Intestinal epithelial cells are adapted in mucosal hypoxia and hypoxia-inducible factors in these cells can fortify barrier integrity to support mucosal tissue healing. Here we investigated whether ...hypoxia-related pathways could be proposed as potential therapeutic targets for inflammatory bowel disease. We developed a novel hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, CG-598 which stabilized HIF-1α in the gut tissue. Treatment of CG-598 did not affect extra-intestinal organs or cause any significant adverse effects such as erythropoiesis. In the experimental murine colitis model, CG-598 ameliorated intestinal inflammation with reduction of inflammatory lesions and pro-inflammatory cytokines. CG-598 treatment fortified barrier function by increasing the expression of intestinal trefoil factor, CD73, E-cadherin and mucin. Also, IL-10 and IL-22 were induced from lamina propria CD4
T-cells. The effectiveness of CG-598 was comparable to other immunosuppressive therapeutics such as TNF-blockers or JAK inhibitors. These results suggest that CG-598 could be a promising therapeutic candidate to treat inflammatory bowel disease.
Crohn's disease (CD) with recurrent inflammation can cause intestinal fibrostenosis due to dysregulated deposition of extracellular matrix. However, little is known about the pathogenesis of ...fibrostenosis. Here, we performed a differential proteomic analysis between normal, inflamed, and fibrostenotic specimens of patients with CD and investigated the roles of the candidate proteins in myofibroblast activation and fibrosis.
We performed two-dimensional difference gel electrophoresis and identified candidate proteins using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and orbitrap liquid chromatography-mass spectrometry. We also verified the levels of candidate proteins in clinical specimens and examined their effects on 18Co myofibroblasts and Caco-2 intestinal epithelial cells.
We identified five of 30 proteins (HSP72, HSPA5, KRT8, PEPCK-M, and FABP6) differentially expressed in fibrostenotic CD. Among these proteins, the knockdown of heat shock protein 72 (HSP72) promoted the activation and wound healing of myofibroblasts. Moreover, knockdown of HSP72 induced the epithelial-mesenchymal transition of intestinal epithelial cells by reducing E-cadherin and inducing fibronectin and α-smooth muscle actin, which contribute to fibrosis.
HSP72 is an important mediator that regulates myofibroblasts and epithelial-mesenchymal transition in fibrosis of CD, suggesting that HSP72 can serve as a target for antifibrotic therapy.
Gut dysbiosis is one of prominent features in inflammatory bowel diseases (IBDs) which are of an unknown etiology. Although the cause-and-effect relationship between IBD and gut dysbiosis remains to ...be elucidated, one area of research has focused on the management of IBD by modulating and correcting gut dysbiosis. The use of antibiotics, probiotics either with or without prebiotics, and fecal microbiota transplantation from healthy donors are representative methods for modulating the intestinal microbiota ecosystem. The gut microbiota is not a simple assembly of bacteria, fungi, and viruses, but a complex organ-like community system composed of numerous kinds of microorganisms. Thus, studies on specific changes in the gut microbiota depending on which treatment option is applied are very limited. Here, we review previous studies on microbial modulation as a therapeutic option for IBD and its significance in the pathogenesis of IBD.
Background Recent studies suggest that there is a substantial risk of perforation after colorectal stent placement. Objective To identify risk factors for perforation from colonic stenting. Design A ...meta-analysis of 86 studies published between 2005 and 2011. Setting Multicenter review. Patients All patients who underwent colorectal stent placement. Intervention Colorectal stent placement. Main Outcome Measurements The occurrence of perforation with subgroup analyses for stent design, stricture etiology, stricture dilation, and concomitant chemotherapy, including the use of bevacizumab. Results A total of 4086 patients underwent colorectal stent placement; perforation occurred in 207. Meta-analysis revealed an overall perforation rate of 7.4%. Of the 9 most frequently used stent types, the WallFlex, the Comvi, and the Niti-S D-type had a higher perforation rate (>10%). A lower perforation rate (<5%) was found for the Hanarostent and the Niti-S covered stent. Stenting benign strictures was associated with a significantly increased perforation rate of 18.4% compared with 7.5% for malignant strictures. Dilation did not increase the risk of perforation: 8.5% versus 8.5% without dilation. The subgroup of post-stent placement dilation had a significantly increased perforation risk of 20.4%. With a perforation rate of 12.5%, bevacizumab-based therapy was identified as a risk factor for perforation, whereas the risk for chemotherapy without bevacizumab was 7.0% and not increased compared with the group without concomitant therapies during stent therapy (9.0%). Limitations Heterogeneity; a considerable proportion of data is unavailable for subgroup analysis. Conclusions The perforation rate of colonic stenting is 7.4%. Stent design, benign etiology, and bevacizumab were identified as risk factors for perforation. Intraprocedural stricture dilation and concomitant chemotherapy were not associated with an increased risk of perforation.
