Wall Thickness Ratio-A New Magnetic Resonance Parameter-Is Associated With the Outcome of Biological Therapy in Patients With Ileal and Ileocolonic Crohn's Disease.

GOALS: The present study was aimed at identifying a new magnetic resonance enterography (MRE) parameter assessing the clinical outcome of biological therapy in patients with active ileal/ileocolonic Crohn's disease (CD). BACKGROUND: Transmural healing (TH) has been associated with improved outcomes in CD. However, some patients with clinical remission and inactive disease at endoscopy do not achieve TH. MATERIALS AND METHODS: Ileal/ileocolonic CD patients scheduled for biological therapy were prospectively evaluated, at baseline (T0) and after 1 year of treatment (T1), with Harvey Bradshaw Index score, blood tests, ileocolonscopy, and MRE. Clinical activity was assessed after 2 years of treatment (T2). Wall thickness ratio (WTR) was calculated in the same affected ileal segment, as the ratio between the ileum wall thickness value at T1 and the ileum wall thickness value at T0. RESULTS: A total of 103 patients were included. Mean WTR at T1 in nonresponders was significantly higher than in responders. At receiver operating characteristic analysis, WTR values were significantly associated to biological therapy responsiveness. A WTR cutoff value of 0.77 mm was identified to discriminate responders from nonresponders (sensitivity: 79%; specificity: 67%). In responders, the proportion of patients with a WTR<0.77 was significantly higher than the proportion of patients achieving TH at T1. Among patients achieving endoscopic remission, 11/29 (37.9%) presented TH, while 20/29 (68.9%) presented WTR<0.77 ( P : 0.035). At multivariate logistic regression analysis, WTR<0.77 was significantly associated to biological therapy response. CONCLUSION: WTR index represents an easy-to-calculate MRE parameter and seems to be a promising tool for monitoring therapeutic response in CD patients during biological therapy.

Arjunolic acid protects the intestinal epithelial barrier, ameliorating Crohn's disease-like colitis by restoring gut microbiota composition and inactivating TLR4 signalling.

BACKGROUND AND AIMS: Crohn's disease (CD) is characterized by an overabundance of epithelial cell death and an imbalance in microflora, both of which contribute to the dysfunction of the intestinal barrier. Arjunolic acid (AA) has anti-apoptotic effects and regulates microbiota efficacy. The objective of this study was to assess the impact of the treatment on colitis resembling Crohn's disease, along with exploring the potential underlying mechanism. METHODS: CD animal models were created using Il-10-/- mice, and the impact of AA on colitis in mice was evaluated through disease activity index, weight fluctuations, pathological examination, and assessment of intestinal barrier function. To clarify the direct role of AA on intestinal epithelial cell apoptosis, organoids were induced by LPS, and TUNEL staining was performed. To investigate the potential mechanisms of AA in protecting the intestinal barrier, various methods including bioinformatics analysis and FMT experiments were employed. RESULTS: The treatment for AA enhanced the condition of colitis and the function of the intestinal barrier in Il-10-/- mice. This was demonstrated by the amelioration of weight loss, reduction in tissue inflammation score, and improvement in intestinal permeability. Moreover, AA suppressed the apoptosis of intestinal epithelial cells in Il-10-/- mice and LPS-induced colon organoids, while also reducing the levels of Bax and C-caspase-3. In terms of mechanism, AA suppressed the activation of TLR4 signaling in Il-10-/- mice and colon organoids induced by LPS. In addition, AA increased the abundance of short-chain fatty acid-producing bacteria in the stool of Il-10-/- mice, and transplantation of feces from AA-treated mice improved CD-like colitis. CONCLUSIONS: The results of our study demonstrate that AA has a protective effect on the intestinal barrier in Crohn's disease-like colitis by preventing apoptosis. Additionally, this groundbreaking study reveals the capacity of AA to hinder TLR4 signaling and alter the makeup of the intestinal microbiome. The findings present fresh possibilities for treating individuals diagnosed with Crohn's disease. AA offers a hopeful novel strategy for managing Crohn's disease by obstructing crucial pathways implicated in intestinal inflammation and enhancing the gut microbiota.

Higher Intra-Abdominal Visceral Adipose Tissue Mass Is Associated With Lower Rates of Clinical and Endoscopic Remission in Patients With Inflammatory Bowel Diseases Initiating Biologic Therapy: Results of the Constellation Study.

