Pathogenesis Of Ulcerative Colitis Research Articles

The traditional herb Sargentodoxa cuneata alleviates DSS-induced colitis by attenuating epithelial barrier damage via blocking necroptotic signaling

Ethnopharmacological relevanceThe traditional Chinese herb, Sargentodoxa cuneata, is primarily utilized as a crucial herb for managing ulcerative colitis (UC), also known as “Da Xue Teng (DXT)” or “Hong Teng” in Chinese. Nevertheless, the chemical composition, prototype, and metabolite constituents of DXT and its pharmacological mechanism of treatment for UC remain unclear. Aim of the studyNecroptosis, a caspase-independent form of programmed cell death, plays a crucial role in the inflammatory pathogenesis of UC. The occurrence of necroptosis in intestinal epithelial cells triggers a robust inflammatory response and disrupts the integrity of both the mucinous barrier and tight junction construction. The objective of our study was to determine the chemical composition of DXT, identify its absorbed active ingredients and metabolites in rat serum, and investigate whether DXT possesses epithelial barrier protective effects by inhibiting necroptosis. Materials and methodsFirst, the UPLC-Q-TOF/MS was applied to identify the chemical composition of DXT, as well as the absorption components and metabolites of DXT in rat serum. Second, the network pharmacology analysis was further investigated to elucidate the potential targets for treating UC. Finally, the mechanism of action was validated by necroptosis-based experiment in vitro and an in vivo model of colitis. ResultsA comprehensive analysis revealed the presence of 31 phytochemicals derived from DXT herb, as well as a total of 39 components in rat serum. Network pharmacology analysis indicated that TNF, EGFR, HSP90, etc. are the potential targets. Experimental in vitro and in vivo verified that the DXT could improve disease activity index, body weight, colon length and intestinal barrier permeability in mice with colitis by inhibiting necroptosis of intestinal epithelial cells. ConclusionsIn this study, the phytochemicals derived from DXT herb and absorption active ingredients and metabolites of DXT in rat serum were analyzed. The biological mechanism of treatment for UC can be elucidated by combining network pharmacology investigation with experimental in vitro and in vivo studies. The findings offered a theoretical basis for comprehending the bioactive substances and the pharmacological process of DXT.

Identifying Macrophage-Related Genes in Ulcerative Colitis Using Weighted Coexpression Network Analysis and Machine Learning.

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown cause that typically affects the colon and rectum. Innate intestinal immunity, including macrophages, plays a significant role in the pathological development of UC. Using the CIBERSORT algorithm, we observed elevated levels of 22 types of immune cell infiltrates, as well as increased M1 and decreased M2 macrophages in UC compared to normal colonic mucosa. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with macrophages and UC, resulting in the identification of 52 macrophage-related genes (MRGs) that were enriched in macrophages at single-cell resolution. Consensus clustering based on these 52 MRGs divided the integrated UC cohorts into three subtypes. Machine learning algorithms were used to identify ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14), and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the training set, and their diagnostic value was validated in independent validation sets. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed the main biological effects, and that interleukin-17 was one of several signaling pathways enriched by the three genes. We also constructed a competitive endogenous RNA (CeRNA) network reflecting a potential posttranscriptional regulatory mechanism. Expression of diagnostic markers was validated in vivo and in biospecimens, and our immunohistochemistry (IHC) results confirmed that HMGCS2 gradually decreased during the transformation of UC to colorectal cancer. In conclusion, ENPP1, SLC6A14, and HMGCS2 are associated with macrophages and the progression of UC pathogenesis and have good diagnostic value for patients with UC.

Repairing the intestinal mucosal barrier of traditional Chinese medicine for ulcerative colitis: a review

Damage to the intestinal mucosal barrier play an important role in the pathogenesis of ulcerative colitis (UC). Discovering the key regulators and repairing the disturbed barrier are crucial for preventing and treating UC. Traditional Chinese medicine (TCM) has been proved to be effective on treating UC and has exhibited its role in repairing the intestinal mucosal barrier. We summarized the evidence of TCM against UC by protecting and repairing the physical barrier, chemical barrier, immune barrier, and biological barrier. Mechanisms of increasing intestinal epithelial cells, tight junction proteins, and mucins, promoting intestinal stem cell proliferation, restoring the abundance of the intestinal microbiota, and modulating the innate and adaptive immunity in gut, were all involved in. Some upstream proteins and signaling pathways have been elucidated. Based on the existing problems, we suggested future studies paying attention to patients’ samples and animal models of UC and TCM syndromes, conducting rescue experiments, exploring more upstream regulators, and adopting new technical methods. We hope this review can provide a theoretical basis and novel ideas for clarifying the mechanisms of TCM against UC via repairing the intestinal mucosal barrier.