The gut metabolite composition determined by the microbiota has paramount impact on gastrointestinal physiology. However, the role that bacterial metabolites play in communicating with host cells ...during inflammatory diseases is poorly understood. Here, we aim to identify the microbiota-determined output of the pro-inflammatory metabolite, succinate, and to elucidate the pathways that control transepithelial succinate absorption and subsequent succinate delivery to macrophages. We show a significant increase of succinate uptake into pro-inflammatory macrophages, which is controlled by Na+-dependent succinate transporters in macrophages and epithelial cells. Furthermore, we find that fecal and serum succinate concentrations were markedly augmented in inflammatory bowel diseases (IBDs) and corresponded to changes in succinate-metabolizing gut bacteria. Together, our results describe a succinate production and transport pathway that controls the absorption of succinate generated by distinct gut bacteria and its delivery into macrophages. In IBD, this mechanism fails to protect against the succinate surge, which may result in chronic inflammation.
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•Succinate uptake is elevated in macrophages to perpetuate their pro-inflammatory state•Na+-dependent transporters mediate transepithelial succinate delivery into macrophages•Succinate concentrations are elevated in the serum and feces of IBD patients•Succinate-metabolizing bacteria are altered in IBD patients
Succinate is emerging as a prominent pro-inflammatory metabolite. Fremder et al. show that transporter-mediated succinate uptake into macrophages is elevated to enhance and perpetuate inflammation. In IBD, high succinate metabolized by distinct gut bacteria may cause chronic inflammation. Hence, this pathway is a potential therapeutic target to treat inflammatory diseases.
Increased prevalence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) has been reported. However, the effects of NAFLD on the outcome of IBD remains unclear. We ...investigated whether the presence of NAFLD could influence the outcomes of patients with IBD.
We recruited 3,356 eligible patients with IBD into our study between November 2005 and November 2020. Hepatic steatosis and fibrosis were diagnosed using hepatic steatosis index of ≥30 and fibrosis-4 of ≥1.45, respectively. The primary outcome was clinical relapse, defined based on the following: IBD-related admission, surgery, or first use of corticosteroids, immunomodulators, or biologic agents for IBD.
The prevalence of NAFLD in patients with IBD was 16.7%. Patients with hepatic steatosis and advanced fibrosis were older, had a higher body mass index, and were more likely to have diabetes (all p<0.05).
Hepatic steatosis was independently associated with increased risks of clinical relapse in patients with ulcerative colitis and Crohn's disease, whereas fibrotic burden in the liver was not. Future studies should investigate whether assessment and therapeutic intervention for NAFLD will improve the clinical outcomes of patients with IBD.
In recent years, the global epidemiology of inflammatory bowel disease (IBD) has changed rapidly.
We described the updated global IBD epidemiology results based on the 2019 Global Burden of Diseases, ...Injuries, and Risk Factors Study (GBD).
We estimated the prevalence rate, death rate, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) from GBD 2019 in 195 countries and territories between 1990 and 2019.
The crude prevalence of IBD increased by 47% in 2019 globally. Accordingly, the age-standardized prevalence rate showed 19% decrease. The age-standardized death rates, YLDs, YLLs, and DALYs of IBD in 2019 decreased compared to those in 1990. The annual percentage change in age-standardized prevalence rate decreased most in United States and increased in East Asia and high-income Asia Pacific from 1990 to 2019. Continents with high socioeconomic index (SDI) had higher age-standardized prevalence rates compared to continents with low SDI. The 2019 age-standardized prevalence rate of high latitudes was higher than that of low latitudes in Asia, Europe, and North America.
The observed trends and geographic variations in IBD documented in the 2019 GBD study will aid policymakers in policy, research, and investment development.
Previous studies have investigated the relationship between visceral obesity and the risk of colorectal tumors. Visceral obesity may affect the outcome of colorectal cancer (CRC), including survival ...and metastasis. We investigated the associations between visceral adipose tissue and oncologic outcomes in stage III CRC.
Four hundred seventy-two patients with stage III CRC were identified. Subcutaneous and visceral adipose tissue areas were measured volumetrically via computed tomography for each patient at different levels of the lumbar spine. After adjusting for age, sex, and other clinical factors, the effects of visceral adipose tissue area on mortality and recurrence were assessed using Cox proportional hazard regression.