BACKGROUND & AIMS: We sought to assess the association between intra-abdominal visceral adipose tissue (IA-VAT) and response to 3 different biologic drugs in patients with inflammatory bowel disease (IBD) and to investigate its effects on inflammatory cytokine expression, pharmacokinetics, and intestinal microbiota. METHODS: We prospectively enrolled subjects with active IBD initiating infliximab, vedolizumab, or ustekinumab and a healthy control group. Baseline body composition (including IA-VAT as percent of total body mass [IA-VAT%]) was measured using GE iDXA scan. Primary outcome was corticosteroid- free deep remission at weeks 14-16, defined as Harvey Bradshaw Index <5 for Crohn's disease and partial Mayo score <2 for ulcerative colitis, with a normal C-reactive protein and fecal calprotectin. Secondary outcomes were corticosteroid-free deep remission and endoscopic remission (Endoscopic Mayo Score ≤1 in ulcerative colitis or Simple Endoscopic Score for Crohn's disease ≤2) at weeks 30-46. RESULTS: A total of 141 patients with IBD and 51 healthy controls were included. No differences in body composition parameters were seen between the IBD and healthy control cohorts. Patients with higher IA-VAT% were less likely to achieve corticosteroid-free deep remission (P < .001) or endoscopic remission (P = .02) vs those with lower IA-VAT%. Furthermore, nonresponders with high IA-VAT% had significantly higher serum interleukin-6 and tumor necrosis factor at baseline compared with responders and patients with low IA-VAT%. Drug pharmacokinetic properties and microbiota diversity were similar when comparing high and low IA-VAT% groups. CONCLUSIONS: Higher IA-VAT% was independently associated with worse outcomes. This association could be driven at least partially by discrete differences in inflammatory cytokine expression.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor.

OBJECTIVE: This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR). METHODS: Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway. RESULTS: Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon. CONCLUSION: Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Amino acids-targeted metabolomics reveals novel diagnostic biomarkers for ulcerative colitis and Crohn's disease.

Inflammatory bowel disease (IBD), which mainly comprises ulcerative colitis (UC) and Crohn's disease (CD), is a common chronic intestinal inflammatory disease that affects the ileum, rectum, and colon. Currently, the diagnosis of IBD is based on clinical history, physical examination and complementary diagnostic tests. It is challenging for physicians to make a definitive diagnosis. This study aimed to analyze the variation in amino acid metabolites in IBD serum and to identify potential predictive biomarkers of IBD diagnosis and progression. Serum samples were collected from 158 UC patients, 130 CD patients and 138 healthy controls (HCs). The 37 amino acids in serum were determined by ultra-high-pressure liquid chromatography coupled to a mass spectrometer. A panel of three-amino-acid metabolites (taurine, homocitrulline and kynurenine) was identified as a specific biomarker panel of IBD. Receiver operating characteristic analysis (ROC) showed that the panel had a sensitivity of 88.4% with a specificity of 84.6% for discriminating CD patients from UC patients. The biomarkers identified are increased in CD compared to UC. Our approach demonstrated a strong relationship between serum amino acid levels and IBD. We successfully identified serum amino acid biomarkers associated with CD and UC. The biomarker panel has potential in clinical practice for IBD diagnosis and will provide new insights into IBD pathogenesis.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

MRI-Based Characterization of Intestinal Motility in Children and Young Adults With Newly Diagnosed Ileal Crohn Disease Treated by Biologic Therapy: A Controlled Prospective Study.

