Propionate alleviated colitis by modulating iron homeostasis to inhibit ferroptosis and macrophage polarization.

The main aim of the present study was to measure hypoxia-inducible factor-1α (HIF-1α) in serum and colonic mucosa of ulcerative colitis (UC) patients and to analyze its role in the pathogenesis, disease activity and severity of UC. A total of 47 UC patients and 13 UC in remission patients were recruited for the present study. Ten healthy subjects were also included to serve as controls. HIF-1α in the serum was measured using ELISA. The citrate-microwave-SP immunohistochemical method was used to measure the expression of HIF-1α in colonic mucosa. The results showed that, HIF-1α in serum was notably higher in UC patients (73.21±28.65) than UC in remission patients (44.54±14.75) and controls (42.83±15.49). The difference between UC patients and UC in remission patients was significant (P<0.05). A correlation analysis revealed that, the HIF-1α level in serum was positively associated with disease activity, disease severity and endoscopic grade. The expression of HIF-1α in colonic mucosa of UC patients was (58.05±13.83) higher than that in UC in remission patients (3.00±2.72) and controls (3.04±2.69) and this difference was statistically significant (P<0.05). A positive correlation was identified between the expression of HIF-1α in colonic mucosa and the disease activity, severity and endoscopic grade. Thus, the present findings indicated that, HIF-1α is likely to play an important role in the pathogenesis of UC and may serve as a biomarker to evaluate disease activity and severity in UC patients.

Ulcerative Colitis and Crohn's Disease Genetics: More Similar Than We Thought?

Objective To investigate the levels of CD4 + CD25 + regulatory T cells and the Foxp3 in the peripheral blood of patients with ulcerative colitis ( UC), and analyze its role in the pathogenesis of UC. Methods From February 2007 to December 2008, 40 UC patients (23 active and 17 remissive), 33 irritable bowel syndrome (IBS) patients, and 32 normal controls entered our study. CD4 + CD25 + T cells were detected with flow cytometric assay. The expression of Foxp3 mRNA in peripheral blood mononuclear cell (PBMC) was detected by RTPCR. Interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) in the serum from the peripheral blood of UC patients, IBS patients, and normal controls were determined with ELISA. Results There were no significant differences of the peripheral CD4 +T cell numbers among the active, remissive UC and IBS patients, and normal control groups (P=0. 126). The positive rate of CD4+ CD25+ T cells in patients with active and remissive UC were significantly lower than those in IBS patients and normal controls ( both P ＜ 0. 01 ) it was more lower in the active UC patients than the remissive UC patients ( P ＜ 0. 001 ). However, the positive rate of CD4 + CD25 + T cells showed no significant difference between IBS patients and normal control groups ( P = 0. 343 ). The percentage of CD4 + CD25 + T cells was negatively correlated with UC disease activity index ( r = - 0. 660, P ＜ 0. 001 ) and with erythrocyte sedimentation rate (r = -0. 572, P =0. 001 ). The expressions of Foxp3 mRNA in PBMC from active and remissive UC patients were significantly lower than those in both IBS patients and normal controls ( both P ＜0. 001 ). There was no significant difference of the plasma levels of IL-10 or TGF-β among the active/remissive UC patients, IBS patients, and normal controls ( all P ＞ 0. 05 ). Conclusions CD4+ CD25 + regulatory T cells remarkably decline in the active UC and show certain increase in remissive UC, indicating that these cells may be involved in the pathogenesis of UC. The decreased expression of Foxp3 mRNA may be an important factor of the aberrant developmental disorder of CD4 + CD25 + regulatory T cells. Key words: Ulcerative colitis; CD4 + CD25 + T cell; Foxp3

