulcerative colitis (UC). MATERIAL AND METHODS Patients with UC and healthy individuals who served as the healthy control at the Affiliated Hospital of Qingdao University September 2017 to August 2018 were retrospectively analyzed. Clinical data and laboratory examination indexes were collected. The skeletal muscle area (SMA) of the third lumbar vertebra cross-section, the subcutaneous fat area (SFA), and the visceral fat area (VFA) at the umbilical level were measured by computed tomography (CT), and the skeletal muscle index (SMI) was calculated to evaluate the loss of muscle mass. RESULTS Data from a total of 80 patients (median age, 49.49 years; 44 [55%] men) with active UC in the UC group and 80 healthy people age- and sex-matched in the healthy control group were collected. The incidence of low SMI and malnutrition was remarkably higher in the UC group than in the healthy control group (P<0.05). Low SMI was observed in 62.5% of UC patients who had a normal body mass index. Based on classification by the Truelove and Witts' criteria, the prevalence of malnutrition in severe UC patients was remarkably higher than that in mild and moderate UC patients (P<0.05). Based on the disease extent, the prevalence of low SMI in E3 type UC was dramatically higher than that in E2 type (P=0.028). CONCLUSIONS Loss of muscle mass was related to disease extent in patients with UC. Loss of muscle mass is more likely to be associated with malnutrition.

Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity.

Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.

Clinical factors to predict flare-up in patients with inflammatory bowel disease during international air travel: A prospective study.

BACKGROUNDS AND AIMS: Inflammatory bowel disease (IBD) patients often experience disease flare-ups during international air travel. We aimed to identify risk factors associated with IBD flare-up during international air travel. METHODS: Patients with scheduled international air travel were enrolled in the study from the Seoul National University Bundang Hospital IBD clinic. Flight information and clinical data were collected via questionnaires and personal interviews, and risk factors associated with IBD flares were determined. RESULTS: Between May 2018 and February 2020, 94 patients were prospectively enrolled in the study (mean age, 33.0 years; males, 53.2%; mean disease duration, 56.7 months), including 56 (59.6%) with ulcerative colitis and 38 (40.4%) with Crohn's disease. Of the 94 patients enrolled, 15 (16.0%) experienced an IBD flare-up and 79 (84.0%) remained in remission throughout travel. Logistic regression analysis revealed that high fecal calprotectin levels before travel (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.000-1.001, p = 0.016), the presence of a comorbidity (OR: 6.334, 95% CI: 1.129-35.526, p = 0.036), and history of emergency room visit (OR: 5.283, 95% CI: 1.085-25.724, p = 0.039) were positively associated with disease flare-up. The previous and current use of immunomodulators and biologics, time of flight, altitude, number countries visited, travel duration, objective of visit, and previous medical consultations were not associated with disease flare-up. CONCLUSIONS: Elevated fecal calprotectin levels, history of emergency room visits, and the presence of a comorbidity predicted IBD flare-up during international air travel.

Assessment of patients' understanding of inflammatory bowel diseases: Development and validation of a questionnaire.

BACKGROUND: Educating patients regarding thier inflammatory bowel disease (IBD) is important for their empowerment and disease management. We aimed to develop a questionnaire to evaluate patient understanding and knowledge of IBD. METHODS: We have developed the Understanding IBD Questionnaires (U-IBDQ), consisting of multiple-choice questions in two versions [for Crohn's disease (CD) and ulcerative colitis (UC)]. The questionnaires were tested for content and face validity, readability, responsiveness and reliability. Convergent validity was assessed by correlating the U-IBDQ score with physician's subjective assessment scores. Discriminant validity was assessed by comparison to healthy controls (HC), patients with chronic gastrointestinal (GI) conditions other than IBD, and to GI nurses. Multivariate analysis was performed to determine factors associated with a high level of disease understanding. RESULTS: The study population consisted of IBD patients (n = 106), HC (n = 35), chronic GI disease patients (n = 38) and GI nurses (n = 19). Mean U-IBDQ score among IBD patients was 56.5 ± 21.9, similar for CD and UC patients (P = 0.941), but significantly higher than that of HC and chronic GI disease patients and lower than that of GI nurses (P < 0.001), supporting its discriminant validity. The U-IBDQ score correlated with physician's subjective score (r = 0.747, P < 0.001) and was found to be reliable (intra-class correlation coefficient = 0.867 P < 0.001). Independent factors associated with high U-IBDQ scores included academic education (OR = 1.21, 95% CI 1.10-1.33, P < 0.001), biologic therapy experience (OR = 1.24, 95% CI 1.01-1.53, P = 0.046), and IBD diagnosis at <21 years of age (OR = 2.97, 95% CI 1.05-8.87, P = 0.050). CONCLUSIONS: The U-IBDQ is a validated, reliable and short, self-reported questionnaire that can be used for assessing understanding of disease pathophysiology and treatment by IBD patients.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Systematic review: disease activity indices for immune checkpoint inhibitor-associated enterocolitis.

