Etiology Of Ulcerative Colitis Research Articles

A Traditional Chinese Medicine, Zhenqi Granule, Potentially Alleviates Dextran Sulfate Sodium-Induced Mouse Colitis Symptoms.

Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the large intestine. The etiology of UC is complex and incompletely understood, with potential contributing factors including genetic susceptibility, environmental influences, immune dysregulation, and gut barrier dysfunction. Despite available therapeutic drugs, the suboptimal cure rate for UC emphasizes the necessity of developing novel therapeutics. Traditional Chinese Medicine (TCM) has attracted great interest in the treatment of such chronic inflammatory diseases due to its advantages, such as multi-targets and low side effects. In this study, a mouse model of Dextran Sulfate Sodium (DSS)-induced acute colitis was established and the efficacy of Zhenqi Granule, a TCM preparation composed of the extractives from Astragali Radix and Fructus Ligustri Lucidi, was evaluated. The results showed that treatment with Zhenqi Granule prior to or post-DSS induction could alleviate the symptoms of colitis, including weight loss, diarrhea, hematochezia, colon length shortening, and pathological damage of colon tissues of the DSS-treated mice. Further, network pharmacology analysis showed that there were 98 common targets between the active components of Zhenqi Granule and the targets of UC, and the common targets were involved in the regulation of inflammatory signaling pathways. Our results showed that Zhenqi Granule had preventive and therapeutic effects on acute colitis in mice, and the mechanism may be that the active components of Zhenqi Granule participated in the regulation of inflammatory response. This study provided data reference for further exploring the mechanism of Zhenqi Granule and also provided potential treatment strategies for UC.

Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review.

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.

Gaining new insights into the etiology of ulcerative colitis through a cross-tissue transcriptome-wide association study.

Genome-wide association studies (GWASs) have identified 38 loci associated with ulcerative colitis (UC) susceptibility, but the risk genes and their biological mechanisms remained to be comprehensively elucidated. Multi-marker analysis of genomic annotation (MAGMA) software was used to annotate genes on GWAS summary statistics of UC from FinnGen database. Genetic analysis was performed to identify risk genes. Cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signatures (UTMOST) was performed to compare GWAS summary statistics with gene expression matrix (from Genotype-Tissue Expression Project) for data integration. Subsequently, we used FUSION software to select key genes from the individual tissues. Additionally, conditional and joint analysis was conducted to improve our understanding on UC. Fine-mapping of causal gene sets (FOCUS) software was employed to accurately locate risk genes. The results of the four genetic analyses (MAGMA, UTMOST, FUSION and FOCUS) were combined to obtain a set of UC risk genes. Finally, Mendelian randomization (MR) analysis and Bayesian colocalization analysis were conducted to determine the causal relationship between the risk genes and UC. To test the robustness of our findings, the same approaches were taken to verify the GWAS data of UC on IEU. Multiple correction tests screened PIM3 as a risk gene for UC. The results of Bayesian colocalization analysis showed that the posterior probability of hypothesis 4 was 0.997 and 0.954 in the validation dataset. MR was conducted using the inverse variance weighting method and two single nucleotide polymorphisms (SNPs, rs28645887 and rs62231924) were included in the analysis (p < 0.001, 95%CI: 1.45-1.89). In the validation dataset, MR result was p < 0.001, 95%CI: 1.19-1.72, indicating a clear causal relationship between PIM3 and UC. Our study validated PIM3 as a key risk gene for UC and its expression level may be related to the risk of UC, providing a novel reference for further improving the current understanding on the genetic structure of UC.

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.

Intestinal epithelial barrier integrity investigated by label-free techniques in ulcerative colitis patients

The intestinal epithelial barrier, among other compartments such as the mucosal immune system, contributes to the maintenance of intestinal homeostasis. Therefore, any disturbance within the epithelial layer could lead to intestinal permeability and promote mucosal inflammation. Considering that disintegration of the intestinal epithelial barrier is a key element in the etiology of ulcerative colitis, further assessment of barrier integrity could contribute to a better understanding of the role of epithelial barrier defects in ulcerative colitis (UC), one major form of chronic inflammatory bowel disease. Herein, we employ fast, non-destructive, and label-free non-linear methods, namely coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), two-photon excited fluorescence (TPEF), and two-photon fluorescence lifetime imaging (2P-FLIM), to assess the morpho-chemical contributions leading to the dysfunction of the epithelial barrier. For the first time, the formation of epithelial barrier gaps was directly visualized, without sophisticated data analysis procedures, by the 3D analysis of the colonic mucosa from severely inflamed UC patients. The results were compared with histopathological and immunofluorescence images and validated using transmission electron microscopy (TEM) to indicate structural alterations of the apical junction complex as the underlying cause for the formation of the epithelial barrier gaps. Our findings suggest the potential advantage of non-linear multimodal imaging is to give precise, detailed, and direct visualization of the epithelial barrier in the gastrointestinal tract, which can be combined with a fiber probe for future endomicroscopy measurements during real-time in vivo imaging.

