Mesenteric fat wrapping and thickening are typical characteristics of Crohns disease (CD). The purpose of this study was to explore the cause of mesenteric adipose hypertrophy and analyze the role of lymphatic vessels in mesenteric adipose tissue in CD. Twenty-three CD patients who underwent ileocolonic resection were included. In CD patients, specimens were obtained from hypertrophic mesenteric adipose tissue (htMAT) next to the diseased ileum. The mesenteric lymphatic vessels in mesenteric adipose tissue were separated under stereoscope microscope. Transmission electron microscopy and immunofluorescence were used to observe the structure of mesenteric lymphatic vessels. The NF-B signaling pathway in mesenteric adipose tissue was detected in CD specimens using Western blotting. Electron microscopy showed that the structure of mesenteric lymphatic vessel was discontinuous, and the microstructure of lymphatic endothelial cells appeared ruptured and incomplete. Through an immunofluorescence technique, we found that the surface of lymphatic endothelial cells lacked tight junction protein staining in CD. Also, the expression of claudin-1, occludin, and ZO-1 in the mesenteric lymphatic vessel of htMAT was significantly lower than that of control. These results indicated that the structure of the mesenteric lymphatic vessel in htMAT was mispatterned and ruptured, which could lead to lymph leakage. Leaky lymph factors could stimulate adipose tissue to proliferate. Antigens that leaked into the mesenteric adipose tissue could effectively elicit an immune response. The levels of cytokines (TNF-a, IL-1, IL-6) was increased in the htMAT of CD patients by activated NF-B signaling pathway. Our findings demonstrated that the hypertrophy of mesenteric adipose tissue may result from mispatterned and ruptured lymphatic vessels. Alteration of mesenteric adipose tissue was associated with activated NF-B signaling pathway. This study enhances support for elucidating the importance of mesenteric lymphatic vessels and adipose tissue in CD.
Infliximab (IFX) is a breakthrough treatment for refractory Crohns disease (CD) whose effect on postoperative complications of CD remains controversial. The purpose of this study was to conduct a meta-analysis examining the effect of IFX on postoperative complications of CD. We searched PubMed, EMBASE, and Cochrane Library databases from inception of each database until March 2018. All eligible articles were screened according to the inclusion criteria. The cumulative overall, major, minor, infectious, noninfectious, surgical, and medical complications, as well as reoperation, readmission, and mortality of CD patients who received IFX and underwent ileocolonic resection were extracted and analyzed using Review Manager 5.3. The random effects model was used to calculate the odds ratio (OR) and 95% confidence interval (CI). A total of 18 nonrandomized controlled trial studies, with 1407 patients who received IFX and 4589 patients who did not were identified. The incidence of complications was 9.38%60.56% in the IFX group and 12.73%53.85% in the control group. Overall, major, minor, infectious, noninfectious, surgical, and medical complications could be assessed in 16, 12, 11, 14, 12, 12, and 11 studies, respectively. There were no statistically significant differences between the 2 groups for any complication (P > 0.05, all comparisons). Reoperation (P = 0.70), readmission (P = 0.22) and mortality (P = 0.86) showed no significant difference between the 2 groups. Subgroup analysis showed that complications were not significantly different among the countries represented in the studies. Based on this analysis, there does not appear to be an association between preoperative IFX treatment and postoperative complications of CD; IFX appears relatively safe for preoperative use in the treatment of CD.
Adipose tissue is present in close proximity to various organs in the human body. One prominent example is fat contained in the mesentery that is contiguous with all abdominal digestive organs including the intestine. Despite the fact that mesenteric fat-wrapping around the inflamed gut (so called creeping fat) was described as a characteristic feature of Crohn's disease (CD) in the early 1930s, the functional implications of creeping fat have received only recent attention. As a potent producer of fatty acids, cytokines, growth factors, and adipokines, creeping fat plays an important role in regulation of immunity and inflammation. Increasing evidence points to a link between creeping fat and intestinal inflammation in CD, where histopathologic evaluation shows a significant association between creeping fat and connective tissue changes in the bowel wall, such as muscular hypertrophy, fibrosis, and stricture formation. In addition, emerging mechanistic data indicate a link between creeping fat, muscularis propria hyperplasia, and stricturing disease. Information on fat-mesenchymal interactions in other organs could provide clues to fill the fundamental knowledge gap on the role of distinct components of creeping fat in intestinal fibrosis and stricture formation. Future studies will provide important new information that in turn could lead to novel therapeutic agents aimed at prevention or treatment of CD-associated fibrosis and stricture formation.
Background: We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology. Methods: Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data. Results: At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR. Conclusions: Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition-mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients.
Background: An association between inflammatory bowel diseases (IBD) and increased susceptibility to sexual dysfunction (SD) was reported in a number of studies. Method: MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched for all relevant studies reporting the sexual function in IBD patients. Relative risk (RR) with a 95% confidence interval (CI) was used to summarize the association between IBD and risk of SD. Subgroup and sensitivity analyses were applied to detect potential bias. Results: Overall, 351,668 male individuals and 1309 female individuals (the mean age ranged from 33.6 years to 52.4 years) were included from 8 studies (of which 4 studies provided the outcomes of both sexes). Synthesis of results revealed that IBD was significantly associated with an elevated risk of SD in male subjects (7 studies, RR = 1.41, 95% CI, 1.09-1.81, P = 0.008; heterogeneity: I-2 = 80.2%, P < 0.001) and female subjects (5 studies, RR = 1.76, 95% CI, 1.28-2.42, P < 0.001; heterogeneity: I-2 = 69.6%, P = 0.011). Stratified analysis by the mean age of the individuals indicated that patients with IBD with a relatively young age (male: younger than 50 years; female: younger than 40 years) exhibited a significantly increased odds of SD. Sensitivity analyses showed that no single study dominated the overall combined RR. Conclusion: Evidence from this meta-analysis revealed that both male and female patients with IBD have a significantly increased risk of SD, which should remind both gastroenterologists and urologists to be aware of the potential hazardous effect of IBD for developing SD.