Objective To compare the levels of mRNA expression of triggering receptor expressed in myeloid cells-l (TREM-1) in peripheral blood mononuclear cell ( PBMC) of active ulcerative colitis (UC) patients, remittent UC patients and healthy controls and find out the relationship between TREM-1 and disease activity. Methods The patients with UC were divided into active group and remittent group according to results from colonoscopy and biopsy. The expressions of TREM-1 mRNA in PBMC were detected by real-time quantitative polymerase chain reaction (FQ-RT-PCR) in 70 UC patients (38 active patients, 32 remittent patients) and 20 healthy controls, and the levels of gene expression were analyzed by the relative quantitative ACt values. The correlations between the expressions of TREM-1 mRNA, ESR and CRP were identified by analyzing the relationship between the level of TREM-1 mRNA expression and the quantity of ESR and CRP in active UC patients. Results Expressions of TREM-1 mRNA in active UC patients(4. 19 ± 1. 86) were higher than those of remittent UC patients ( 5. 29 ± 1. 71, P = 0. 007 ) and healthy controls (5. 19 ± 1. 04,P = 0. 032). There was no statistical difference between remittent UC patients and healthy controls(P =0. 892). The area under receiver operating characteristic (ROC) curve (0.763) was above 0.5(P < 0. 001) , showing that TREM-1 mRNA was of value for prediction the disease activity in patients with UC.ΔCt of 4. 63 was the best threshold to determine the disease activity and its diagnostic sensitivity and specificity were 73. 7% and 68.1% , respectively. In active UC patients, expression of TREM-1 mRNA was correlated with ESR( r = 0. 582, P = 0. 03 ) , but there was no correlation with CRP( r =0.447, P = 0. 055). Conclusions Expression of TREM-1 mRNA is significantly elevates in active UC patients, which suggests that TREM-1 might be involved in the pathogenesis of UC. In active UC patients, there is a correlation between expression of TREM-1 mRNA and ESR, but not CRP. Key words: Colitis; ulcerative; Leukocytes; mononuclear; Membrane glycoproteins; Receptors; immunologic; Reverse transcriptase polymerase chain reaction

Metallothionein 2A alleviates ulcerative colitis by inhibiting ferroptosis in intestinal epithelial cells with Tfrc downregulation.

A Common Barrier Defect for Celiac Disease and Ulcerative Colitis

BackgroundUlcerative colitis is a type of inflammatory bowel disease posing a great threat to the public health worldwide. Previously, gene expression studies of mucosal colonic biopsies have provided some insight into the pathophysiological mechanisms in ulcerative colitis; however, the exact pathogenesis is unclear. The purpose of this study is to identify the most related genes and pathways of UC by bioinformatics, so as to reveal the core of the pathogenesis.MethodsGenome-wide gene expression datasets involving ulcerative colitis patients were collected from gene expression omnibus database. To identify most close genes, an integrated analysis of gene expression signature was performed by employing robust rank aggregation method. We used weighted gene co-expression network analysis to explore the functional modules involved in ulcerative colitis pathogenesis. Besides, biological process and pathways analysis of co-expression modules were figured out by gene ontology enrichment analysis using Metascape.ResultsA total of 328 ulcerative colitis patients and 138 healthy controls were from 14 datasets. The 150 most significant differentially expressed genes are likely to include causative genes of disease, and further studies are needed to demonstrate this. Seven main functional modules were identified, which pathway enrichment analysis indicated were associated with many biological processes. Pathways such as ‘extracellular matrix, immune inflammatory response, cell cycle, material metabolism’ are consistent with the core mechanism of ulcerative colitis. However, ‘defense response to virus’ and ‘herpes simplex infection’ suggest that viral infection is one of the aetiological agents. Besides, ‘Signaling by Receptor Tyrosine Kinases’ and ‘pathway in cancer’ provide new clues for the study of the risk and process of ulcerative colitis cancerization.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, the etiology and pathogenesis of which have been suggested to be influenced by cytokines. Two main clinical types of IBD are recognized, namely ulcerative colitis (UC) and Crohn's disease (CD). The present study examined serum levels of two cytokines (IL-17A and IL-23) in 60 IBD patients (30 UC and 30 CD) and 30 healthy controls. The levels were correlated with age, gender, cigarette-smoking status, disease duration, family history, disease extension, symptoms, extra-intestinal manifestations, and medication. The results depicted that IL-17A level was significantly higher in UC and CD patients compared to control (45.2 ± 23.3 and 47.5 ± 34.4 vs. 15.6 ± 7.5 pg/ml, respectively; p &lt; 0.001). Serum level of IL-23 was similarly increased in UC and CD patients compared to control (64.1± 23.7 and 62.5 ± 27.3 vs. 25.2 ± 11.1 pg/ml, respectively). However, the level of both cytokines showed no significant variation between UC and CD patients (p = 0.713 and 0.777, respectively). Distributing UC and CD patients into subgroups according to some characteristics revealed that IL-17A level was significantly increased in UC male compared to female patients (57.3 ± 18.2 vs. 34.5 ± 22.5 pg/ml; p = 0.005). It was also significantly increased in smoker UC patients compared with non-smoker patients (51.9 ± 19.4 vs. 31.6 ± 25.5 pg/ml; p = 0.022). Smoker CD patients also showed a significantly increased level of IL-23 compared to non-smoker patients (72.7 ± 28.5 vs. 52.2 ± 22.6 pg/ml; p = 0.038). In the case of family history, IL-23 level was significantly decreased in UC patients with a family history of IBD compared to CD patients with a family history (84.5 ± 24.3 vs. 50.4 ± 17.0 pg/ml.; p = 0.042). In conclusion, the present data suggest a role for IL-17A and IL-23 in the etiology and pathogenesis of UC and CD.