Identification of ferroptosis-related genes in ulcerative colitis: a diagnostic model with machine learning.

Ulcerative colitis (UC) is an idiopathic, chronic disorder characterized by inflammation, injury, and disruption of the colonic mucosa. However, there are still many difficulties in the diagnosis and differential diagnosis of UC. An increasing amount of research has shown a connection between ferroptosis and the etiology of UC. Therefore, our study aimed to identify the key genes related to ferroptosis in UC to provide new ideas for diagnosis UC. Gene expression profiles of normal and UC samples were extracted from the Gene Expression Omnibus (GEO) database. By combining differentially expressed genes (DEGs), Weighted correlation network analysis (WGCNA) genes, and ferroptosis-related genes, hub genes were identified and then screened using Lasso regression. Based on the key genes, gene ontology (GO) and gene set enrichment analysis (GSEA) analyses were performed. We used NaiveBeyas, Logistic, IBk, and RandomForest algorithms to build a disease diagnosis model using the hub genes. The model was validated using GSE87473 as the validation set. Gene expression matrices of GSE87466 and GSE75214 were downloaded from the GEO database, including 184 UC patients and 43 control samples. A total of 699 DEGs were obtained. From FerrDb, 565 genes related to ferroptosis were identified. The 1,513 genes with the highest absolute correlation coefficient value in the MEblue module were obtained from WGCNA analysis. Five hub genes (LCN2, MUC1, PARP8, PLIN2, and TIMP1) were identified using the Lasso regression algorithm based on the overlapped DEGs, WGCNA-identified genes, and ferroptosis-related genes. GO and GSEA analyses revealed that 5 hub genes were identified as being involved in the negative regulation of transcription by competitive promoter binding, cellular response to citrate cycle_tca_cycle, cytosolic_dna_sensing pathway, UV-A, and beta-alanine metabolism. The logistic algorithm's values of the area under the curve (AUC)were 1.000 and 0.995 for training and validation cohorts, and sensitivity is 0.962, specificity is 1.000, respectively, as determined by comparing various methods. The previously described hub genes were identified as being intimately related to ferroptosis in UC and capable of distinguishing UC patients from controls. By detecting the expression of several genes, this model may aid in diagnosing UC and understanding the etiology and treatment of the disease.

Therapy Used to Promote Disease Remission Targeting Gut Dysbiosis, in UC Patients with Active Disease.

Ulcerative colitis (UC) is a relapsing non-transmural chronic inflammatory disease of the colon characterized by bloody diarrhea. The etiology of UC is unknown. The goal is to reduce the inflammation and induce disease remission in UC patients with active disease. The aim of this study is to investigate the innovative treatment method used to promote disease remission in UC patients with active disease targeting gut dysbiosis. Immunosuppressants such as TNF-α blocker are used to promote disease remission in UC, but it is expensive and with side effects. Probiotic, prebiotic and diet are shown to be effective in maintaining disease remission. Fecal microbiota transplantation (FMT) might be the future therapy option to promote disease remission in UC patients with active disease. However, correct manufacturing and administration of the FMT are essential to achieve successful outcome. A few cohorts with FMT capsules show promising results in UC patients with active disease. However, randomized controlled clinical trials with long-term treatment and follow-up periods are necessary to show FMT capsules' efficacy to promote disease remission in UC patients.

The pharmacological evidence of the chang-yan-ning formula in the treatment of colitis.

