Pathogenesis Of Ulcerative Colitis Research Articles

Increased circulating PD-1hiCXCR5- peripheral helper T cells are associated with disease severity of active ulcerative colitis patients

PurposeA recently identified population of T cells, phenotypically CD4+PD-1hiCXCR5−, has been firstly termed as peripheral helper T cells (Tph) and found to be pathogenic in autoimmune diseases. However, the potential role of Tph in ulcerative colitis (UC) remains unclear. We aim to investigate the changes of circulating Tph in UC patients and their potential significance in the pathogenesis of UC. MethodsTotally 68 UC patients and 34 age- and sex-matched healthy controls were enrolled. Circulating Tph and B cell subsets were analyzed by flow cytometry. Expressions of inducible T-cell co-stimulator (ICOS) on Tph cells were analyzed. Serum IL-4, IL-10, IL-12 and IL-21 were detected using ELISA. Correlation analyses were conducted between Tph cells and disease severity, functional B cell subsets and serum cytokines. ResultsBoth the frequency and absolute number of Tph were significantly increased in active UC patients and ICOS levels in Tph cells were also elevated, compared with remission UC patients and healthy controls. Tph and ICOS expression were significantly positively correlated with Mayo score and serum CRP in active UC patients, and were significantly decreased when achieving remission after treatment. Tph levels were correlated with new memory B cells, plasmablasts, serum IL-4 and IL-21. Meanwhile, serum IL-10 showed negative correlation while IL-12 exhibited positive correlation with circulating Tph cells in UC patients. ConclusionsCirculating Tph cells are elevated in active UC patients and are associated with the disease activity, which may contribute to the pathogenesis of UC.

Study of microbiome changes in patients with ulcerative colitis in the Central European part of Russia

Ulcerative colitis (UC) is an inflammatory disease that affects the colon and rectum. Recently, evidence has emerged about the influence of microbiota on the development of this disease. However, studies on the role of intestinal microbiota in the pathogenesis of UC have been incomplete. In addition, there are no comprehensive studies of the causes of ulcerative colitis and data on the microbiological composition of the intestines of patients with ulcerative colitis in Russia. We carried out a study of the microbiological composition of the intestines of patients with ulcerative colitis and healthy individuals. We found significant changes in the bacteria genera and species in patients with UC compared with the control group using sequencing on the IonTorrent PGM system and subsequent data analysis. In our study we observed a significant increase of the genus Haemophilus, Olsenella, Prevotella, Cedecea, Peptostreptococcus, Faecalibacterium, Lachnospira, Negativibacillus, Butyrivibrio, and the species Bacteroides coprocola, Phascolarctobacterium succinatutens, Dialister succinatiphilus, Sutterella wadsworthensis, Faecalibacterium prausnitzii in patients with ulcerative colitis. In addition, in patients with ulcerative colitis there was a significant decrease in the genus Fusicatenibacter, Butyricimonas, Lactococcus, Eisenbergiella, Coprobacter, Cutibacterium, Falsochrobactrum, Brevundimonas, Yersinia, Leuconostoc and in the species Fusicatenibacter saccharivorans. We found confirmation of our data with literary sources and studies of UC. In addition, we discovered a few taxa such as Negativibacillus spp. and Falsochrobactrum spp. that have not been previously found in human stool samples. Our data confirm that more research is needed to understand the role of microbiome changes in the development of UC in different people populations.

Gegen Qinlian decoction relieved DSS-induced ulcerative colitis in mice by modulating Th17/Treg cell homeostasis via suppressing IL-6/JAK2/STAT3 signaling