BACKGROUND: Although there is interest in developing pharmacotherapies for the treatment of immune checkpoint inhibitor-associated enterocolitis (ICIC), there is currently no consensus on how to optimally measure disease activity in this condition. AIMS: To identify all scoring indices used for the measurement of disease activity in ICIC, assess their operating properties, and explore their potential utility as outcome measures. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library from inception to November 2020 to identify studies that evaluated disease activity and severity in patients with ICI-associated enterocolitis. These scoring tools could be designed specifically for ICIC or adapted from other diseases, and assessed clinical, endoscopic, or histologic disease activity. RESULTS: Sixty-four studies were included. The Common Terminology Criteria for Adverse Events is commonly used to describe symptoms, although has only been partially validated and was not designed as a disease activity index. Endoscopic and histologic indices used in inflammatory bowel disease have been adopted for ICIC including the Mayo Endoscopic Subscore, Ulcerative Colitis Endoscopic Index of Severity, Simple Endoscopic Score for Crohn's Disease, Nancy Histological Index, Robarts Histopathological Index, and Geboes Score, among others. None of these indices has been validated for use in ICIC, and all lacked content validity and responsiveness. CONCLUSIONS: There are no validated clinical, endoscopic, or histologic outcomes to assess disease activity in ICIC. Development and validation of reliable and responsive outcome measures that can be used to measure disease activity will be paramount for both clinical practice and for the development of treatments.

Modulation of Gut Barrier Functions in Ulcerative Colitis by Hyaluronic Acid System.

The active stages of intestinal inflammation and the pathogenesis of ulcerative colitis are associated with superficial mucosal damage and intermittent wounding that leads to epithelial barrier defects and increased permeability. The standard therapeutic interventions for colitis have focused mainly on maintaining the remission levels of the disease. Nonetheless, such treatment strategies (using anti-inflammatory, immunomodulatory agents) do not address colitis' root cause, especially the mucosal damage and dysregulated intestinal barrier functions. Restoration of barrier functionality by mucosal healing or physical barrier protecting strategies shall be considered as an initial event in the disease suppression and progression. Herein, a biphasic hyaluronan (HA) enema suspension, naïve-HA systems that protect the dysregulated gut epithelium by decreasing the inflammation, permeability, and helping in maintaining the epithelial barrier integrity in the dextran sodium sulfate-induced colitis mice model is reported. Furthermore, HA-based system modulates intestinal epithelial junctional proteins and regulatory signaling pathways, resulting in attenuation of inflammation and mucosal protection. The results suggest that HA-based system can be delivered as an enema to act as a barrier protecting system for managing distal colonic inflammatory diseases, including colitis.

Inflammatory Bowel Disease Patients Who Respond to Treatment with Anti-tumor Necrosis Factor Agents Demonstrate Improvement in Pre-treatment Frailty.

