Background and Aim
Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to ...colitis‐associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti‐inflammatory and anti‐cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC.
Methods
Colitis‐associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor‐α (TNF‐α). Expression of interleukin (IL)‐8 was determined by real‐time reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA‐binding activity of NF‐κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real‐time reverse transcription‐polymerase chain reaction of bcl‐xL, MCL1, c‐FLIP‐L, and VEGF were performed.
Results
Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho‐IκB kinase in the colon. In HCT 116 cells stimulated with TNF‐α, TUDCA significantly inhibited IL‐8 and IL‐1α expression and suppressed TNF‐α‐induced IκBα phosphorylation/degradation and DNA‐binding activity of NF‐κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl‐xL, MCL1, c‐FLIP‐L, and VEGF.
Conclusion
These results demonstrated that TUDCA suppresses NF‐κB signaling and ameliorates colitis‐associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.
Background and Aim
The aim of this study is to evaluate the effect of metformin on intestinal inflammation.
Methods
COLO205 cells were pretreated with metformin and stimulated with tumor necrosis ...factor (TNF)‐α. Expression of interleukin (IL)‐8 was determined by luciferase assay and real‐time PCR. Inhibitor of kappaB (IκB) phosphorylation/degradation and adenosine monohosphate‐activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA‐binding activity of transcription factor nuclear factor‐kappaB (NF‐κB) was assessed by electrophoretic mobility shift assay. In an acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL‐10−/− mice were used to evaluate the effect of metformin on chronic colitis. In an inflamation‐associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.
Results
Metformin significantly inhibited IL‐8 induction in COLO 205 cells stimulated with TNF‐α. Metformin attenuated IκBα phosphorylation and NF‐κB DNA‐binding activity. Administration of metformin significantly reduced the severity of DSS‐induced colitis. In addition, DSS‐induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL‐10−/− mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice.
Conclusions
These results indicate that metformin suppresses NF‐κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis‐associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.
Background
Helicobacter pylori causes chronic gastritis, gastroduodenal ulcers, and gastric cancer, and has been treated with two antibiotics (amoxicillin and clarithromycin) and proton‐pump ...inhibitors (PPIs). However, antibiotic treatment alters the indigenous gut microbiota to cause side effects. Therefore, the effects of probiotic supplementation on therapy have been studied. Although several studies have covered the probiotics’ effects, details about the gut microbiota changes after H. pylori eradication have not been evaluated. Therefore, we analyzed the influences of antibiotics and their combination with probiotics on the composition of the gut microbiota using high‐throughput sequencing.
Methods
Subjects were divided into two groups. The antibiotics group was treated with general therapy, and the probiotics group with general therapy and probiotic supplementation. Fecal samples were collected from all subjects during treatments, and the influences on gut microbiota were analyzed by 16S rRNA gene‐pyrosequencing.
Results
Three phyla, Firmicutes, Bacteroidetes, and Proteobacteria, were predominant in the gut microbiota of all subjects. After treatment, the relative abundances of Firmicutes were reduced, whereas those of Proteobacteria were increased in both groups. However, the changed proportions of the gut microbiota in the antibiotics group were higher than those in the probiotics group. In addition, the increase in the levels of antibiotic‐resistant bacteria was higher in the antibiotics group than in the probiotics one.
Conclusion
Probiotic supplementation can reduce the antibiotic‐induced alteration and imbalance of the gut microbiota composition. This effect may restrict the growth of antibiotic‐resistant bacteria in the gut and improve the H. pylori eradication success rate.
Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates ...innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4
) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-β was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.
Inflammatory bowel disease (IBD) presents with various extraintestinal manifestations. As part of them, various skin diseases are suggested to be related to IBD. We aimed to identify the epidemiology ...and risk of developing skin manifestations in patients with IBD. We used Korean insurance claims data and selected patients with IBD and age/sex‐matched non‐IBD subjects between 2013 and 2017 using the diagnosis code and prescription records of IBD‐specific medications. The prevalence and risk of concurrent skin diseases were estimated. We identified 64 837 patients with IBD. Reactive skin eruptions including pyoderma gangrenosum and erythema nodosum were associated with IBD with highest odds ratios among three categories of reactive, inflammatory, and autoimmune skin diseases. Inflammatory skin diseases including rosacea, psoriasis, atopic dermatitis, hidradenitis suppurativa, and acne conglobata were significantly associated with IBD, but the association was less marked compared to reactive skin eruptions. The patients with IBD also had a higher risk of autoimmune skin diseases including vitiligo and alopecia areata than non‐IBD subjects. We determined that IBD was related to various skin diseases including reactive, inflammatory, and autoimmune skin diseases. Considering these relationships can allow better management of patients with IBD and comorbid skin diseases.
Background
Gastrostomy tube insertion is beneficial to selected patients, and percutaneous endoscopic gastrostomy (PEG) and percutaneous radiological gastrostomy (PRG) are two of the frequently used ...methods in gastrostomy. This study aimed to investigate the indications and complications of both PEG and PRG.
Methods
This was a retrospective multicenter cohort study. Patients who underwent initial PEG or PRG tube insertion for nutritional purpose between January 2010 and December 2015 at five university hospitals were included in the study. We analyzed the indications and all complications related to gastrostomy, which were divided into the major (systemic or life-threatening) and minor (local and non-life-threatening) categories.