BackgroundGegen Qinlian decoction (GQ) is a traditional Chinese herbal prescription that has been widely used for the treatment of bacterial dysentery and enteric typhoid fever. Recently, GQ has been clinically reported to be a potential candidate for the treatment of ulcerative colitis (UC). However, the immunoregulatory function of GQ in the treatment of UC has not been fully elucidated. PurposeThis study focused on the role of immune imbalance in the pathogenesis of UC and the immunomodulatory effect of GQ in the treatment of UC. MethodsThe UC model was established by treating female mice with 3.0% dextran sulfate sodium (DSS) for 7 days, and GQ was orally administered at dosages of 1.5 and 7.5 g/kg/day. Inflammatory factors were detected by ELISA and qRT-PCR. Treg and Th17 cell dysregulation was analyzed by qRT-PCR, immunohistochemistry and flow cytometry. Proteins related to IL-6/JAK2/STAT3 signaling were detected by western blotting. ResultsGQ significantly alleviated the symptoms of UC mice and suppressed the activity of myeloperoxidase (MPO). Furthermore, the production of proinflammatory factors, such as IL-1β, TNF-α and IL-6, was dramatically reduced after GQ administration. Furthermore, GQ improved the infiltration of Treg and Th17 cells into the colons and decreased the expression of inflammatory factors, such as TGF-β1 and IL-17. The frequencies of Treg and Th17 cells in the Peyer's patches and spleen were reduced by GQ administration; however, GQ had no significant regulatory effect on normal mice. The western blotting results showed that GQ markedly suppressed the phosphorylation of JAK2 and STAT3 and decreased the transcription function of phosphorylated STAT3. ConclusionsTaken together, these results indicated that GQ alleviated DSS-induced UC by suppressing IL-6/JAK2/STAT3 signaling to restore Treg and Th17 cell homeostasis in colonic tissue.

M1 Macrophage exosomes MiR-21a-5p aggravates inflammatory bowel disease through decreasing E-cadherin and subsequent ILC2 activation.

Abnormal immune regulation is a key feature of the complex pathogenic mechanism of ulcerative colitis (UC). In particular, macrophages and group 2 innate lymphoid cells (ILC2s) are important components of natural immunity that have been shown to play important roles in the pathogenesis of UC, as well as decreased E‐cadherin expression on the colonic mucosa. However, it remains unclear how these components interact with each other. In this study, we investigated the molecular mechanisms of UC mediated by macrophage‐derived exosomes. We showed for the first time that miR‐21a‐5p expression is increased in the peritoneal exosomes of mice with dextran sulphate sodium induced enteritis and that miR‐21a‐5p expression correlates negatively with E‐cadherin expression in enterocytes. Moreover, we confirmed that miR‐21a‐5p was mainly derived from M1 macrophages and demonstrated that KLRG1, a surface inhibitory receptor on ILC2s, participated in excessive ILC2 activation in UC by promoting GATA‐3. In conclusion, our results suggest molecular targets and provide a theoretical basis for elucidating the pathogenesis of UC and improving its treatment.

ADENOSINE A3 RECEPTOR INTERACTS WITH GASDERMIN D TO MODULATE INTESTINAL EPITHELIAL CELL PYROPTOSIS IN ULCERATIVE COLITIS

Adenosine A3 receptor (A3AR) plays a role in intestinal inflammation, but little is known about its mechnisms in intestinal inflammation such as ulcerative colitis (UC). Pyroptosis, characterized by Gasdermin D (GSDMD) activation, is implicated in the pathogenesis of UC. We investigated the role of A3AR in GSDMD-mediated pyroptosis in UC and its underlying molecular mechanisms.

Cross Talk between Gut Microbiota and Intestinal Mucosal Immunity in the Development of Ulcerative Colitis.

Ulcerative colitis (UC), a nonspecific inflammatory disease, is characterized by inflammation and mucosal damage in the colon, and its prevalence in the world is increasing. Nevertheless, the exact pathogenesis of UC is still unclear. Accumulating data have suggested that its pathogenesis is multifactorial, involving genetic predisposition, environmental factors, microbial dysbiosis, and dysregulated immune responses. Generally, UC is aroused by inappropriate immune activation based on the interaction of host and intestinal microbiota. The relationship between microbiota and host immune system in the pathogenesis of UC is complicated. However, increasing evidence indicates that the shift of microbiota composition can substantially influence intestinal immunity. In this review, we primarily focus on the delicate balance between microbiota and gut mucosal immunity during UC progression.

MiR-330 alleviates dextran sodium sulfate-induced ulcerative colitis through targeting IRAK1 in rats.