Background: The long noncoding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) has been reported to play a vital role in the development of cancer. Although the link between inflammation and cancer initiation is well established, whether CCAT1 is involved in inflammation and promotes inflammatory bowel disease (IBD) malignancy remains undetermined. We aimed to investigate the expression of CCAT1 in IBD and the effect of CCAT1 overexpression on intestinal epithelial barrier function. Methods: The relationship between CCAT1 and the inflammation-related pathway was analyzed in both colorectal cancer (CRC) and IBD patients. Gene expression was detected by real-time polymerase chain reaction and Western blot. Transepithelial electrical resistance (TEER) and FD-4 flux measurement were used to test the effect of CCAT1 and miR-185-3p on intestinal epithelial barrier function. Luciferase assay was performed to validate the target site of miR-185-3p on 3'-UTR of MLCK mRNA. Results: Gene set enrichment analysis revealed that several inflammation-related genes were enriched in the CCAT1 high-expressed group of CRC patients. The relationship between CCAT1 and inflammation activation in IBD patients was further confirmed. CCAT1 expression positively correlated with MLCK, which acts as a protein kinase to phosphorylate myosin light chain and induces tight junction protein distribution, whereas it was negatively correlated with miR-185-3p in IBD tissues. We also determined that CCAT1 overexpression increased Caco-2 monolayer permeability and upregulated MLCK. Furthermore, CCAT1-induced MLCK overexpression and IBD disease progression were significantly attenuated by miR-185-3p. Conclusions: The CCAT1/miR-185-3p/MLCK signaling pathway is strongly activated to destroy barrier function and promotes the pathogenesis of IBD.
Purpose Silibinin possesses the efficacy of anticancer and anti-inflammation. We aimed to test whether silibinin could prevent colitis-associated carcinogenesis in mouse model. Experimental Design Azoxymethane (AOM) and dextran sulfate sodium (DSS) were used to induce colitis-associated tumorigenesis in C57BL mice. Six-to-eight-week-old male mice were gavaged with 350 or 750 mg/kg of silibinin for 10 weeks right after DSS administration. The mice were then sacrificed, and colon tissues were measured for tumor multiplicity and size. Molecular changes about proliferation, apoptosis and inflammation were tested. Results Silibinin feeding showed a dose-dependent inhibition on the size of tumor induced by AOM/DSS in mice. In addition, silibinin inhibited cell proliferation evidenced by a decrease (P < 0.05) in Ki-67 and proliferating cell nuclear antigen (PCNA). However, silibinin did not show any significant effect on inflammation, apoptosis, and the mRNA expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF). The experiments in vitro showed that silibinin induced cell cycle arrest at G2/M phase in CT-26 cells, a mouse colonic cancer cell line. Furthermore, silibinin reduced the expression of Cdc25C and blocked the dephosphorylation of CDK1 at multiple sites both in vitro and in vivo. Conclusions Silibinin targets Cdc25C/CDK1 pathway and mitigates colitis-associated tumorigenesis in mice. Thus, our findings indicate the chemopreventive potential of silibinin for inflammation-associated colon cancer.
Background: Carcinogenesis is a severe consequence of chronic ulcerative colitis. We investigated the somatic mutations and pathway alterations in ulcerative colitis-associated colorectal cancer (CRC) in Chinese patients compared with sporadic CRCs to reveal potential therapeutic targets in ulcerative colitis-associated CRC. Methods: Whole exome sequencing was performed on archival tumor tissues and paired adjacent nondysplastic mucosa from 10 ulcerative colitis-associated CRC patients at a high risk of carcinogenesis. Genomic alteration profiles from 223 primary CRCs from The Cancer Genome Atlas served as sporadic CRC controls. A meta-analysis was performed to investigate differences in major genetic mutations between ulcerative colitis-associated and Crohn's disease-associated CRCs. Results: We identified 44 nonsilent recurrent somatic mutations via whole exome sequencing, including 25 deleterious mutations involved in apoptosis and the PI3K-Akt pathway (COL6A3, FN1), autophagy (ULK1), cell adhesion (PODXL, PTPRT, ZFHX4), and epigenetic regulation (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). In total, 11 of the 25 mutated genes significantly differed between ulcerative colitis-associated CRC and sporadic CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). Somatic TP53 mutations occurred in 33% of ulcerative colitis-associated CRCs. Subsequent meta-analysis revealed distinct mutation profiles for Crohn's disease- and ulcerative colitis-associated CRCs. Mutations involving the NF-kB pathway and epigenetic regulation were more common in ulcerative colitis-associated CRCs than in sporadic CRCs. Conclusion: Distinct genomic alteration profiles of deleterious somatic mutations were found in ulcerative colitis-associated and sporadic CRCs. Mutations of epigenetic regulators, such as KMT2D and NCOA6, were common, suggesting an epigenetic pathomechanism for colitis-associated carcinoma in Chinese patients.