BACKGROUND. Changes in intestinal motility in patients with newly diagnosed Crohn disease have historically been evaluated primarily in a subjective manner. OBJECTIVE. The purpose of this study was to assess longitudinal changes in objective intestinal motility scores in children and young adults with newly diagnosed ileal Crohn disease treated with biologic (anti-tumor necrosis factor-α) medical therapy compared with those in control participants. METHODS. This prospective study included 20 children and young adults (eight female and 12 male patients; mean age, 14.6 ± 2.1 [SD] years) with newly diagnosed ileal Crohn disease who were recruited between December 2018 and October 2021 as well as 15 control participants without any known gastrointestinal conditions (eight female and seven male patients; mean age, 18.1 ± 4.4 years). All participants underwent research MRI examinations of the small bowel, including dynamic cine 2D SSFP sequences. Patients with Crohn disease underwent additional research MRI examinations performed at both 6 weeks and 6 months after initiation of biologic therapy. Two operators independently derived terminal ileal intestinal motility scores from the dynamic cine sequences by use of FDA-approved software (with higher scores indicating greater intestinal motility). Intestinal motility scores were compared between patient and control groups by use of t tests, whereas changes in intestinal motility scores after treatment were assessed using linear mixed models. Interoperator absolute agreement was assessed using the intra-class correlation coefficient (ICC). RESULTS. Mean terminal ileal intestinal motility scores were not significantly different between patients with newly diagnosed ileal Crohn disease and control participants (for operator 1, 180.9 ± 63.3 vs 229.7 ± 115.2, respectively [p = .12]; for operator 2, 175.0 ± 62.2 vs 236.4 ± 117.4, respectively [p = .05]). Mean intestinal motility scores changed over time compared with baseline in response to biologic therapy, for operator 1 (180.9 ± 63.3 at baseline, 248.1 ± 104.9 at 6 weeks after treatment initiation, and 249.1 ± 73.2 at 6 months after treatment initiation [p = .04]) and operator 2 (175.0 ± 62.2 at baseline, 247.8 ± 112.7 at 6 weeks after treatment initiation, and 239.6 ± 72.7 at 6 months after treatment initiation [p = .03]). Absolute agreement in intestinal motility scores was excellent between operators (ICC = 0.89). CONCLUSION. MRI measurements of intestinal motility are dynamic in children and adults with newly diagnosed small-bowel Crohn disease, showing early increases in response to biologic therapy. CLINICAL IMPACT. MRI-based intestinal motility scores may aid individualized assessment of disease activity and treatment response in patients with small-bowel Crohn disease.

Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy.

Comparison of Magnetic Resonance Enterography Global Score (MEGS) with indices of Crohn's disease activity in South Asian population.

PURPOSE: Assessment of disease activity in Crohn's helps predict important clinical outcomes. Among the various modalities available to assess disease activity, magnetic resonance enterography (MRE) is considered a safe and reliable imaging option. Various MRE-based scoring systems have been developed to measure disease activity, one of which being the MRE global score (MEGS). We aimed to correlate MEGS with some of the important indices of Crohn's disease activity. METHODOLOGY: Crohn's disease patients referred for MRE were included in the study. Along with demographic profile and relevant investigations, MRE parameters related to MEGS were also assessed. RESULT: A total of 47 patients were recruited for the study. Their median age was 34 years (range 18-68 years), and male:female ratio was 16:31. There was modest positive correlation between MEGS and faecal calprotectin (r = 0.3, p = 0.04), CRP level (r = 0.34, p = 0.02) and Harvey Bradshaw index (r = 0.3, p = 0.043), respectively. However, there was strong correlation between segmental MEGS and Simple Endoscopic Score in those with terminal ileal disease (r = 0.81, p < 0.001). Mural thickness was the only MRE parameter that correlated with active disease (OR - 1.35, 95% CI 1.01, 1.81, p = 0.041) on multivariate analysis. There was moderate inter-observer agreement (Lin's r = 0.78, p < 0.001). CONCLUSION: MEGS showed modest correlation with indices of Crohn's disease activity which corroborates the complementary role of MRE in management of such patients.

Adiponectin Alleviates Intestinal Fibrosis by Enhancing AMP-Activated Protein Kinase Phosphorylation.