Ulcerative Colitis and Nursing

Ulcerative colitis is a chronic disease of attacks and remissions characterized by bloody diarrhea, abdominal pain, and abdominal cramps involving the colonic mucosa starting from the rectum. The etiology and pathogenesis of ulcerative colitis are unknown. The most common signs and symptoms of ulcerative colitis are bloody diarrhea, abdominal pain, and abdominal cramps. Nurses, who are health professionals, are obligated to take the symptoms and signs under control and to care for patients through the treatment planned by the physician. Patient care is very important in the nursing profession. The nurse's primary role is to support the patient and his/her family to live a long, trouble-free life and comply with the treatment. This study aims to give information about Ulcerative Colitis and to discuss the nursing approach to providing professional health care.

Multi-omics revealed the mechanisms of Codonopsis pilosula aqueous extract in improving UC through blocking abnormal activation of PI3K/Akt signaling pathway

EthnopharmacologicalrelevanceCodonopsis pilosula (DS), a traditional Chinese medicine, had been used to regulate the immune, digestive and circulatory systems of the human, as well as protect the gastrointestinal tract, improve lung function. Aim of the studyThe aim of study was to explore the effects and mechanism of Codonopsis pilosula aqueous extract (DS) intervention in improving ulcerative colitis (UC). Materials and methodsUC model rats were established using combination of TNBS and ethanol. Tissue samples were collected for transcriptome and metabolomics analysis. Network pharmacology was performed on DS to identify bioactive compounds. Western blot was used to detect the key proteins involved in UC pathogenesis and PI3K/AKT pathways. ResultsDS exerted the preventive and therapeutic effects in improving UC via inhibiting abnormal inflammatory responses and promoting antioxidant capacity. Levels of intestinal barrier, oxidative stress and inflammatory mediators were improved to nearly normal level in vivo by DS. Metabolome profiles showed that DS could restore the metabolic disorders associated with the UC pathogenesis. Further transcriptome results showed that DS mainly alleviate UC through inhibiting PI3K/Akt signaling pathway, and various related genes that dramatically expressed in UC Model rats were downregulated by DS. Typically, network pharmacology analysis identified that Glycitein was the hub compounds that involved in the mechanism of DS in improving UC. ConclusionsThe results show that Codonopsis pilosula (DS) was an potential excellent material in treating of UC depending on its suitable concentration. Possible therapeutic mechanisms of the DS involved in mitigating colonal inflammation, restoring metabolic disorders, promoting antioxidant capacity, and especially blocking the activation of PI3K/Akt pathway.

Single-cell dissection, hdWGCNA and deep learning reveal the role of oxidatively stressed plasma cells in ulcerative colitis.

Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the pathogenesis of ulcerative colitis at the single-cell level and unveil its clinical significance. Using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis, we identify a subpopulation of plasma cells (PCs) with significantly increased infiltration in UC colonic mucosa, characterized by pronounced oxidative stress. Combining 10 machine learning approaches, we find that the PC oxidative stress genes accurately distinguish diseased mucosa from normal mucosa (independent external testing AUC=0.991, sensitivity=0.986, specificity=0.909). Using MCPcounter and non-negative matrix factorization, we identify the association between PC oxidative stress genes and immune cell infiltration as well as patient heterogeneity. Spatial transcriptome data is used to verify the infiltration of oxidatively stressed PCs in colitis. Finally, we develop a gene-immune convolutional neural network deep learning model to diagnose UC mucosa in different cohorts (independent external testing AUC=0.984, sensitivity=95.9%, specificity=100%). Our work sheds light on the key pathogenic cell subpopulations in UC and is essential for the development of future clinical disease diagnostic tools.