Ulcerative colitis (UC) is a chronic multifactorial inflammatory bowel disease that severely impairs patients' life quality. microRNAs (miRNAs) have been reported to exhibit potential therapeutic effects in the management of UC. With the aim to investigate the regulatory effects of miR-330 on UC-related colon tissue damage and inflammation, a rat model of experimental colitis was established by oral administration of dextran sodium sulfate (DSS). DSS-treated rats showed mucosal damage, colonic inflammation, and elevated myeloperoxidase activity compared with the healthy controls. Dual-luciferase reporter assay confirmed the binding of interleukin-1 receptor-associated kinase 1 (IRAK1) and miR-330. Subsequently, rats were intracolonically injected with miR-330 argomir with/without administration of IRAK1 during DSS treatment. The miR-330 overexpression reduced DSS-induced colonic injury and the production of proinflammatory cytokines. The level of IRAK1 was negatively regulated by the expression of miR-330. IRAK1 overexpression abolished the protective effect of miR-330 on DSS-induced colonic inflammation and mucosal injury in rats. In conclusion, we clarify the role of miR-330 in pathogenesis of UC, suggesting miR-330 alleviated DSS-induced colitis by downregulating IRAK1, shedding lights on miR-330 as a therapeutic candidate for UC treatment.

Metformin alleviates inflammation in oxazolone induced ulcerative colitis in rats: plausible role of sphingosine kinase 1/sphingosine 1 phosphate signaling pathway

Objectives Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with high sphingosine kinase 1(SPHK1) expression in the colon, however its role in pathogenesis of UC is not clearly understood so, the aim of the present study was to clarify the role of SPHK1 and investigate whether the anti-inflammatory effects of metformin in UC is mediated by Sphingosine kinase 1/sphingosine 1 phosphate (S1P) signaling pathway. Material and methods Colitis was induced in adult male wistar rats by intra rectal administration of oxazolone in the fifth and seventh days from initial presensitization. Oxazolone treated rats were divided into untreated oxazolone group, metformin and mesalazine treated groups both in a dose of 100 mg/kg/day orally for 21 days. Along with these groups normal control and saline groups were used .Colitis was assessed by colon length, disease activity index (DAI) and histological examination of colontissue. Plasma samples were used to measure S1P.SPHK1 activity, signal transducer and activator of transcription −3(STAT-3), interleukin-6 (IL-6), nitric oxide (NO), myeloperoxidase activity (MPO), reduced glutathione (GSH) and tissue expression of intracellular cell adhesion molecule −1(ICAM-1) and caspase-3 genes were measured in tissue. Results Metformin successfully attenuated oxazolone colitis by increasing colon length, decreasing DAI and improved colon histologic picture. Metformin also induced a significant decrease in Plasma SIP, SPHK1 activity, inflammatory, oxidative stress markers, ICAM-1 and Caspase-3 genes expression compared to oxazolone group. Conclusion It is revealed that metformin alleviated inflammation and underlying mechanism may result from inhibition of SPHK1/S1P signaling pathway.

Dysbiosis of gut microbiota in Polish patients with ulcerative colitis: a pilot study

Ulcerative colitis (UC) is a chronic immune-mediated disorder, whose etiology is not fully understood and for which no effective treatment is available. Recently, research has focused on the dysbiosis of gut microbiome in UC. However, the results so far remain inconsistent and insufficient to understand the microbial component in UC pathogenesis. In this study, we determine specific changes in the gut microbial profile in Polish UC patients compared to healthy subjects for the first time. Using 16S rRNA gene-based analysis we have described the intestinal microbial community in a group of 20 individuals (10 UC patients and 10 controls). Our results after multiple hypothesis testing correction demonstrated substantially lower gut microbiome diversity in UC cases compared to the controls and considerable differences at the phylum level, as well as among 13 bacterial families and 20 bacterial genera (p < 0.05). UC samples were more abundant in Proteobacteria (8.42%), Actinobacteria (6.89%) and Candidate Division TM7 (2.88%) than those of healthy volunteers (2.57%, 2.29% and 0.012%, respectively). On the other hand, Bacteroidetes and Verrucomicrobia were presented at a lower level in UC relative to the controls (14% and 0% vs 27.97% and 4.47%, respectively). In conclusion, our results show a reduced gut microbial diversity in Polish UC patients, a reduction of taxa with an anti-inflammatory impact and an increased abundance of potentially pathogenic bacteria.