BACKGROUND: Frailty may be a risk factor for complications in inflammatory bowel diseases (IBD) patients. We examined the impact of treatment on IBD patients who were frail prior to treatment and identified predictors of post-treatment change in frailty. METHODS: In an electronic health record-based cohort of IBD patients initiating anti-tumor necrosis factor (TNF)-α agents, we applied a validated claims-based frailty index to determine frailty in the 1 year prior to and after treatment initiation. We characterized treatment non-response using a composite outcome of IBD-related hospitalization, surgery, change in therapy, or initiation of systemic steroids. We constructed multivariable logistic regression models to identify determinants of post-treatment frailty. RESULTS: The 1210 patients initiating anti-TNF therapy had a median age of 30 years; 20% were ≥ 50 years. In the first year after anti-TNF initiation, 40% were non-responders. Many more treatment non-responders were frail in the year following treatment compared with treatment responders (27% vs 7%, p < 0.001). Pre-treatment frailty (OR 2.01, 95% CI 1.35-3.00) and prior IBD-related hospitalization (OR 1.63, 95% CI 1.15-2.30) were independently predictive of higher likelihood of post-treatment frailty. Therapy response was associated with a lower likelihood (OR 0.24, 95% CI 0.16-0.34) of post-treatment frailty. Nearly 85% of patients who were frail prior to treatment demonstrated improvement in frailty following treatment CONCLUSIONS: Response to anti-TNF therapy is an important determinant of post-treatment frailty in patients with IBD. Our findings suggest that effectively treating inflammatory states in older patients with IBD may improve frailty.

A Simple Emergency Department-Based Score Predicts Complex Hospitalization in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Thirty percent of inflammatory bowel disease (IBD) patients hospitalized with flare require salvage therapy or surgery. Additionally, 40% experience length of stay (LOS) > 7 days. No emergency department (ED)-based indices exist to predict these adverse outcomes at admission for IBD flare. We examined whether clinical, laboratory, and endoscopic markers at presentation predicted prolonged LOS, inpatient colectomy, or salvage therapy in IBD patients admitted with flare. METHODS: Patients with ulcerative colitis (UC) or colonic involvement of Crohn's disease (CD) hospitalized with flare and tested for Clostridioides difficile infection (CDI) between 2010 and 2020 at two urban academic centers were studied. The primary outcome was complex hospitalization, defined as: LOS > 7 days, inpatient colectomy, or inpatient infliximab or cyclosporine. A nested k-fold cross-validation identified predictive factors of complex hospitalization. RESULTS: Of 164 IBD admissions, 34% (56) were complex. Predictive factors included: tachycardia in ED triage (odds ratio [OR] 3.35; confidence interval [CI] 1.79-4.91), hypotension in ED triage (3.45; 1.79-5.11), hypoalbuminemia at presentation (2.54; 1.15-3.93), CDI (2.62; 1.02-4.22), and endoscopic colitis (4.75; 1.75-5.15). An ED presentation score utilizing tachycardia and hypoalbuminemia predicted complex hospitalization (area under curve 0.744; CI 0.671-0.816). Forty-four of 48 (91.7%) patients with a presentation score of 0 (heart rate < 99 and albumin ≥ 3.4 g/dL) had noncomplex hospitalization. CONCLUSIONS: Over 90% of IBD patients hospitalized with flare with an ED presentation score of 0 did not require salvage therapy, inpatient colectomy, or experience prolonged LOS. A simple ED-based score may provide prognosis at a juncture of uncertainty in patient care.

Safety evaluation of ustekinumab for moderate-to-severe ulcerative colitis.

INTRODUCTION: Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rß1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED: We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION: Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.

HLA-DQA1*05 Associates with Extensive Ulcerative Colitis at Diagnosis: An Observational Study in Children.

The human leukocyte antigen (HLA) allele group HLA-DQA1*05 predisposes to ulcerative colitis (UC) and is associated with the development of antibodies against infliximab in patients with inflammatory bowel disease (IBD). Therefore, we hypothesized that the presence of HLA-DQA1*05 correlates with characteristics of pediatric IBD. Within a multi-center cohort in Poland, the phenotype at diagnosis and worst flare was established and HLA-DQA1*05 status was assessed enabling genotype-phenotype analyses. HLA-DQA1*05 was present in 221 (55.1%) out of 401 children with IBD (UC n = 188, Crohn's disease n = 213). In UC, the presence of HLA-DQA1*05 was moderately associated with a large extent of colonic inflammation at diagnosis (E4 55% more frequent in HLA-DQA1*05-positive patients, p = 0.012). PUCAI at diagnosis (p = 0.078) and the time from UC diagnosis to the first administration of biologic treatment (p = 0.054) did not differ depending on HLA-DQA1*05 status. The number of days of hospitalization for exacerbation was analyzed in 98 patients for whom sufficient follow-up was available and did not differ depending on HLA-DQA1*05 carriership (p = 0.066). HLA-DQA1*05 carriers with CD were less likely to present with both stenosing and penetrating disease (B2B3, p = 0.048) and to have active disease proximal to the ligament of Treitz (L4a) at the worst flare (p = 0.046). Future research focusing on explaining and preventing anti-TNF immunogenicity should take into account that ADA may develop not only as an isolated reaction to anti-TNF exposure but also as a consequence of intrinsic differences in the early course of UC.