Dynamics of the Gut Mycobiome in Patients With Ulcerative Colitis

Intestinal fungi have been implicated in the pathogenesis of ulcerative colitis (UC). However, it remains unclear if fungal composition is altered during active versus quiescent disease. We analyzed clinical and metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD), available via the IBD Plexus Program of the Crohn's & Colitis Foundation. We evaluated the fungal composition of fecal samples from 421 patients with UC during clinical activity and remission. Within a longitudinal subcohort (n= 52), we assessed for dynamic taxonomic changes across alterations in clinical activity over time. We examined if fungal amplicon sequence variants and fungal-bacterial relationships were altered during activity versus remission. Finally, we classified activity in UC using a supervised machine learning random forest model trained on fungal abundance data. During clinical activity, the relative abundance of genus Candida was increased 3.5-fold (P-adj < 1× 10-4) compared with during remission. Patients with longitudinal reductions in clinical activity demonstrated parallel reductions in Candida relative abundance (P < .05). Candida relative abundance correlated with Parabacteroides diastonis, Faecalibacterium prausnitzii, and Bacteroides dorei relative abundance (P < .05) during remission; however, these correlations were disrupted during activity. Fungal abundance data successfully classified patients with active or quiescent UC (area under the curve ∼0.80), with Candida relative abundance critical to the success of the model. Clinical activity in UC is associated with an increased relative abundance of Candida, cross-sectionally and dynamically over time. The role of fecal Candida as a target for therapeutics in UC should be evaluated.

Molecular analyses of ADAMTS-1, -4, -5, and IL-17 a cytokine relationship in patients with ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease that develops due to the impaired immune response in genetically susceptible individuals, and its etiopathogenesis is not fully elucidated. IL-17 A is a cytokine that is produced by a type of immune cell called Th17 cells and is involved in the immune response and inflammation. On the other hand, ADAMTS-1, -4, and − 5 are enzymes that are involved in the breakdown of extracellular matrix proteins, including proteoglycans, which are important components of the intestinal wall. This study aimed to evaluate the relationship between interleukin 17 (IL-17 A) cytokine, which plays a role in the pathogenesis of ulcerative colitis, and the inflammation-controlled a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-1, -4, and − 5 protein members.MethodsBowel tissue samples and blood serum from 51 patients with UC and 51 healthy controls were included in this study. mRNA expression levels of the ADAMTS-1, -4, -5, and IL-17 A were analyzed by RT-qPCR, and immunohistochemical analyses were performed to evaluate ADAMTS-1, -4, -5, and IL-17 A proteins in tissue samples. In addition, ELISA analysis determined serum levels of the ADAMTS-1, -4, -5, and IL-17 A.ResultsRT-qPCR results reveal that the expression of ADAMTS-1, -4, -5, and IL-17 A genes in the UC tissue samples were significantly high according to the control tissue samples. Also, ADAMTS-1, -4, -5, and IL-17 A proteins revealed enhanced expression pattern UC groups according to the control. Also, ADAMTS-1, -4, -5, and IL-17 A protein showed cytoplasmic localization patterns in both control and UC groups. The serum levels of ADAMTS-1,-5, and IL-17 A were significantly higher in UC samples than in the control group.ConclusionsWe observed a positive correlation between the ADAMTS-1, -5 and IL17A cytokine expression in UC samples. These results provide a new understanding of controlling crucial ADAMTS family protein members by IL-17 A cytokines with UC.

Impact of ulcerative colitis therapy on the bacterial profile of the intestinal microbiota

Inflammatory bowel diseases represent a heterogeneous group of chronic diseases occurring as a result of disruption of interaction processes between the mucosal immune system and the colon commensal ecosystem. The key role of the intestinal microbiota in the pathogenesis of ulcerative colitis, as well as its definition as a deterministic factor influencing the status of immune activation and the severity of the disease, is confirmed in many studies. Accumulating evidence suggests that non-antibacterial drugs are able to modulate the composition of the intestinal microbiota, which in turn may determine the effectiveness of pharmacological therapy and the clinical outcome. The article presents a review of literature on the impact of drugs used in the treatment of ulcerative colitis on the bacterial community of the colon.