ADENOSINE A3 RECEPTOR INTERACTS WITH GASDERMIN D TO MODULATE INTESTINAL EPITHELIAL CELL PYROPTOSIS IN ULCERATIVE COLITIS

Abstract Background Adenosine A3 receptor (A3AR) plays a role in intestinal inflammation, but little is known about its mechnisms in intestinal inflammation such as ulcerative colitis (UC). Pyroptosis, characterized by Gasdermin D (GSDMD) activation, is implicated in the pathogenesis of UC. We investigated the role of A3AR in GSDMD-mediated pyroptosis in UC and its underlying molecular mechanisms. Methods The expression of A3AR in colonic mucosa of patients with UC were examined. A3AR agonist was used to study the role of A3AR in ex vivo colonic explants of UC patients. In addition, human intestinal epithelial cells Caco-2 were used to further verify the effect of A3AR on pyroptosis induced by LPS+ATP. RT-qPCR and western blotting were used to detect the expression levels of pyroptosis-associated factors including NLRP3, caspase-1, gasdermin-D N-terminal domain (GSDMD-NT), IL-1β and IL-18 in colonic tissues and Caco-2 cells. Immunofluorescence was used to detect the protein expression in tissues and cells. Enzyme-linked immunosorbent assay was used to determine the levels of IL-1β and IL-18 in tissue and cell culture supernatants. Lactate dehydrogenase (LDH) release assay and propidium iodide (PI) staining were used to measure cell pyroptosis. Molecular interactions beween A3AR and GSDMD were investigated using Co-IP and GST pull-down assays. Results A3AR expression was significantly reduced in colonic mucosa of patients with active UC, and colonic epithelial cells were the main cell subpopulation with down-regulated A3AR expression. Pyroptosis-associated factors, including Caspase-1, NLRP3, and GSDMD-NT, were upregulated in UC colonic tissues. The expression of A3AR and GSDMD-NT was negatively correlated. A3AR agonist reduced the production of cytokines (IL-1β and IL-18) and attenuates the expression levels of NLRP3 and GSDMD-NT in the colonic tissues of patients with UC. Furthermore, A3AR overexpression alleviated pyroptosis with reduced LDH release, PI-stained cell number and decreased expressions of GSDMD-NT, NLRP3, caspase-1, IL-1β, and IL-18 in the LPS+ATP-stimulated Caco-2 cells, whereas the opposite occurred in cells treated with small interfeing RNA (siRNA) targeting A3AR. Knockdown of GSDMD in Caco-2 cells significantly blocked the effects of A3AR overexpression or down-regulation on pyroptosis, suggesting that A3AR acts through the GSDMD-mediated pyroptosis pathway. Co-IP and GST pull-down assays showed that A3AR interacted with GSDMD. Conclusion A3AR modulates intestinal inflammation in UC through GSDMD-mediated intestinal epithelial cell pyroptosis. We propose a novel mechanism by which A3AR-GSDMD interaction affects UC through pyroptosis, suggesting that A3AR is a potential target for the treatment of UC.

Association of Interleukin-10 Gene Polymorphisms with Ulcerative Colitis

This literature review is devoted to the study of the role of polymorphic variants of the anti-inflammatory interleukin-10 gene (Interleukin-10, IL10) in the etiology and pathogenesis of ulcerative colitis in patients of various ethnic groups. Aim . To generalize the results obtained from electronic databases on the study of the characteristics of the course of ulcerative colitis in patients of different ethnic groups, taking into account the carriage of IL10 gene polymorphisms. Materials and methods . Twenty-five studies were selected, including four meta-analyzes devoted to the study of associative relationships of single nucleotide polymorphisms (SNPs) of the IL10 gene isolated from blood samples at positions -592AA/CA, -819CT, -1082АА/GA, and rs3024505 in the development and course of ulcerative colitis. Results. A number of researchers from Europe, Saudi Arabia report an increased incidence of ulcerative colitis among carriers of the IL10-1082AA SNP and a low incidence among carriers of -592AA. Positive associations of IL10-819CT with the prevalence of ulcerative colitis are presented in single reports from Europe, the Middle East and in a number of studies from Asian countries. However, the identified associations, even within the same population, are often contradictory. Perhaps the discrepancies are due to the ethnic heterogeneity of the groups in the considered cohorts, and therefore it is necessary to continue epidemiological studies with a large sample size in specific geographic areas.