Background A higher abundance of colonic naive B-cells and IgG plasma cells is implicated in the pathogenesis of ulcerative colitis (UC) during active inflammatory episodes. However, B-cell inhibition by targeting CD20 was found to be ineffective in achieving remission in UC patients indicating that the causal role of the B-cell expansion in UC is not well understood. In this study, we performed single cell RNA-sequencing (scRNA-seq) on mucosal tissue where we interrogated the B-cells in inflamed and non-inflamed UC colon biopsies. We subsequently explored the pathogenic role of B-cells in colitis mouse models. Methods We collected biopsies from the colon of 5 UC patients with active inflammation and 5 UC patients showing no inflamed mucosa. Three mucosal biopsies were collected from the same colon location for each patient and processed for scRNA-seq. We acquired usable transcriptomes of 21.475 cells. In a T-cell transfer colitis mice model, we evaluated the effects of the co-transfer of naive B-cells. Both CD4+ T and naive B-cells were transferred into SCID mice through intraperitoneal injection in ratios of 2:1, 1:1 and 1:2 (T:B ratio). The colitis course was followed for 35 days. Results Differential abundance analysis relative to all immune cells confirmed a higher abundance of naive B-cells (p= 0.03) and IgG plasma B-cells (p= 0.002) in inflamed relative to non-inflamed UC patient tissue, whereas no differences in abundance of transitional B-cells and memory B-cells were found. Pseudo-time analysis indicated a higher rate of maturation in the naive B-cells in inflamed tissue. This was evidenced by higher expression of IGHG1 (p= 0.025) and IGHG3 (p&amp;lt; 0.001) in naive B-cells in inflamed tissue. In a T-cell transfer model, we co-transferred naive B-cells to the CD4+ T-cell pool into SCID mice in various ratios (2:1, 1:1 and 1:2 T to B-cells respectively) and T-cell only control. Significant increase in disease severity was observed in a 1:2 T:B ratio based on body weight loss, increase of colon density, mouse colitis histology index and histological changes by disrupted mucosa. This observation was associated to significant elevated IgG concentration in serum and colon and B-cell presence in colon through immunohistochemistry. Conclusion We observed significantly higher abundance of naive B-cells and IgG plasma cells in inflamed relative to non-inflamed UC colon tissue, where naive B-cells were shown to be more mature and IgG-like in inflamed condition. Notably, transferring increased ratio of naive B-cells resulted in elevated disease severity in a colitis model, demonstrating its pathogenic role. Our findings suggest that specific targeting of the IgG-like naive B-cell may be beneficial for UC patients.