Revisiting the relationship between complement and ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disorder (IBD) characterized by relapsing chronic inflammation of the colon that causes continuous mucosal inflammation. The global incidence of UC is steadily increasing. Immune mechanisms are involved in the pathogenesis of UC, of which complement is shown to play a critical role by inducing local chronic inflammatory responses that promote tissue damage. However, the function of various complement components in the development of UC is complex and even paradoxical. Some components (e.g. C1q, CD46, CD55, CD59, and C6) are shown to safeguard the intestinal barrier and reduce intestinal inflammation, while others (e.g. C3, C5, C5a) can exacerbate intestinal damage and accelerate the development of UC. The complement system was originally thought to function primarily in an extracellular mode; however, recent evidence indicates that it can also act intracellularly as the complosome. The current study provides an overview of current studies on complement and its role in the development of UC. While there are few studies that describe how intracellular complement contributes to UC, we discuss potential future directions based on related publications. We also highlight novel methods that target complement for IBD treatment.

The impact of proton pump inhibitors on the course of ulcerative colitis: a cohort study of over 10,000 newly diagnosed patients in Norway

Background and Aims Proton pump inhibitors (PPI) affect the gastrointestinal microbiota, which is thought to play a role in the pathogenesis of ulcerative colitis (UC). Previous studies suggest an association between PPI use and risk of incident UC as well as disease course. The aim of the study was to examine if PPI exposure is associated with disease course in UC patients. Methods A national cohort consisting of all newly diagnosed UC patients from 2010 to 2020 was defined combining data from Norwegian registries. PPI exposure was included as a time dependent variable with a 30 day time lag from starting the drug. Outcomes were starting advanced therapies including anti-TNF, systemic glucocorticoids, any additional systemic anti-inflammatory medication and undergoing colectomy during follow-up. Time-dependent Cox regressions included the variables PPI use, first systemic glucocorticoid prescription, first UC hospitalization, age-groups and sex. Results The study cohort consisted of 10,149 patients with median age 40 years (IQR 27–56) and 56% males. PPI use independently increased the risk of starting advanced therapies (HR 1.54, 95% CI 1.36–1.73, p < 0.005), starting systemic glucocorticoids (HR 1.20, 95% CI 1.07–1.34, p < 0.005), starting any additional anti-inflammatory treatment (HR 1.18, 95%CI 1.05–1.32, p < 0.01) and undergoing colectomy (HR 1.52, 95%CI 1.17–1.98, p < 0.005). Conclusions PPI use was associated with unfavorable outcomes including advanced therapy initiation, additional anti-inflammatory medications and undergoing colectomy. Although further studies are needed, the evidence suggests that PPIs could affect the course of UC and should be used cautiously in UC patients.

VDUP1 Deficiency Promotes the Severity of DSS-Induced Colitis in Mice by Inducing Macrophage Infiltration.

The loss of vitamin D3 upregulated protein 1 (VDUP1) has been implicated in the pathogenesis of various inflammation-related diseases. Notably, reduced expression of VDUP1 has been observed in clinical specimens of ulcerative colitis (UC). However, the role of VDUP1 deficiency in colitis remains unclear. In this study, we investigated the role of VDUP1 in dextran sulfate sodium (DSS)-induced experimental colitis in mice. VDUP1-deficient mice were more susceptible to DSS-induced colitis than their wild-type (WT) littermates after 2% DSS administration. VDUP1-deficient mice exhibited an increased disease activity index (DAI) and histological scores, as well as significant colonic goblet cell loss and an increase in apoptotic cells. These changes were accompanied by a significant decrease in MUC2 mRNA expression and a marked increase in proinflammatory cytokines and chemokines within damaged tissues. Furthermore, phosphorylated NF-κB p65 expression was significantly upregulated in damaged tissues in the context of VDUP1 deficiency. VDUP1 deficiency also led to significant infiltration of macrophages into the site of ulceration. An in vitro chemotaxis assay confirmed that VDUP1 deficiency enhanced bone marrow-derived macrophage (BMDM) chemotaxis induced by CCL2. Overall, this study highlights VDUP1 as a regulator of UC pathogenesis and a potential target for the future development of therapeutic strategies.