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease (IBD) and occurs mainly in the colon. The etiology of UC is rather complex and involves various pathological factors, including genetic susceptibility, dietary intakes, environment, and microbiota. In China, the Chang-Yan-Ning (CYN) formula has been utilized in the clinic to treat gastrointestinal disorders, but its pharmacological evidence remains elusive. The investigation was designed to explore the molecular and cellular mechanisms of CYN. Liquid Chromatography with tandem mass spectrometry (LC/MS) was performed to identify the key components in the formula; Network pharmacology analysis was executed to predict the potential targets of CYN; An experimental murine colitis model was established by utilizing 2% dextran sodium sulfate (DSS), and CYN was administered for 14 days. The pharmacological mechanism of the CYN formula was corroborated by in-vivo and in-vitro experiments, and high throughput techniques including metabolomics and 16S rRNA sequencing. Results: LC/MS identified the active components in the formula, and network pharmacology analysis predicted 37 hub genes that were involved in tumor necrosis factor (TNF), interleukin (IL)-17, hypoxia-inducible factor (HIF) signaling pathways. As evidenced by in-vivo experiments, DSS administration shortened the length of the colon and led to weight loss, with a compromised structure of epithelium, and the CYN formula reversed these pathological symptoms. Moreover, CYN suppressed the levels of pro-inflammatory cytokines, including IL-4, IL-1b, and TNFαin the serum, inhibited the protein abundance of IL17 and HIF-1αand increased PPARγ and CCL2 in the colon, and facilitated the alternative activation of peritoneal macrophages. While peritoneal macrophages of colitis mice enhanced reactive oxygen species (ROS) production in murine intestinal organoids, the ROS level remained stable co-cultured with the macrophages of CYN-treated mice. Furthermore, the decreased microbiota richness and diversity and the prevalence of pathogenic taxa in colitis mice were rescued after the CYN treatment. The altered metabolic profile during colitis was also restored after the therapy. We posit that the CYN therapy attenuates the development and progression of colitis by maintaining the homeostasis of immune responses and microbiota.

Oral manifestations serve as potential signs of ulcerative colitis: A review.

As an immune dysregulation-related disease, although ulcerative colitis (UC) primarily affects the intestinal tract, extraintestinal manifestations of the disease are evident, particularly in the oral cavity. Herein, we have reviewed the various oral presentations, potential pathogenesis, and treatment of oral lesions related to UC. The oral manifestations of UC include specific and nonspecific manifestations, with the former including pyostomatitis vegetans and the latter encompassing recurrent aphthous ulcers, atrophic glossitis, burning mouth syndrome, angular cheilitis, dry mouth, taste change, halitosis, and periodontitis. Although the aetiology of UC has not been fully determined, the factors leading to its development include immune system dysregulation, dysbiosis, and malnutrition. The principle of treating oral lesions in UC is to relieve pain, accelerate the healing of lesions, and prevent secondary infection, and the primary procedure is to control intestinal diseases. Systemic corticosteroids are the preferred treatment options, besides, topical and systemic administration combined with dietary guidance can also be applied. Oral manifestations of UC might accompany or precede the diagnosis of UC, albeit with the absence of intestinal symptoms; therefore, oral lesions, especially pyostomatitis vegetans, recurrent aphthous ulcer and periodontitis, could be used as good mucocutaneous signs to judge the occurrence and severity of UC, thus facilitating the early diagnosis and treatment of UC and avoiding severe consequences, such as colon cancer.

Probiotic-Based Intervention in the Treatment of Ulcerative Colitis: Conventional and New Approaches.

Although there are number of available therapies for ulcerative colitis (UC), many patients are unresponsive to these treatments or experience secondary failure during treatment. Thus, the development of new therapies or alternative strategies with minimal side effects is inevitable. Strategies targeting dysbiosis of gut microbiota have been tested in the management of UC due to the unquestionable role of gut microbiota in the etiology of UC. Advanced molecular analyses of gut microbiomes revealed evident dysbiosis in UC patients, characterized by a reduced biodiversity of commensal microbiota. Administration of conventional probiotic strains is a commonly applied approach in the management of the disease to modify the gut microbiome, improve intestinal barrier integrity and function, and maintain a balanced immune response. However, conventional probiotics do not always provide the expected health benefits to a patient. Their benefits vary significantly, depending on the type and stage of the disease and the strain and dose of the probiotics administered. Their mechanism of action is also strain-dependent. Recently, new candidates for potential next-generation probiotics have been discovered. This could bring to light new approaches in the restoration of microbiome homeostasis and in UC treatment in a targeted manner. The aim of this paper is to provide an updated review on the current options of probiotic-based therapies, highlight the effective conventional probiotic strains, and outline the future possibilities of next-generation probiotic and postbiotic supplementation and fecal microbiota transplantation in the management of UC.

Critical role of interferons in gastrointestinal injury repair

The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

Fecal Microbiota Transplantation as Therapy for Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis.