Association Between Peripheral Blood Monocyte Count and Mucosal Healing in Japanese Patients With Ulcerative Colitis.

INTRODUCTION: Monocytes play an important role in innate immunity. Some epidemiological evidence indicates an association between peripheral blood monocytes and ulcerative colitis (UC). The association between peripheral blood monocytes and mucosal healing (MH), however, remains unclear. We evaluated this issue in patients with UC. METHODS: Study subjects consisted of 272 Japanese patients with UC. Monocyte counts were taken in the morning after overnight fasting. Monocyte count was divided into tertiles based on the distribution of values among all study subjects. Information on clinical remission was obtained from medical records. MH was assessed using the Mayo endoscopic subscore. RESULTS: The mean monocyte count was 360.1 ± 155.3/mm3. Rates of clinical remission, MH, and complete MH were 61.0%, 66.2%, and 27.9%, respectively. High monocyte count was significantly inversely associated with clinical remission, MH, and complete MH (adjusted odds ratio [OR] 0.45 [95% confidence interval [CI]: 0.23-0.89], OR 0.45 [95% CI: 0.23-0.89], and OR 0.48 [95% CI: 0.23-0.97], respectively). Patients were also classified according to C-reactive protein (CRP) levels; in the low CRP group (<0.1 mg/dL), high monocyte count was independently inversely associated with complete MH but not with clinical remission or MH (OR 0.33 [95% CI: 0.10-0.92], P for trend = 0.027). In the high CRP group, there was no association between monocyte count and clinical outcomes. DISCUSSION: Our findings suggest that peripheral blood monocyte count can be used as a serum supplemental marker for MH in UC patients with low CRP levels.

Investigation of the Active Ingredients and Mechanism of Hudi Enteric-Coated Capsules in DSS-Induced Ulcerative Colitis Mice Based on Network Pharmacology and Experimental Verification.

BACKGROUND: Hudi enteric-coated capsule (HDC) is a Chinese medicine prescribed to treat ulcerative colitis (UC). However, its anti-inflammatory active ingredients and mechanisms remain unknown. This study aimed to investigate the active components of HDC and explore its potential mechanisms against UC by integrating network pharmacology and experimental verification. METHODS: A DSS-induced colitis murine model was established to validate the efficacy of HDC by detecting disease activity index (DAI) and histopathological changes. Network pharmacological analysis was performed to identify the active compounds and core targets of HDC for the treatment of UC. The main compounds in HDC were identified by high-performance liquid chromatography. The relative expressions of HDC's core targets were also determined in vivo. Finally, molecular docking was applied to model the interaction between HDC and target proteins. RESULTS: In an in vivo experiment, HDC, especially the middle-dose HDC, effectively reduced clinical symptoms of UC, including weight loss, bloody stool, and colon shortening. Besides, the severity of colitis was considerably suppressed by HDC as evidenced by reduced DAI scores. A total of 118 active compounds and 69 candidate targets from HDC closely related to UC progression were identified via network pharmacology. Enrichment analysis revealed that the key targets of HDC correlated with the expressions of PTGS2, TNF-α, IL-6, and IL-1ß. Meanwhile, these cytokines were enriched in various biological processes through the IL-17/JAK2/STAT3 signaling pathway. The middle-dose HDC contributed more to ameliorating DSS-induced colitis through this signaling pathway than other dosages. Nine components binding to JAK2, STAT3, IL-17 and IL-6 were identified by molecular docking, confirming again the inhibition effects of HDC on the IL-17/JAK2/STAT3 signaling pathway. CONCLUSION: The HDC treatment, particularly the middle-dose, exerted an anti-UC effect in a multi-component, multi-target, and multi-mechanism manner, especially inhibiting the IL-17/JAK2/STAT3 signaling pathway to downregulate the secretion of proinflammatory cytokines.