Fluoxetine Ameliorates the Aggravation of UC Symptoms in C57BL/6 Mice Induced by CUMS.

Patients with chronic ulcerative colitis (UC) often have mental symptoms such as depression and anxiety, and stress can lead to gastrointestinal diseases. However, the correlation between mental stress and UC is unclear. In this paper, chronic unpredictable mild stress (CUMS) was utilized to evaluate the involvement of mental factors in the pathogenesis of UC. The CUMS model was used to evaluate the direct/indirect involvement of mental factors in the pathogenesis of UC. The behavior was evaluated by the open field, forced swimming, and tail suspension tests. Body weight, the disease activity index (DAI) score, colon length, and HE staining of colon tissue were used to evaluate the action of CUMS and fluoxetine. The results showed that weight loss and the DAI score increased in CUMS mice, but they had no meaningful effect on colon length and morphological structure of colon tissue. However, CUMS aggravated dextran sulfate sodium (DSS)-induced colon length shortening and colon morphological structure damage. Fluoxetine significantly improved the DAI score, shortened colon length, and damaged morphology and structure of the colons induced by CUMS combined with DSS in mice. Fluoxetine also decreased the level of IL-6 in the serum and the TNF-α and IFN-γ levels of colon tissue. Fluoxetine simultaneously improved behavioral abnormalities induced by CUMS combined with DSS in mice. CUMS aggravated the UC symptoms induced by DSS, and fluoxetine could improve the UC symptoms due to its improvement in the inflammatory level and behavioral abnormalities.

Mechanism of Qingchang Suppository on repairing the intestinal mucosal barrier in ulcerative colitis.

Ulcerative colitis (UC) is a refractory inflammatory bowel disease, and the outcomes of conventional therapies of UC, including 5-aminosalicylic acid, glucocorticoids, immunosuppressants, and biological agents, are not satisfied with patients and physicians with regard to adverse reactions and financial burden. The abnormality of the intestinal mucosal barrier in the pathogenesis of UC was verified. Qingchang Suppository (QCS) is an herbal preparation and is effective in treating ulcerative proctitis. The mechanism of QCS and its active ingredients have not been concluded especially in mucosal healing. This review elucidated the potential mechanism of QCS from the intestinal mucosal barrier perspective to help exploring future QCS research directions.

Analysis and identification of ferroptosis-related genes in ulcerative colitis

Background Previous studies have shown that ferroptosis is associated with the pathogenesis of ulcerative colitis (UC). Therefore, this study aimed to identify key ferroptosis-related genes (FRGs) associated with the diagnosis of UC. Methods UC-related expression datasets were downloaded from the Gene Expression Omnibus (GEO) database. First, Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify UC-related genes (UCRGs). Differentially expressed genes (DEGs) between normal and UC groups were screened in GSE87466, and DEGs were subjected to an intersection analysis with FRGs and UCRGs to obtain ferroptosis-related DEGs (FR DEGs). Then a protein-protein interaction (PPI) network was constructed for FR DEGs. The hub genes were extracted based on the degree, Maximum Neighborhood Component (MNC), closeness, and Maximal Clique Centrality (MCC). Biomarkers with diagnostic values were screened by support vector machine (SVM) and the least absolute shrinkage and selection operator (LASSO) algorithms. Next, the infiltration of immune cells was compared between UC and normal groups, and the correlation between different immune cells and diagnostic genes was analyzed. The biological functions, classical pathways, and intermolecular interaction networks of diagnostic genes were characterized utilizing ingenuity pathway analysis (IPA). Finally, a TF-mRNA network was constructed and potential small-molecule compounds were screened. Results Thirty-six FR DEGs were obtained, and these were enriched in biological processes such as positive regulation of cytokine production, cytokine-mediated signalling pathway, long-chain fatty acid-CoA ligase activity, etc. Among 18 hub genes, five genes (ALOX5, TIMP1, TNFAIP3, SOCS1, DUOX2) were captured with diagnostic values for UC, and they displayed significant differences between UC and normal groups. Sixteen immune cell infiltrates were significantly different between UC and normal groups, such as activated dendritic cells and resting dendritic cells. TNFAIP3 and ALOX5 were positively correlated with neutrophils, and TIMP1, SOCS1, ALOX5, and DUOX2 were negatively correlated with M2 macrophages. IPA showed that diagnostic genes were related to 43 function modules and activated 17 pathways. The constructed TF-mRNA regulatory network comprised three diagnostic genes and 17 differentially expressed TFs. Potential small-molecule compounds including helveticoside and cymarin were identified. Conclusion Our findings yielded several promising FRGs for UC, providing a scientific reference for further studies on the pathogenesis of UC.