Results
A total of 418 patients who underwent PEG (
n
= 324) and PRG (
n
= 94) were reviewed. The indications for gastrostomy tube insertion were different and included mainly neurological disease (
n
= 240, 74.1%) such as cerebrovascular accident in the PEG group (
n
= 119, 36.7%) and mainly surgical disease (
n
= 28, 29.8%) such as head and neck cancer (
n
= 16, 17.0%) in the PRG group (
p
= 0.05). There were no differences in the minor (16.4% vs. 19.1%,
p
= 0.52) and major (12.3% vs. 14.9%,
p
= 0.51) complication rates between the PEG and PRG groups. The risk factors for complications were age yearly increments; odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01–1.06, tube diameter (1-Fr increments; OR 1.26, 95% CI 1.01–1.58), insertion time (1-min increments; OR 1.07, 95% CI 1.01–1.13), and neurological disease as the gastrostomy indication (vs. surgical disease; OR 4.61 95% CI 1.47–14.42).
Conclusions
In our study, both PEG and PRG provided a safe route for nutrition delivery despite their different indications. Our data suggest that PEG might be the procedure of choice for patients with medical or neurological disease and PRG for patients with surgical disease in whom PEG is technically difficult or contraindicated.
Unregulated activation of nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of Crohn's disease. In this study, we investigated the clinical characteristics and disease outcome of ...Crohn's disease patients with varying levels of the NF-κB activation.
Crohn's disease patients who underwent surgical bowel resection were divided into two groups, based on the activation status of NF-κB. NF-κB activation was assessed by the immunoreactivity of nuclear NF-κB during immunohistochemical staining of bowel resection specimens. We compared the demographic, clinical and histologic characteristics between groups. Furthermore, the occurrence of reoperation, readmission, and medication change due to disease flare-up were investigated according to NF-κB activation status.
Among 83 Crohn's disease patients, 47 (56%) showed high NF-κB activity and 36 (44%) showed low NF-κB activity. Patients with high NF-κB activity had higher frequency of ileocolonic involvement (P = 0.028) and lower frequency of perianal involvement (P = 0.042) relative to those with low NF-κB activity. Total histologic scores were significantly higher in patients with high NF-κB activity than those with low NF-κB activity (P = 0.044). There was no significant difference in the frequency of reoperation, readmission, and medication change in relation to NF-κB activation status.
Crohn's disease patients with high NF-κB activation showed specific clinical manifestations of higher frequency of ileocolonic involvement and lower frequency of perianal involvement relative to those with low NF-κB activation. High NF-κB activity was associated with higher histologic scores. However, the NF-κB activity did not affect the outcome and disease course after surgery.
•Radiologic complete remission (CR) outperformed endoscopic CR in predicting long-term clinical outcomes in Crohn’s disease.•Mean fecal calprotectin level was significantly lower in the radiologic CR ...group than in the non-CR group.•Radiologic CR represents a better therapeutic endpoint in Crohn’s disease, showing superiority over endoscopic CR in predicting both clinical and biochemical outcomes.
To determine the clinical implications of radiologic complete remission (CR) in Crohn’s disease (CD) evaluated by computed tomography (CT) or magnetic resonance enterography (MRE) in comparison with endoscopic CR.
Twenty-five CD patients who achieved endoscopic CR after medical treatment were retrospectively enrolled in this study. All patients underwent ileocolonoscopy, CT, or MRE at baseline, at the time of endoscopic CR, and during follow-up. Two radiologists assessed the mural and perienteric abnormalities on pre- and post-treatment CT or MRE in consensus. Patients were divided into radiologic CR and non-CR groups at the time of endoscopic CR. CD recurrence during subsequent follow-up periods was evaluated using clinical, laboratory, and CT/MRI findings. Statistical analysis was performed to assess whether there were significant differences in patient outcomes between the groups.
At the time of endoscopic CR, nine patients (mean age, 36.6 years) showed normalization of all radiologic features and were designated as the radiologic CR group. However, 16 patients (mean age: 32.9 years) showed residual CT/MRE abnormalities, suggesting persistent active inflammation, and were designated as the radiologic non-CR group. During follow-up, there was a significant difference between the groups regarding clinical outcomes (deep CR, 8/9 vs 5/16, P = 0.011; CD recurrence, 1/9 vs 14/16, P < 0.001). The mean fecal calprotectin level was significantly lower in the radiologic CR group (287.5 ug/g) than in the non-CR group (652.4 ug/g) (P = 0.023).
Radiologic CR can represent a better therapeutic endpoint in CD, showing superiority over endoscopic CR in predicting both clinical and biochemical outcomes.
Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a lifelong disease that manifests with chronic intestinal inflammation, sequential fibrosis, and an increased ...risk of colitis-associated colon cancer (CAC). The combined effects of genetic, immunological, environmental, and microbial factors render it difficult to determine the specific mechanism underlying the induction and perpetuation of IBD. Various animal models of IBD have contributed enormously to the understanding of IBD pathogenesis in terms of genomics, transcriptomics, proteomics, microbiome, and drug development of novel therapeutics. Although comprehensive research on IBD has been enabled by advanced technologies, such as genetically engineered models, there is a great need to develop relevant in vivo models of colitis and fibrosis. Here, we review 4 categories of animal models of acute and chronic intestinal inflammation, fibrosis, and CAC: chemically induced, genetically engineered, T cell transfer, and spontaneous gene mutation models.
PDF