BACKGROUND: Intestinal fibrosis is a common complication of Crohn's disease (CD). Adiponectin reportedly exerts anti-inflammatory effects in various disease models, including colitis models. AIMS: In this study, we aimed to determine the effects of adiponectin on intestinal fibrosis and the underlying mechanisms. METHODS: A murine model of intestinal fibrosis was established by administering increasing doses of 2,4,6-trinitrobenzene sulfonic acid to Balb/c mice via enema for 7 weeks. Primary human fibroblasts were isolated from the colon tissues of patients with CD. The fibroblasts were incubated with transforming growth factor (TGF)-ß1 to establish a fibrosis model in vitro. Pathway inhibitors were used to verify the potential signaling pathways involved in the anti-fibrogenic effect of adiponectin. RESULTS: Compared with the normal mesentery, adiponectin expression was significantly increased in the hypertrophic mesentery of patients with CD. Intraperitoneal injection of adiponectin significantly decreased the activity of myeloperoxidase and the expression of pro-inflammatory cytokines (tumor necrosis factor α and interleukin 6) in the colon of fibrosis model mice, whereas the expression of the anti-inflammatory cytokine interleukin 10 was substantially increased. Moreover, adiponectin treatment inhibited colon shortening, decreased colon weight, and reduced fibrotic protein deposition in the model mice. Adiponectin reduced the phosphorylation of Smad2 and collagen deposition induced by TGF-ß1 in primary human intestinal fibroblasts, with an increase in AMP-activated protein kinase (AMPK) phosphorylation. Furthermore, this phenomenon was reversed by the AMPK inhibitor. CONCLUSIONS: Adiponectin can protect against intestinal fibrosis by enhancing the phosphorylation of AMPK and inhibiting the activity of the TGF-ß1/Smad signaling pathway.

Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn's Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells.

Crohn's disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1ß and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn's disease.

Sarcopenia and Vitamin D Deficiency in Patients with Crohn's Disease: Pathological Conditions That Should Be Linked Together.

Sarcopenia is a prevalent condition in patients with Crohn's disease (CD), representing an independent predictor factor for the development of major postoperative complications. Thus, a proper assessment of the muscle strength, by using different validated tools, should be deemed an important step of the clinical management of these patients. Patients with CD are frequently malnourished, presenting a high prevalence of different macro- and micro-nutrient deficiencies, including that of vitamin D. The available published studies indicate that vitamin D is involved in the regulation of proliferation, differentiation, and regeneration of muscle cells. The relationship between vitamin D deficiency and sarcopenia has been extensively studied in other populations, with interesting evidence in regards to a potential role of vitamin D supplementation as a means to prevent and treat sarcopenia. The aim of this review was to find studies that linked together these pathological conditions.

Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways-Crohn's Disease Model Study.

BACKGROUND: Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract with alternating periods of exacerbation and remission. The aim of this study was to determine the time-dependent effects of dietary oat beta-glucans on colon apoptosis and autophagy in the CD rat model. METHODS: A total of 150 Sprague-Dawley rats were divided into two main groups: healthy control (H) and a TNBS (2,4,6-trinitrobenzosulfonic acid)-induced colitis (C) group, both including subgroups fed with feed without beta-glucans (ßG-) or feed supplemented with low- (ßGl) or high-molar-mass oat beta-glucans (ßGh) for 3, 7, or 21 days. The expression of autophagy (LC3B) and apoptosis (Caspase-3) markers, as well as Toll-like (TLRs) and Dectin-1 receptors, in the colon epithelial cells, was determined using immunohistochemistry and Western blot. RESULTS: The results showed that in rats with colitis, after 3 days of induction of inflammation, the expression of Caspase-3 and LC3B in intestinal epithelial cells did not change, while that of TLR 4 and Dectin-1 decreased. Beta-glucan supplementation caused an increase in the expression of TLR 5 and Dectin-1 with no changes in the expression of Caspase-3 and LC3B. After 7 days, a high expression of Caspase-3 was observed in the colitis-induced animals without any changes in the expression of LC3B and TLRs, and simultaneously, a decrease in Dectin-1 expression was observed. The consumption of feed with ßGl or ßGh resulted in a decrease in Caspase-3 expression and an increase in TLR 5 expression in the CßGl group, with no change in the expression of LC3B and TLR 4. After 21 days, the expression of Caspase-3 and TLRs was not changed by colitis, while that of LC3B and Dectin-1 was decreased. Feed supplementation with ßGh resulted in an increase in the expression of both Caspase-3 and LC3B, while the consumption of feed with ßGh and ßGl increased Dectin-1 expression. However, regardless of the type of nutritional intervention, the expression of TLRs did not change after 21 days. CONCLUSIONS: Dietary intake of ßGl and ßGh significantly reduced colitis by time-dependent modification of autophagy and apoptosis, with ßGI exhibiting a stronger effect on apoptosis and ßGh on autophagy. The mechanism of this action may be based on the activation of TLRs and Dectin-1 receptor and depends on the period of exacerbation or remission of CD.