Bioinformatics Analysis of Differentially Expressed Genes and Protein-Protein Interaction Networks Associated with Functional Pathways in Ulcerative Colitis.

BackgroundThis bioinformatics study aimed to identify differentially expressed genes (DEGs) and protein–protein interaction (PPI) networks associated with functional pathways in ulcerative colitis based on 3 Gene Expression Omnibus (GEO) datasets.Material/MethodsThe GSE87466, GSE75214, and GSE48958 MINiML formatted family files were downloaded from the GEO database. DEGs were identified from the 3 datasets, and volcano maps and heat maps were drawn after R language standardization and analysis, respectively. Venn diagram software was used to identify common DEGs. PPI analysis of common DEGs was performed using the Search Tool for the Retrieval of Interacting Genes. Gene modules and hub genes were visualized in the PPI network using Cytoscape. Enrichment analysis was performed for all common DEGs, module genes, and hub genes.ResultsA total of 90 DEGs were selected, which included 3 functional modules and 1 hub gene module. CXCL8 module genes were mainly enriched in cytokine-mediated signaling pathways and interleukin (IL)-10 signaling. CCL20 module genes were mainly enriched in the IL-17 signaling pathway and cellular response to IL-1. Hub gene modules mainly involved IL-10, IL-4, and IL-13 signaling pathways. CXCL8, CXCL1, and IL-1β were the top 3 hub genes and were mainly involved in IL-10 signaling.ConclusionsBioinformatics analysis using 3 GEO datasets identified CXCL8, CXCL1, and IL-1β, which are involved in IL-10 signaling, as the top 3 hub genes in ulcerative colitis. The findings from this study remain to be validated, but they may contribute to the further understanding of the pathogenesis of ulcerative colitis.

Anemoside B4 ameliorates TNBS-induced colitis through S100A9/MAPK/NF-\u03baB signaling pathway

BackgroundDespite the increased morbidity of ulcerative colitis (UC) in the developing countries, available treatments remain unsatisfactory. Therefore, it is urgent to discover more effective therapeutic strategies. Pulsatilla chinensis was widely used for the treatment of inflamed intestinal diseases including UC for thousands of years in China. Anemoside B4, the most abundant triterpenoid saponin isolated from P. chinensis, exerts anti-inflammatory and antioxidant effects and may be the most active compounds, which is responsible for the therapeutic effects. However, the mechanism how anemoside B4 executes its biological functions is still elusive.MethodsHere, we used the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model to evaluate the therapeutic effect of anemoside B4. Blood samples of colitis rats were collected for hematology analysis. The inflammation-associated factors were investigated by enzyme-linked immunosorbent assay (ELISA). Cell proliferation and apoptosis was determined with EdU cell proliferation assay and TUNEL assay. The proteins regulated by anemoside B4 were identified by label-free quantitative proteomics. The significantly down-regulated proteins were verified by Western blotting analysis. mRNA expression was analyzed by quantitative real-time RT-PCR.ResultsThe results showed that anemoside B4 ameliorated TNBS-induced colitis symptoms, including tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine production, apoptosis and slowed proliferation in colon. Quantitative proteomic analyses discovered that 56 proteins were significantly altered by anemoside B4 in the TNBS-induced rats. These proteins mainly clustered in tricarboxylic acid (TCA) cycle and respiratory electron transport chain. Among the altered proteins, S100A9 is one of the most significantly down-regulated proteins and associated with NF-κB and MAPK signaling pathways in the pathogenesis of UC. Further experiments revealed that anemoside B4 suppressed the expression of S100A9 and its downstream genes including TLR4 and NF-κB in colon. In vitro, anemoside B4 could inhibit the NF-κB signaling pathway induced by recombinant S100A9 protein in human intestinal epithelial Caco-2 cells. Moreover, anemoside B4 inhibits neutrophils recruitment and activation in colon induced by TNBS.ConclusionsOur results demonstrate that anemoside B4 prevents TNBS-induced colitis by inhibiting the NF-κB signaling pathway through deactivating S100A9, suggesting that anemoside B4 is a promising therapeutic candidate for colitis.

Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity

The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.