Biomarkers of ulcerative colitis disease activity CXCL1, CYP2R1, LPCAT1, and NEU4 and their relationship to immune infiltrates

The diagnosis and assessment of ulcerative colitis (UC) poses significant challenges, which may result in inadequate treatment and a poor prognosis for patients. This study aims to identify potential activity biomarkers for UC and investigate the role of infiltrating immune cells in the disease. To perform gene set enrichment analysis, we utilized the cluster profiler and ggplot2 packages. Kyoto encyclopedia of genes and genomes was used to analyze degenerate enrichment genes. Significant gene set enrichment was determined using the cluster profiler and ggplot2 packages. Additionally, quantitative PCR (qRT-PCR) was employed to validate the expression of each marker in the ulcerative colitis model. We identified 651 differentially expressed genes (DEGs) and further investigated potential UC activity biomarkers. Our analysis revealed that CXCL1 (AUC = 0.710), CYP2R1 (AUC = 0.863), LPCAT1 (AUC = 0.783), and NEU4 (AUC = 0.833) were promising activity markers for the diagnosis of UC. Using rat DSS model, we validated these markers through qRT-PCR, which showed statistically significant differences between UC and normal colon mucosa. Infiltrating immune cell analysis indicated that M1 macrophages, M2 macrophages, activated dendritic cells (DCs), and neutrophils played crucial roles in the occurrence and progression of UC. Moreover, the activity markers exhibited varying degrees of correlation with activated memory CD4 T cells, M0 macrophages, T follicular helper cells, memory B cells, and activated DCs. The potential diagnostic genes for UC activity, such as CXCL1, CYP2R1, LPCAT1, and NEU4, as well as the infiltration of immune cells, may contribute to the pathogenesis and progression of UC.

Hyper α2,6-Sialylation Promotes CD4+ T-Cell Activation and Induces the Occurrence of Ulcerative Colitis.

α2,6-sialylation, catalyzed by α2,6-sialyltransferase (ST6GAL1), plays a pivotal role in immune responses. However, the role of ST6GAL1 in the pathogenesis of ulcerative colitis (UC) remains unknown. ST6GAL1 mRNA is highly expressed in UC tissues compared with the corresponding adjacent normal tissues, and α2,6-sialylation is significantly increased in the colon tissues of patients with UC. The expression of ST6GAL1 and proinflammatory cytokines, such as interleukin (IL)-2, IL-6, IL-17, and interferon-gamma, is also increased. The number of CD4+ T cells increases in UC patients. St6gal1 gene knockout (St6gal1-/- ) rats are established by clustered regularly interspaced short palindromic repeats (CRISPR)-associated gene knockout system. St6gal1 deficiency reduces the levels of pro-inflammatory cytokines and alleviates colitis symptoms in UC model rats. Ablation of α2,6-sialylation inhibits the transport of the TCR to lipid rafts and suppresses CD4+ T-cell activation. The attenuation of TCR signaling downregulates the expression of NF-κB in ST6GAL1-/- CD4+ T-cells. Moreover, NF-κB could bind to the ST6GAL1 promoter to increase its transcription. Ablation of ST6GAL1 downregulates the expression of NF-κB and reduces the production of proinflammatory cytokines to relieve UC pathogenesis, which is a potential novel target for the clinical treatment of UC.

Probiotics for the treatment of ulcerative colitis: a review of experimental research from 2018 to 2022.