Artemisinin ameliorates intestinal inflammation by skewing macrophages to the M2 phenotype and inhibiting epithelial-mesenchymal transition.

BACKGROUND: Inflammatory bowel disease (IBD) is a self-destructive intestinal disease whose etiology is unclear but complex and the effective treatment is deficient. Increasing evidences have indicated that immune dysfunction and epithelial-mesenchymal transition (EMT)-related intestinal mucosal barrier impaired hold critical position in the pathogenesis of IBD. Artemisinin (ART) is a sesquiterpenoid compound extracted from Chinese herbal medicine which has good immunomodulatory effects. Studies have shown that artemisinin and its analogues have therapeutic effects on a variety of tumors and immune-related disorders. The purpose of current study was to research the effect and mechanism about artemisinin-induced macrophage polarization to M2 phenotype and inhibiting the process of EMT. METHODS: In vitro, the anti-inflammatory effect of artemisinin is mainly verified by RAW264.7 cells and tissue (colon tissue and PBMC) from CD patients with active intestinal inflammation. RAW264.7 cells stimulated with LPS to induce inflammatory state and ART were used as therapeutic treatment in different concentration. Then the expression levels of pro-inflammatory factors, macrophage polarization and ERK pathway were analyzed. Colon tissue and PBMC from CD patients were treated with ART in different concentrations and macrophage polarization, pro-inflammatory factors expression, EMT-related protein were analyzed. In vivo, DSS-induced colitis mice were treated by ART for seven days. The DAI score was calculated and the colons and spleens were harvested after the animals were sacrificed. The expression of macrophage markers and EMT-related markers in the intestines of mice in each group were monitored by qPCR and western blot. RESULT: ART treatment could decrease the levels of pro-inflammatory coefficient expressed in theRAW264.7 cells and human PBMC. Moreover, ART could ameliorate the intestinal inflammation in vivo through down-regulating the expression of pro-inflammatory factors, promoting macrophage polarization to M2 phenotype and inhibiting the process of EMT. CONCLUSION: Taken together, our findings demonstrated that artemisinin might ameliorate inflammation by inducing macrophage polarization to M2 phenotype and inhibiting the process of EMT, suggesting that ART may be applied to the rehabilitation of IBD in the future.

Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review.

Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn's disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.

Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study.

Several studies have examined environmental factors and inflammatory bowel diseases (IBD) using traditional approaches; however, provided results are still conflicting. Our aim was to determine whether lifestyle and nutrient exposures, related to IBD in observational meta-analyses, influence IBD risk using a Mendelian randomization (MR) approach. A two-sample MR approach was applied on summary-level genome-wide association results. Genetic variants strongly associated with measures of tobacco smoking, obesity and fat distribution, physical activity, and blood levels of vitamins and fatty acids were evaluated on genetic data from international IBD consortia including a total of 25,042 IBD cases (12,194 cases of Crohn's disease (CD) and 12,366 cases of ulcerative colitis (UC)) and 34,915 controls. Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02), but it was not associated with UC risk (OR 0.99, P = 0.88). Body-mass index (BMI) and body fat percentage were positively associated with CD (OR 1.11, P = 0.02, per standard deviation (SD) of 4.6 kg/m2; and OR 1.50, P = 3 × 10-10, per SD of 6.6%; respectively); while for UC, BMI was inversely associated (OR 0.85, P = 5 × 10-5; per SD) and body fat percentage showed a OR of 1.11 (P = 0.11; per SD). Additionally, among nutrient exposures, omega-3 fatty acids levels were inversely associated with CD (OR 0.67, P = 2 × 10-6). Our MR results did not support a protective effect for being a smoker on UC risk; however, they are compatible with a risk effect for higher body fat proportion and a protective role for higher levels of omega-3 fatty acids on CD etiology.

MR enterocolonography in patients with Crohn's disease and healthy volunteers - Do we achieve diagnostic bowel distension?