The rectal mucosal but not fecal microbiota detects subclinical ulcerative colitis

ABSTRACT Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is characterized by repetitive remission and relapse. Gut microbiome is critically involved in pathogenesis of UC. The shifts in microbiome profile during disease remission remain under-investigated. Recent studies revealed that UC pathogenesis is likely to originate in the mucosal barrier. Therefore, we investigated the effectiveness of mucosal tissue microbiomes to differentiate patients with subclinical UC from healthy individuals. The microbiomes of cecal and rectal biopsies and feces were characterized from 13 healthy individuals and 45 patients with subclinical UC. Total genomic DNA was extracted from the samples, and their microbial communities determined using next-generation sequencing. We found that changes in relative abundance of subclinical UC were marked by a decrease in Proteobacteria and an increase in Bacteroidetes phyla in microbiome derived from rectal tissues but not cecal tissue nor feces. Only in the microbiome of rectal tissue had significantly higher community richness and evenness in subclinical UC patients than controls. Twenty-seven operational taxonomic units were enriched in subclinical UC cohort with majority of the taxa from the Firmicutes phylum. Inference of putative microbial functional pathways from rectal biopsy microbiome suggested a differential increase in interleukin-17 signaling and T-helper cell differentiation pathways. Rectal biopsy tissue was suggested to be more suitable than fecal samples for microbiome assays to distinguish patients with subclinical UC from healthy adults. Assessment of the rectal biopsy microbiome may offer clinical insight into UC disease progression and predict relapse of the diseases.

CircRNA malignant fibrous histiocytoma amplified Sequence 1 (MFHAS1) reduced inflammatory responses in a Colitis Model via SIRT1/NF-κB

Abstract Ulcerative colitis (UC) is a chronic and non-specific inflammatory bowel disease (IBD). Its pathogenesis remains unclear, but its morbidity shows an increasing trend year by year. The pathogenesis of UC may be related to the genetic susceptibility, immune factor and intestinal microflora. In the last few years, an increasing number of studies have examined the relationship between the expression levels of peripheral CircRNA and UC. We aimed to evaluate the efficacy of CircRNA MFHAS1 in colitis and its possible mechanism. The expression of CircRNA MFHAS1 was reduced in colitis, and miR-486-5p expression was also increased in citrobacter rodentium-induced murine colitis. In vitro model, over-expression of CircRNA MFHAS1 reduced inflammatory responses, induced SIRT1 protein expression, and suppressed NF-κB protein expression. However, miR-486-5p CircRNA MFHAS1 suppressed SIRT1 protein expression, and induced NF-κB protein expression in vitro model. The inactivation of SIRT1 reduced the anti-inflammation effects of CircRNA MFHAS1 on inflammatory responses in vitro model. Over-expression of miR-486-5p also reduced the anti-inflammation effects of CircRNA MFHAS1 in vitro model. Our results demonstrated that CircRNA MFHAS1 reduces inflammatory responses in Colitis via SIRT1/NF-κB by miR-486-5p.

Identification of Novel Population-Specific Cell Subsets in Chinese Ulcerative Colitis Patients Using Single-Cell RNA Sequencing.

Background & AimsGenome-wide association studies (GWAS) and transcriptome analyses have been performed to better understand the pathogenesis of ulcerative colitis (UC). However, current studies mainly focus on European ancestry, highlighting a great need to identify the key genes, pathways and cell types in colonic mucosal cells of adult UC patients from other ancestries. Here we aimed to identify key genes and cell types in colonic mucosal of UC.MethodsWe performed Single-cell RNA sequencing (scRNA-seq) analysis of 12 colon biopsies of UC patients and healthy controls from Chinese Han ancestry.ResultsTwo novel plasma subsets were identified. Five epithelial/stromal and three immune cell subsets show significant difference in abundance between inflamed and non-inflamed samples. In general, UC risk genes show consistent expression alteration in both Immune cells of inflamed and non-inflamed tissues. As one of the exceptions, IgA defection, marking the signal of immune dysfunction, is specific to the inflamed area. Moreover, Th17 derived activation was observed in both epithelial cell lineage and immune cell lineage of UC patients as compared to controls , suggesting a systemic change of immune activities driven by Th17. The UC risk genes show enrichment in progenitors, glial cells and immune cells, and drug-target genes are differentially expressed in antigen presenting cells.ConclusionsOur work identifies novel population-specific plasma cell molecular signatures of UC. The transcriptional signature of UC is shared in immune cells from both inflamed and non-inflamed tissues, whereas the transcriptional response to disease is a local effect only in inflamed epithelial/stromal cells.