Ulcerative colitis (UC) has become a worldwide public health problem, and the prevalence of the disease among children has been increasing. The pathogenesis of UC has not been elucidated, but dysbiosis of the gut microbiota is considered the main cause of chronic intestinal inflammation. This review focuses on the therapeutic effects of probiotics on UC and the potential mechanisms involved. In animal studies, probiotics have been shown to alleviate symptoms of UC, including weight loss, diarrhea, blood in the stool, and a shortened colon length, while also restoring intestinal microecological homeostasis, improving gut barrier function, modulating the intestinal immune response, and attenuating intestinal inflammation, thereby providing theoretical support for the development of probiotic-based microbial products as an adjunctive therapy for UC. However, the efficacy of probiotics is influenced by factors such as the bacterial strain, dose, and form. Hence, the mechanisms of action need to be investigated further. Relevant clinical trials are currently lacking, so the extension of animal experimental findings to clinical application requires a longer period of consideration for validation.

Topotecan alleviates acetic acid-induced ulcerative colitis in rats via attenuation of the RORγT transcription factor

AimsUlcerative colitis is characterized as a chronic immune-mediated inflammatory condition, affecting the intestinal gastroenteric tissue. Previous studies revealed that Th-17 cells are key players in the pathogenesis of ulcerative colitis. RORγT (Retinoic-acid-receptor-related orphan receptor-gamma T) is a lineage-specific transcription factor of Th-17 cells and thus has a role in their differentiation. Transient inhibition of RORγT has been reported to attenuate the differentiation of Th-17 cells and secretion of interleukin-17 (IL-17). Here, we investigated the efficacy of topotecan in ameliorating ulcerative colitis in rodents, via inhibition of the RORγT transcription factor. Main methods and key findingsExperimental ulcerative colitis was induced in rats by intrarectal acetic acid administration. Topotecan attenuated the severity of ulcerative colitis in rats by revoking neutrophils and macrophage infiltration to the colon. It also alleviated diarrhea and rectal bleeding and improved body weight. Further, attenuation of RORγT and IL-17 expression was observed in topotecan treated animals. Levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β in the colon tissue were reduced by topotecan treatment. Significant reduction in malondialdehyde level, elevation of superoxide dismutase (SOD) and catalase activity was observed in the colon tissue of rats treated with topotecan compared to the diseased group. SignificanceThis study shows the therapeutic potential of topotecan in attenuating ulcerative colitis in rats probably via inhibition of the RORγT transcription factor and downstream mediators of Th-17 cells.

Altered Phenotypes of Colonic and Peripheral Blood Follicular Helper and Follicular Cytotoxic T Cells in Mice with DSS-Induced Colitis.

Follicular helper T (Tfh), follicular regulatory T (Tfr), and follicular cytotoxic T (Tfc) cells play important roles in autoimmune diseases. Nevertheless, their changes of functional phenotypes in ulcerative colitis (UC), most importantly, their changes in colon tissue as the target-organ, have not been explored. DSS-colitis was induced in Balb/c mice and lymphocytes were collected from spleen, mesenteric lymph nodes, peripheral blood and colon. Tfh, Tfr, and Tfc cells were analyzed using flow cytometry based on their CD4+CXCR5+FOXP3-Tfh, CD4+CXCR5+FOXP3+Tfr and CD8+CXCR5+Tfc expressions. Various functional characterization markers including CD44, CD62L, TIGIT, CD226, PD-1, ICOS, Helios, CTLA-4 and Bcl6 were analyzed in the T cell subsets of the organs. Tfh and Tfr cells in the colon were significantly increased in DSS-colitis mice. Additionally, the proportions of Tfr and Tfc cells in the peripheral blood were also increased, while Tfc cell proportions in the colon were decreased. The proportion of naïve cells in the Tfh, Tfr and Tfc cells in the colon and peripheral blood decreased, while the proportion of effector memory T cells increased. The TIGIT+CD226-Tfh and Tfc cells were upregulated in the colon of DSS-colitis mice. The PD-1+, ICOS+ and PD-1+ICOS+ Tfh cells were increased in both the colonic and peripheral blood Tfh and Tfc of DSS-colitis mice. The Bcl6+ proportions in the Tfh and Tfr were increased in the colon of DSS-colitis mice. The colonic and peripheral blood Tfh and Tfc cells of DSS-colitis mice have a significantly activated T cell phenotype, which may play a significant role in the pathogenesis of UC.