Characterization of Stool Virome in Children Newly Diagnosed With Moderate to Severe Ulcerative Colitis.
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SUBMITTER: Tokarz R
PROVIDER: S-EPMC7108593 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundInflammatory bowel disease (IBD) is characterized by gut dysbiosis. To date, the large bowel microbiota has been in focus. However, the microbiota of the small intestine may also be of importance, as the small bowel is a site for the induction and control of mucosal immune responses, which can be modulated by constituents of the local microbiota.MethodsDuodenal fluids were collected during diagnostic work-up of treatment-naïve children who were suspected of having IBD. The duodenal fluids were analyzed by pyrosequencing (average of 32,000 reads/sample, read length of 500 nucleotides). After diagnosis, the duodenal microbiota of subjects with ulcerative colitis (N = 8) or Crohn's disease (N = 5), and non-IBD controls (N = 8) were compared.ResultsPyrosequencing revealed that the duodenal microbiota of children with ulcerative colitis contained fewer Operational Taxonomic Units (OTUs) per individual than the duodenal microbiota of the controls (P = 0.005). This reduction in richness of the duodenal microbiota was seen for three major phyla: Firmicutes, Actinobacteria, and Bacteroidetes. Several bacterial genera were detected less frequently in the children with ulcerative colitis than in the non-IBD controls, including Collinsella (P = 0.001), Lactobacillus (P = 0.007), and Bacillus (P = 0.007), as well as a non-identified member of the order Sphingobacteriales (P = 0.007).ConclusionsIn this pilot study, we show that the duodenal microbiota of children with ulcerative colitis exhibits reduced overall richness, despite the fact that the inflammation is primarily localized to the colon. These results should be corroborated in a larger study.
| S-EPMC5648149 | biostudies-literature
Project description:To characterize rectal histology in an inception cohort of children newly diagnosed with ulcerative colitis (UC) and to explore its relationship with clinical indices of disease severity. The PROTECT (Predicting Response to Standardized Pediatric Colitis Therapy) Study enrolled children 17 years of age and younger newly diagnosed with UC. Baseline rectal biopsies were evaluated for acute and chronic inflammation, eosinophilic inflammation (peak eosinophil count > 32 eosinophils/high powered field, eosinophilic cryptitis or abscesses), and architectural/nonarchitectural chronic changes. Correlation with clinical indices including Mayo endoscopy subscore and Pediatric Ulcerative Colitis Activity Index was performed. Rectal biopsies from 369 patients (mean age, 12.9±3.1?y, 50% female) were reviewed. Cryptitis was found in 89%, crypt abscesses in 25%, and eosinophilic inflammation in 58%. Crypt distortion/atrophy was present in 98% of specimens. Higher grades of acute and chronic inflammation were associated with the presence of basal plasmacytosis (P<0.0001), basal lymphoid aggregates (P<0.0001), and surface villiform changes (P<0.0001). A severe Mayo endoscopy subscore was most common among those with severe acute and chronic inflammation, although this relationship was not linear. Severe Pediatric Ulcerative Colitis Activity Index scores were associated with the absence of or only mild eosinophilic inflammation (<32 eosinophils/high powered field) (P<0.03) and the presence of surface villiform changes (P<0.005). Acute and chronic inflammation, eosinophilic inflammation and chronic changes are common in children newly diagnosed with UC. The clinical and biological implication of low to absent eosinophilic inflammation and the presence of surface villiform changes requires further study.
| S-EPMC5636675 | biostudies-literature
Project description:ObjectiveThe pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC.DesignDeep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2.ResultsIn UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC.ConclusionWe demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.
| S-EPMC6582748 | biostudies-literature
Project description:OBJECTIVES:We examined the fecal virome and bacterial community composition of children with Crohn disease (CD), ulcerative colitis (UC), and healthy controls to test the hypothesis that unique patterns of viral organisms and/or presence of bacterial pathogens may be identified that could contribute to the pathogenesis of pediatric inflammatory bowel disease (IBD). METHODS:Fecal samples from 24 children (mean 12.2 years) with CD (n?=?7) or UC (n?=?5) and similar aged controls (n?=?12) were processed to determine individual viromes. Viral sequences were identified through translated protein sequence similarity search. Bacterial microbiota were determined by sequencing of the V4 region of the 16S rRNA gene. RESULTS:Only a few human viruses were detected, so virome analyses focused on bacterial viruses. The relative abundance of Caudovirales was greater than that of Microviridae phages in both IBD and healthy controls. Caudovirales phages were more abundant in CD (mean 80.8%) than UC (48.8%) (P?=?0.05) but not controls. The richness of viral strains in Microviridae but not Caudovirales was higher in controls than CD (P?=?0.05) but not UC cases. No other measure of phage abundance, richness, or Shannon diversity showed significant difference between the 2 IBD and control groups. Bacterial microbiota analysis revealed that IBD diagnosis, albumin, hemoglobin, erythrocyte sedimentation rate, and probiotic supplementation correlated to the composition of gut bacterial microbiota. CONCLUSIONS:Minor patterns in gut virome and bacterial community composition distinguish pediatric IBD patients from healthy controls. Probiotics are associated with bacterial microbiota composition. These exploratory results need confirmation in larger studies.