Aim Increasing evidence supports the role of the gut microbiota in the etiology of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) is a highly effective treatment against recurrent Clostridium difficile infection; however, its efficacy in UC is still controversial. A systematic review and meta-analysis was conducted to evaluate the efficacy and safety of FMT for treatment of active UC. Methods We searched Cochrane, Medline, Web of Science, and Embase from inception to February 2020. Randomized controlled trials (RCTs) recruiting adults with active UC, which compared FMT with controls, were eligible. The primary outcome was combined clinical remission with endoscopic remission/response. Secondary outcomes included clinical remission, endoscopic remission, and serious adverse events. Relative risk (RR) with 95% confidence interval (CI) is reported. Results Five RCTs with 292 participants were eligible for inclusion. When data were pooled for all patients, FMT was associated with a higher combined clinical remission with endoscopic remission/response; the RR of combined outcome not achieving after FMT vs. control was 0.79 (95% CI 0.70-0.88). FMT delivered via lower gastrointestinal route was superior to upper gastrointestinal route with regard to combined clinical remission with endoscopic remission/response (RR = 0.79, 95% CI 0.70-0.89). FMT with pooled donor stool (RR = 0.69, 95% CI 0.56-0.85) and higher frequency of administration (RR = 0.76, 95% CI 0.62-0.93) may be more effective with regard to clinical remission. There was no statistically significant difference in serious adverse events with FMT compared with controls (RR = 0.98, 95% CI 0.93-1.03). Conclusion FMT shows a promising perspective with comparable safety and favorable clinical efficacy for the treatment of active UC in the short term. However, further larger, more rigorously conducted RCTs of FMT in UC are still needed in order to resolve the controversial questions.

Efficacy and Safety of Melatonin as an Adjunctive Therapy on Clinical, Biochemical, and Quality of Life in Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon. The exact etiology of UC is unknown, but the role of autoimmunity and activated inflammatory cascade is quite clear. Melatonin possesses anti-inflammatory and immune-modulative properties in animal and clinical trials. The aim of the present study was to evaluate the efficacy and safety of oral melatonin as an adjudicative therapy in clinical, biochemical, and quality of life in UC patients. Thirty patients diagnosed with mild to moderate UC, were randomly allocated to either receive melatonin (3 mg/d) or the placebo group for three months. Simple clinical colitis activity index (SCCAI), fecal calprotectin (FC), C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), and Sf-36 questionnaire have been used for assessment at the baseline and the end of the trial. Melatonin significantly improve SCCAI score, FC, role-emotional, energy and general health relative to placebo (p = 0.03, 0.05, 0.002, 0.032, 0.004 respectively). Regarding CRP, ESR, and the other components of SF-36 there is not any significant difference between melatonin and placebo group. Melatonin supplementation over a three-month period is effective and safe in improving clinical index, FC, and some quality of life in patients with mild to moderate UC.

Діагностична цінність клініко-лабораторних параметрів у діагностиці неспецифічного виразкового коліту

The etiology of ulcerative colitis is still unknown. The number of works dealing with a comprehensive assessment of the role of clinical, laboratory, endoscopic, as well as immunological and genetic factors in the formation of unfavorable forms of ulcerative colitis is extremely small, and their results seem ambiguous. The purpose of the study was to determine the diagnostic value of clinical and laboratory signs in relation to verification of the depth of endoscopic lesion in patients with ulcerative colitis. Material and methods. 68 patients with ulcerative colitis (36 men and 32 women) were examined. The average age was 38.0±4.5 years. All patients were inspected with colonoscopy. Clinical, laboratory, immunological research, as well as computed tomography were carried out. Disease activity was determined according to the Truelove-Witts classification. Results and discussion. The obtained results showed that all intestinal symptoms (stool frequency more than 4 times a day, abdominal pain, tenesmus, hematochezia) had a reliable diagnostic value (р&lt;0.05) in the presence of contact vulnerability and ulceration of the intestinal mucosa. The greatest sensitivity was characteristic of abdominal pain (94.1 [84.1-96.3]). It was found that the diagnostic sensitivity of tachycardia and uveitis is unreliable. Among the clinical indicators, the greatest diagnostic value was established for anemic syndrome (p&lt;0.05), among additional signs was for sclerosing cholangitis (p&lt;0.05). With regard to laboratory parameters, the diagnostic value was proven for hemoglobin levels &lt;90 g/l (p&lt;0.05) and hypoproteinemia (p&lt;0.05). The diagnostic concentration of C-reactive protein for predicting a mucosal defect was determined at a level of more than 10 mg/L in terms of sensitivity and specificity (p&lt;0.05). The level of fecal calprotectin more than 200 μg/g (p&lt;0.05) was highly sensitive and highly specific. Conclusion. The study showed the possibilities of computed tomography for verifying of ulcerative defects. The method is highly sensitive in ulcerative colitis (sensitivity is 95.6 [85.9-97.1], specificity is (96.7 [83.3-99.4]), with a low probability of false-negative and false-positive results (p&lt;0.05)