PURPOSE: The aim of our prospective randomized study was to assess diagnostic quality and stability of bowel distension in patients with Crohn's disease (CD) and healthy volunteers subjected to synchronous magnetic resonance enterography and colonography (MREC), as well as to test the role of water enema and intravenous spasmolytics. The influence of gastric content, age, gender, and body mass on bowel distension was also evaluated. METHOD: Study groups included 164 CD patients and 53 healthy volunteers. After bowel preparation, randomized subgroups started ingestion ≥1000 mL of hyperosmolar solution within 30, 45, 60, 75, and 90 min before admission to MRI, respectively. Patients were examined in prone position and water enema was applied. Spasmolytics were administered prior to I.V. gadolinium. Distension of five bowel segments was independently assessed by two experienced radiologists. RESULTS: MREC yields diagnostic distension of the jejunum in 81.1 % and 79.2 % patients in the CD group and controls, respectively. For the terminal ileum it was >94 % in both groups. Good and excellent distension was achieved in other bowel segments. Distension was maintained up to 75 min from the start of oral ingestion. Water enema and spasmolytics significantly and independently improved distension of the small bowel. Distension of the cecum after spasmolytics was decreased. Gastric content, age, gender and body mass had no significant influence of bowel distension. CONCLUSIONS: MREC enables diagnostic distension of the colon and ileum (including terminal segment) in CD patients and healthy volunteers and diagnostically acceptable distension of the jejunum.

Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs.

BACKGROUND: Intestinal fibrosis is a hallmark of Crohn's disease. Here, we investigated the impact of several putative antifibrotic compounds on the expression of fibrosis markers using murine precision-cut intestinal slices. METHODS: Murine precision-cut intestinal slices were cultured for 48 hours in the presence of profibrotic and/or antifibrotic compounds. The fibrotic process was studied on gene and protein level using procollagen 1a1 (Col1α1), heat shock protein 47 (Hsp47), fibronectin (Fn2), and plasminogen activator inhibitor-1 (Pai-1). The effects of potential antifibrotic drugs mainly inhibiting the transforming growth factor ß (TGF-ß) pathway (eg, valproic acid, tetrandrine, pirfenidone, SB203580, and LY2109761) and compounds mainly acting on the platelet-derived growth factor (PDGF) pathway (eg, imatinib, sorafenib, and sunitinib) were assessed in the model at nontoxic concentrations. RESULTS: Murine precision-cut intestinal slices remained viable for 48 hours, and an increased expression of fibrosis markers was observed during culture, including Hsp47, Fn2, and Pai-1. Furthermore, TGF-ß1 stimulated fibrogenesis, whereas PDGF did not have an effect. Regarding the tested antifibrotics, pirfenidone, LY2109761, and sunitinib had the most pronounced impact on the expression of fibrosis markers, both in the absence and presence of profibrotic factors, as illustrated by reduced levels of Col1α1, Hsp47, Fn2, and Pai-1 after treatment. Moreover, sunitinib significantly reduced Hsp47 and Fn2 protein expression and the excretion of procollagen 1. CONCLUSIONS: Precision-cut intestinal slices can successfully be used as a potential preclinical screening tool for antifibrotic drugs. We demonstrated that sunitinib reduced the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis.

Early Surgery Versus Biologic Therapy in Limited Nonstricturing Ileocecal Crohn's Disease-A Decision-making Analysis.

BACKGROUND: Surgery is the preferred option for patients with symptomatic localized fibrostenotic ileocecal Crohn's disease (CD) but not for those with predominantly active inflammation without obstruction. The benefit of early surgery in patients with a limited nonstricturing ileocecal CD over biologic treatment is still a debate. OBJECTIVE: Our objective is to formulate a decision analysis model based on recently published data to explore whether early surgery in patients with limited nonstricturing CD is preferred over biologic treatment. METHODS: We constructed a Markov model comparing 2 strategies of treatment: (1) early surgery vs (2) biologic treatment. To estimate the quality-adjusted life years (QALYs) and the costs in each strategy, we simulated 10,000 virtual patients with the Markov model using a Monte Carlo simulation 100 times. Sensitivity analyses were performed to evaluate the robustness of the model and address uncertainties in the estimation of model parameters. RESULTS: The costs were $29,457 ± $407 and $50,382 ± $525 (mean ± SD) for early surgery strategy and biologic treatment strategy, respectively. The QALY was 6.24 ± 0.01 and 5.81 ± 0.01 for early surgery strategy and biologic treatment strategy, respectively. CONCLUSION: The strategy of early surgery dominates (higher QALY value [efficacy] and less cost) compared with the strategy of biologic treatment in patients with limited ileocecal CD.