Nutritional and Botanical Approaches for Inflammatory Bowel Disease

Previous research has yielded conflicting data as to whether the natural history of inflammatory bowel disease follows a seasonal pattern. The purpose of this study was (1) to determine whether the frequency of onset and relapse of inflammatory bowel disease follows a seasonal pattern and (2) to establish a model to predict the frequency of onset, relapse, and severity of inflammatory bowel disease (IBD) with meteorological data based on artificial neural network (ANN). Patients with diagnosis of ulcerative colitis (UC) or Crohn's disease (CD) between 2003 and 2011 were investigated according to the occurrence of onset and flares of symptoms. The expected onset or relapse was calculated on a monthly basis over the study period. For artificial neural network (ANN), patients from 2003 to 2010 were assigned as training cohort and patients in 2011 were assigned as validation cohort. Mean square error (MSE) and mean absolute percentage error (MAPE) were used to evaluate the predictive accuracy. We found no seasonal pattern of onset (P = 0.248) and relapse (P = 0.394) among UC patients. But, the onset (P = 0.015) and relapse (P = 0.004) of CD were associated with seasonal pattern, with a peak in July and August. ANN had average accuracy to predict the frequency of onset (MSE = 0.076, MAPE = 37.58%) and severity of IBD (MSE = 0.065, MAPE = 42.15%) but high accuracy in predicting the frequency of relapse of IBD (MSE = 0.009, MAPE = 17.1%). The frequency of onset and relapse in IBD showed seasonality only in CD, with a peak in July and August, but not in UC. ANN may have its value in predicting the frequency of relapse among patients with IBD.

Elevated colonic microbiota-associated paucimannosidic and truncated N-glycans in pediatric ulcerative colitis

This study investigated the correlation between circadian rhythm genes and ulcerative colitis (UC), aiming to identify biomarkers linked to immune microenvironment changes in UC. Gene expression data from UC patients and healthy controls were obtained from the GEO database. Data preprocessing included batch correction and PCA for consistency assessment. Differentially expressed genes (DEGs) were identified using the "limma" package, and functional enrichment analysis was performed. Machine learning methods (LASSO, SVM, RF) refined candidate biomarkers. RNA sequencing in a mouse colitis model and immune infiltration analysis validated key genes. A regulatory network of lncRNA, miRNA, and mRNA for hub genes was constructed. 805 DEGs were identified, including 15 rhythm genes. Four key genes (CPT1A, PRKG2, PPARGC1A, SLC6A4) were screened, with PPARGC1A and SLC6A4 validated as hub genes. These genes were associated with immune cell infiltration and hold potential as biomarkers for UC diagnosis. Disruptions in circadian rhythm are closely associated with the pathogenesis of ulcerative colitis (UC). The biomarkers PPARGC1A and SLC6A4 demonstrated significantly altered expression in UC patients and were correlated with immune cell infiltration. These findings underscore their potential as diagnostic markers, provide new insights into the immune microenvironment and pathogenesis of UC, and suggest potential therapeutic targets for the disease.

To investigate the role of inhibitory natural killer receptors (iNKRs) in inflammatory bowel disease (IBD), we analyzed the expression of NKG2A, one of the iNKRs, on T cells in a mouse colitis model and human IBD. During the active phase of dextran sulfate sodium (DSS)-induced mouse colitis, the frequency of NKG2A+ T cells was significantly decreased in the peripheral blood, and increased in the intestine, suggesting the mobilization of this T cell subset to the sites of inflammation. Administration of anti-NKG2A antibody increased the number of inflammatory foci in DSS-induced colitis, suggesting the involvement of NKG2A+ T cells in this colitis model. In ulcerative colitis (UC) patients, the frequency of peripheral blood NKG2A+ T cells was significantly decreased, compared with Crohn's disease (CD) patients and healthy controls, regardless of clinical conditions such as treatment modalities and disease activity. Notably, in sharp contrast to the DSS-induced mouse colitis model, the frequency of NKG2A+ cells among intestinal T cells was also decreased in UC patients. These results suggest that inadequate local infiltration of NKG2A+ T cells may be involved in the pathogenesis of UC.