In univariate and multivariate analyses, a higher visceral adipose tissue to total adipose tissue (VT) ratio (hazard ratio HR, 1.041; 95% CI, 1.008 to 1.075; p=0.015) and higher visceral adipose tissue to subcutaneous adipose tissue (VS) ratio (HR, 1.016; 95% CI, 1.005 to 1.028; p=0.006) were both associated with poor CRC-specific survival. Interestingly, in the evaluation of each site of recurrence, a higher VT ratio (HR, 1.069; 95% CI, 1.010 to 1.131; p=0.020) and higher VS ratio (HR, 1.024; 95% CI, 1.003 to 1.045; p=0.023) were both related to a higher risk of peritoneal seeding and tumor recurrence. The VT ratio at the L3-L4 level was significantly associated with a higher risk of peritoneal seeding and tumor recurrence (HR, 4.969; 95% CI, 1.303 to 18.949; p=0.019), while other levels showed no such relationship.
Visceral obesity is closely related to increased risks of CRC-specific mortality and peritoneal seeding metastasis in stage III CRC patients.
Metformin is a well-known AMPK (AMP-activated protein kinase) activator that suppresses cancer stem cells (CSCs) in some cancers. However, the mechanisms of the CSC-suppressing effects of metformin ...are not yet well understood. In this study, we investigated the CSC-suppressive effect of metformin via the mevalonate (MVA) pathway in colorectal cancer (CRC). Two colorectal cancer cell lines, HT29 and DLD-1 cells, were treated with metformin, mevalonate, or a combination of the two. We measured CSC populations by flow cytometric analysis (CD44+/CD133+) and by tumor spheroid growth. The expression of p-AMPK, mTORC1 (pS6), and key enzymes (HMGCR, FDPS, GGPS1, and SQLE) of the MVA pathway was also analyzed. We investigated the effects of metformin and/or mevalonate in xenograft mice using HT29 cells; immunohistochemical staining for CSC markers and key enzymes of the MVA pathway in tumor xenografts was performed. In both HT29 and DLD-1 cells, the CSC population was significantly decreased following treatment with metformin, AMPK activator (AICAR), HMG-CoA reductase inhibitor (simvastatin), or mTOR inhibitor (rapamycin), and was increased by mevalonate. The CSC-suppressing effect of these drugs was attenuated by mevalonate. The results of tumor spheroid growth matched those of the CSC population experiments. Metformin treatment increased p-AMPK and decreased mTOR (pS6) expression; these effects were reversed by addition of mevalonate. The expression of key MVA pathway enzymes was significantly increased in tumor spheroid culture, and by addition of mevalonate, and decreased upon treatment with metformin, AICAR, or rapamycin. In xenograft experiments, tumor growth and CSC populations were significantly reduced by metformin, and this inhibitory effect of metformin was abrogated by combined treatment with mevalonate. Furthermore, in the MVA pathway, CSC populations were reduced by inhibition of protein prenylation with a farnesyl transferase inhibitor (FTI-277) or a geranylgeranyl transferase inhibitor (GGTI-298), but not by inhibition of cholesterol synthesis with a squalene synthase inhibitor (YM-53601). In conclusion, the CSC-suppressive effect of metformin was associated with AMPK activation and repression of protein prenylation through MVA pathway suppression in colorectal cancer.
Lactobacillus plantarum has been identified as a probiotic bacterium owing to its role in immune regulation and maintenance of intestinal permeability. Here, we investigated the anti-colitic effects ...and mechanism of L. plantarum CBT LP3 (LP3). This in vivo study was performed using dextran sodium sulfate (DSS) to induce colitis in mice. Mice were randomly divided into three groups: a control supplied with normal drinking water, a DSS-treated group followed by oral administration of vehicle, and a DSS-treated group gavaged with LP3 daily for 7 days following DSS administration. An analysis of macrophages and T cell subsets harvesting from peritonium cavity cells and splenocytes was performed using a flow cytometric assay. Gene expression and cytokine profiles were measured using quantitative reverse transcriptase polymerase chain reaction. The administration of LP3 significantly attenuated disease activity and histolopathology compared to control. LP3 had anti-inflammatory effects, with increased induction of regulatory T cells and type 2 helper T cells in splenocytes and restoration of goblet cells accompanied by suppression of proinflammatory cytokine expressions. These findings suggest that L. plantarum CBT LP3 can be used as a potent immunomodulator, which has significant implications for IBD treatment.