Virom of intestinal canal and ulcerative colitis: new facets of interaction

Various lifestyle facts influence on microbial landscape of gut and change variety of microbiota with ulcerative colitis. New technologies of nucleotide sequencing, innovating statistics and bioinformatics grade into presentation about etiology and pathogenesis of some illness, for example ulcerative colitis. Current studies demonstrate that microbiome of gut acquaint with eukaryotic and prokaryotic viruses, which make virome of gut and be much part of microbial eco-system of intestinal tract. Number of bacteriophages and viruses escalete in the context of environmental stress so microbiome of the digestive tract disturbed. When we open specific microbiota, which associated with etiology of ulcerative colitis, we will create new treatment modality. Drive of this review is generalization of information about involvement with virome in ulcerative colitis becoming. For searching the literature were use systems PubMed and GoogleScholar with keywords: ulcerative colitis, gut virome, gut microbiome. Nowadays in the literature have limited but necessary information about this question. It requires accumulation scientifi c facts for integrated data.

Oral Janus kinase inhibitors for maintenance of remission in ulcerative colitis.

Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.

Assessment of the Changes in Mitochondrial Gene Polymorphism in Ulcerative Colitis and the Etiology of Ulcerative Colitis-associated Colorectal Cancer

Mitochondria are energy-producing organelles, and dysfunction in these organelles causes various types of disease. Although several studies have identified mutations in nuclear DNA that are associated with the etiology of ulcerative colitis (UC), information regarding mitochondrial DNA (mtDNA) in UC is limited. This study aimed to investigate the mitochondrial DNA polymorphism underlying the etiology of UC and UC-associated colorectal cancer. Next-generation sequencing was performed to assess mitochondrial DNA mutations in 12 patients with UC-associated cancer. The mtDNA mutations in the non-neoplastic mucosa, tumor tissues, and healthy controls were compared. The incidence of mutations of nicotinamide adenine dinucleotide phosphate ubiquinone oxidase subunit, ATP synthetase, and tRNA was higher in non-neoplastic mucosa in those with UC compared with the healthy controls. However, no statistically significant differences were observed in mutations between the tumor tissues and non-neoplastic mucosa in UC. Significant mutations in mtDNA were observed in the non-neoplastic mucosa of patients with UC-associated cancer.

Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis.

Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.

Evaluating tofacitinib citrate in the treatment of moderate-to-severe active ulcerative colitis: design, development and positioning of therapy.

The etiology of ulcerative colitis (UC) is complex and involves a host of genetic, epigenetic and environmental factors. Over the last thirty years, signaling pathways like the Janus kinase (JAK) signaling pathway have been implicated in its pathogenesis. Pharmacologic blockade of this pathway is available through several small molecule inhibitors, including tofacitinib. Tofacitinib is an orally administered pan-JAK inhibitor that was first approved by the Food and Drug Administration (FDA) for use in rheumatologic disorders such as rheumatoid arthritis and psoriatic arthritis. The FDA approved its use in moderate-to-severe active ulcerative colitis in 2018. The aim of this review will be to discuss the role of tofacitinib in ulcerative colitis. We will discuss the role of JAK-STAT signaling, clinical data available for tofacitinib, and the safety profile for this therapy. Tofacitinib’s place in the UC management algorithm is currently being debated. This effective oral therapy is poised to be a mainstay of UC therapeutics. This review will highlight the key clinical features and detail the UC experience to date.

Elucidating the gut microbiome of ulcerative colitis: bifidobacteria as novel microbial biomarkers.

Ulcerative colitis (UC) is associated with a substantial alteration of specific gut commensals, some of which may be involved in microbiota-mediated protection. In this study, microbiota cataloging of UC patients by 16S rRNA microbial profiling revealed a marked reduction of bifidobacteria, in particular the Bifidobacterium bifidum species, thus suggesting that this taxon plays a biological role in the aetiology of UC. We investigated this further through an in vivo trial by testing the effects of oral treatment with B. bifidum PRL2010 in a wild-type murine colitis model. TNBS-treated mice receiving 10(9) cells of B. bifidum PRL2010 showed a marked reduction of all colitis-associated histological indices as well as maintenance of mucosal integrity as it was shown by the increase in the expression of many tight junction-encoding genes. The protective role of B. bifidum PRL2010, as well as its sortase-dependent pili, appears to be established through the induction of an innate immune response of the host. These results highlight the importance of B. bifidum as a microbial biomarker for UC, revealing its role in protection against experimentally induced colitis.