Source: Mawdsley JE, Macey MG, Feakinhs RM, et al. The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Gastroenterology. 2006;110:410–419; doi:10.1053/j.gastro.2006.05.017The results of recent studies suggest that life events and chronic stress increase the risk of relapse in inflammatory bowel disease (IBD).1 The authors from Barts and the London, Queen Mary School of Medicine and Dentistry, Barts and London NHS Trust, and University College London conducted a study to examine the effects of experimentally induced acute psychological stress on a variety of measures of systemic and rectal mucosal inflammatory response in adult patients with inactive ulcerative colitis (UC) and in well controls. A total of 25 patients with inactive UC and 11 healthy volunteers (HV) underwent an experimental stressor involving a need to complete a 60-minute IQ test in 50 minutes while rock music played in one ear and folk music in the other. A separate group of 10 patients with UC and 11 HV underwent a control procedure involving the same 50-minute test, but with their choice of relaxing music playing in their ears. Before and after each procedure, systemic inflammatory response was assessed by measurement of serum inflammatory mediators such as serum interleukins and tumor necrosis factor. In all study patients with UC, sigmoidoscopy was performed before and after the study procedures; rectal mucosal inflammation was assessed by measurement of inflammatory mucosal blood flow (RMBF) and histology.Following the stressor, increased pulse (P<.0001) and systolic blood pressure (P<.0001) were noted in the stressed UC patients and healthy volunteers compared to the unstressed UC and HV participants who underwent the control experience. In both UC patients and HV who were stressed, numerous serum inflammatory mediators significantly increased compared to baseline measurements. However, there were no significant differences in changes between stressed UC and HV participants. There were no significant changes in markers of stress among UC patients or HV in the control group. Among stressed UC patients there was a significant change in RMBF; the changes in control UC patients were not significant. The authors suggest that stress may act as a trigger for exacerbations of UC. However, since stress-induced inflammatory markers also increased in HV, it seems unlikely that an exaggerated autonomic and inflammatory response to stress is a primary etiologic factor in UC.Dr. Nassau has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Dr. LeLeiko has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Every day the effect of stress on our young patients is the subject of parental questions. Patients with chronic IBD (or indeed any chronic illness) are no strangers to stress and we always endorse the virtues of trying to lessen what stressors we can and learning to manage those we cannot avoid. The overall paucity of rigorous scientific studies means that we make recommendations based on our experience, which reflects our biases, rather than on data. Although this study was performed in adults, the results are likely applicable to children with IBDs.Results from this study suggest a possible mechanism for how stress might play a role in increased risk of relapse in IBD. There is a growing body of research on the influence of stress on immunity,2 including the influence of stress on the immune system in children and adolescents with chronic medical conditions (eg, asthma).3 The current study adds to this research and reminds us that physicians who care for children with diseases associated with immunological pathophysiology, such as IBD, need to attend to the stress their patients may be experiencing.The authors also raise the interesting point that if stress may enhance the risk of relapse, then perhaps psychological treatments such as stress management training could mitigate these effects. There are data to suggest that psychological interventions can influence immunological parameters.4 The current study underscores the potential utility of psychological intervention in the total care of patients with inflammatory bowel disease.Despite that fact that stressed healthy volunteers or unstressed UC patients and healthy volunteers did not undergo sigmosidoscopy and rectal mucosal study, which would have added to their stress, the notable elevations in serum inflammatory mediators in the UC patients who were stressed are concerning. Designing a study to evaluate the utility of stress reduction in patients with IBD is a daunting challenge. In the absence of such evidence this study gives added weight to the idea that managing stress might reduce the frequency of exacerbations in patients with IBD.