The association of the quality of sleep with proinflammatory cytokine profile in inflammatory bowel disease patients.

BACKGROUND: The role of circadian rhythm abnormalities in patients with inflammatory bowel disease (IBD) remains relatively unknown. The aim of this study was to identify the inflammatory cytokine profile in the IBD patients and its relationship with the quality of sleep. METHODS: Prospective, single-center observational cohort study was performed. In all enrolled adult IBD patients, the disease activity was assessed using Crohn's Disease Activity Index (CDAI) for Crohn's disease (CD) and Partial Mayo Score for ulcerative colitis (UC), respectively. To assess the quality of sleep, all patients were asked to respond to a questionnaire to define Pittsburgh Quality Sleep Index (PSQI). From all enrolled patients, 15 ml venous blood was taken to determine serum inflammatory cytokine levels and perform standard laboratory tests. RESULTS: Fifty-two IBD patients were enrolled in the study: 32 with CD and 20 with UC. The poor sleep was noted in 69.4% of patients with clinically active and in 6.3% of patients with inactive disease. In the group of IBD patients with poor sleep, the significantly higher level of serum IL-6, IL-17, and IL-23 were observed. In IBD patients with exacerbation, the significantly higher level of serum IL-6, IL-17, and IL-23 were recorded. CONCLUSIONS: The relationship between quality of sleep and proinflammatory cytokine profile may show us a predisposition for the development of inflammatory intestinal lesions in IBD patients with sleep disturbances. This knowledge may allow the pharmacological and behavioral therapies of circadian rhythm abnormalities to become new significant targets in IBD patients.

Orally Deliverable Dual-Targeted Pellets for the Synergistic Treatment of Ulcerative Colitis.

PURPOSE: The effective treatment of ulcerative colitis (UC) poses substantial challenges, and the aetiopathogenesis of UC is closely related to infectious, immunological and environmental factors. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. METHODS: Berberine (BBR) and Atractylodes macrocephala Koidz (AM) volatile oil, derived from the Chinese herbs Coptis chinensis Franch and Atractylodes macrocephala Koidz, have anti-inflammatory and immunomodulatory activities. In this study, we prepared colon-targeted pellets loaded with BBR and stomach-targeted pellets loaded with AM volatile oil for the synergistic treatment of UC. The Box-Behnken design and ß-cyclodextrin inclusion technique were used to optimize the enteric coating formula and prepare volatile oil inclusion compounds. RESULTS: The two types of pellets were spherical and had satisfactory physical properties. The pharmacokinetic results showed that the AUC and MRT values of the dual-targeted (DPs) pellets were higher than those of the control pellets. In addition, in vivo animal imaging confirmed that the DPs could effectively deliver BBR to the colon. Moreover, compared with sulfasalazine and monotherapy, DPs exerted a more significant anti-inflammatory effect by inhibiting the expression of inflammatory factors including IL-1ß, IL-4, IL-6, TNF-α and MPO both in serum and tissues and enhancing immunity by decreasing the production of IgA and IgG. CONCLUSION: The DPs play a synergistic anti-UC effect by exerting systemic and local anti-inflammatory and provide an effective oral targeted preparation for the treatment of UC.

Identification of a choroid plexus vascular barrier closing during intestinal inflammation.

Up to 40% of patients with inflammatory bowel disease present with psychosocial disturbances. We previously identified a gut vascular barrier that controls the dissemination of bacteria from the intestine to the liver. Here, we describe a vascular barrier in the brain choroid plexus (PVB) that is modulated in response to intestinal inflammation through bacteria-derived lipopolysaccharide. The inflammatory response induces PVB closure after gut vascular barrier opening by the up-regulation of the wingless-type, catenin-beta 1 (Wnt/ß-catenin) signaling pathway, rendering it inaccessible to large molecules. In a model of genetically driven closure of choroid plexus endothelial cells, we observed a deficit in short-term memory and anxiety-like behavior, suggesting that PVB closure may correlate with mental deficits. Inflammatory bowel disease­related mental symptoms may thus be the consequence of a deregulated gut­brain vascular axis.