High-altitude hypoxia exacerbates dextran sulfate sodium (DSS)-induced colitis by upregulating Th1 and Th17 lymphocytes

ABSTRACT High altitude hypoxia (HAH) involves the pathogenesis of ulcerative colitis (UC) and gastrointestinal erosions. However, the mechanism of effects of HAH in colitis remains controversial. This study reports the immunomodulation mediated by HAH to enhancing the severity of UC in the mice model. BALB/c mice were used to establish the UC model by dextran sulfate sodium (DSS) compared to wild type mice. Mice groups were exposed to hypoxic conditions in a hypobaric chamber with an altitude of 5000 m for 7 days. Then, Spleen, mesenteric lymph nodes and colon tissues were collected. The activity of UC, the infiltration of the immune cells, and the released cytokines were investigated. Results showed that the severity of DSS-induced UC significantly increased in mice exposed to HAH. The analysis of pathological changes showed increased weight loss and decreased colon length accompanied by diarrhea and bloody feces in the hypobaric hypoxia group. Interestingly, the levels of inflammatory cytokines IL-17, TNF-α, and IFN-γ in the spleen and mesenteric lymph node showed a significant increase within the colon of the hypobaric hypoxia group. The population of Th 1 and Th 17 cells in the spleen was significantly increased in mice exposed to hypobaric hypoxia compared NC group. Suggesting that high altitude hypoxia enhances colitis in mice through activating the increase of inflammatory Th1 and Th17 lymphocytes. In conclusion, this study revealed that hypobaric hypoxia directly increases the severity of UC in the mice model via increasing the activity of inflammatory CD4+ Th1 and Th 17 lymphocytes.

Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells.

Ulcerative colitis (UC) is a chronic relapsed intestinal disease with an increasing incidence around the world. The pathophysiology of UC remains unclear. However, the role of the interaction between the enteric nervous system and the immune system in the pathogenesis of UC has been the focus of attention and has become a research hotspot. Vasoactive intestinal peptide (VIP) is a kind of endogenous neuropeptide with regulatory activity on intestinal immunity. It has been shown to regulate immune disorders in animal and human experiments and has become an effective anti-inflammatory and immune modulator that affects the innate immune system and adaptive immune system. Regulatory B cells (Bregs) are a new group of B cells that negatively regulate the immunity and have received extensive attention in immune circles. Bregs can regulate immune tolerance by producing interleukin (IL)-10, IL-35, and transforming growth factor-β, suppressing autoimmune diseases or excessive inflammatory responses. The secretion of IL-10 by Bregs induces the development of T helper (Th) 0 and Th2 cells. It also induces Th2 cytokines and inhibits Th1 cytokines, thereby inhibiting Th1 cells and the Th1/Th2 balance. With further clarity on the mechanism of the regulation of IL-10 expression by VIP in Bregs in colitis patients, we believe that Bregs can provide a novel strategy for the clinical treatment of UC. Thus, we aim to review the current literature on this evolving topic.

Identification and Validation of Key miRNAs and a microRNA-mRNA Regulatory Network Associated with Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, nonspecific, intestinal inflammatory disease that involves various genes and pathways in its pathogenesis. The current study revealed the key miRNAs and potential target gene regulatory network as a model for predicting the molecular mechanism of UC. This may provide novel insights for unraveling the pathogenesis of UC. Differentially expressed miRNAs (DEMIs) and mRNAs (differentially expressed genes [DEGs]) between UC patients and normal controls were screened using the Gene Expression Omnibus database. DEMI target genes were predicted using the miRDB, miRWalk, starBase, TarBase, and TargetScan databases, and an miRNA-mRNA network was established using DEGs that altered in opposition to DEMIs. We verified the expression of key DEMIs in a rodent UC model. The miRNA-mRNA network contained 31 DEMIs and 199 DEGs, which showed enrichment in inflammatory bowel disease. We selected 2 key miRNAs and 4 hub genes. In addition, we identified six DEMIs and genes from the preliminary validation analysis in model tissues. In the pathophysiological process of UC, various genes and proteins display expression differences and complex interactions with each other. These findings provide new insights into the potential key mechanisms associated with UC development.