| S-EPMC6310095 | biostudies-literature
Project description:A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-? antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-? antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.
| S-EPMC7117094 | biostudies-literature
Project description:BACKGROUND:Sustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6. METHODS:Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ?2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52. RESULTS:The proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage-point difference (?) 12.6%; 95% confidence interval [CI], 5.2-20.0]; RBS: 47.3% vs 28.9% [?18.4%; 95% CI, 10.1-26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab-treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; ?39.8%; 95% CI, 22.7-56.9; RBS: 56.7% vs 20.9%; ?35.7%; 95% CI, 22.3-49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist-naive and antagonist-failure patients. CONCLUSION:Compared with placebo, 35%-40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.
| S-EPMC6499937 | biostudies-literature
Project description:Patients with ulcerative colitis (UC) have an altered gut microbiota composition, but the microbial relationship to disease activity needs to be further elucidated. Therefore, temporal dynamics of the fecal microbial community during remission and flare was determined. Fecal samples were collected at 2-6 time-points from UC patients during established disease (cohort EST) and at diagnosis (cohort NEW). Sampling range for cohort EST was 3-10 months and for cohort NEW 36 months. Relapses were monitored for an additional three years for cohort EST. Microbial composition was assessed by Genetic Analysis GA-map Dysbiosis Test, targeting ≥ 300 bacteria. Eighteen patients in cohort EST (8 with maintained remission and 10 experiencing a flare), provided 71 fecal samples. In cohort NEW, 13 patients provided 49 fecal samples. The microbial composition showed no clustering related to disease activity in any cohort. Microbial dissimilarity was higher between than within patients for both cohorts, irrespective of presence of a flare. Microbial stability within patients was constant over time with no major shift in overall composition nor modification in the abundance of any specific species. Microbial composition was not affected by intensified medical treatment or linked to future disease course. Thus in UC, the gut microbiota is highly stable irrespective of disease stage, disease activity or treatment escalation. This suggests that prolonged dietary interventions or repeated fecal transplantations are needed to be able to induce permanent alterations of the gut microbiota.
| S-EPMC8060394 | biostudies-literature
Project description:AIM:To directly visualize Helicobacter pylori (H. pylori) by the highly sensitive and specific technique of immunohistochemical staining in colonic tissue from patients newly diagnosed with ulcerative colitis (UC). METHODS:Colonoscopic biopsies from thirty patients with newly diagnosed UC and thirty controls were stained with Giemsa stain and immunohistochemical stain for detection of H. pylori in the colonic tissue. Results were confirmed by testing H. pylori Ag in the stool then infected patients were randomized to receive either anti H. pylori treatment or placebo. RESULTS:Twelve/30 (40%) of the UC patients were positive for H. pylori by Giemsa, and 17/30 (56.6%) by immunohistochemistry stain. Among the control group 4/30 (13.3%) and 6/30 (20 %) were positive for H. pylori by Giemsa and immunohistochemistry staining respectively. H. pylori was significantly higher in UC than in controls (P = 0.04 and 0.007). All Giemsa positive patients and controls were positive by immunohistochemical stain. Four cases of the control group positive for H. pylori also showed microscopic features consistent with early UC. CONCLUSION:H. pylori can be detected in colonic mucosa of patients with UC and patients with histological superficial ulcerations and mild infiltration consistent with early UC. There seems to be an association between UC and presence of H. pylori in the colonic tissue. Whether this is a causal relationship or not remains to be discovered.
| S-EPMC6232561 | biostudies-literature
Project description:Controversy exists regarding management of children newly diagnosed with immune thrombocytopenic purpura (ITP). Drug treatment is usually administered to prevent severe hemorrhage, although the definition and frequency of severe bleeding are poorly characterized. Accordingly, the Intercontinental Childhood ITP Study Group (ICIS) conducted a prospective registry defining severe hemorrhage at diagnosis and during the following 28 days in children with ITP. Of 1106 ITP patients enrolled, 863 were eligible and evaluable for bleeding severity assessment at diagnosis and during the subsequent 4 weeks. Twenty-five children (2.9%) had severe bleeding at diagnosis. Among 505 patients with a platelet count less than or equal to 20 000/mm(3) and no or mild bleeding at diagnosis, 3 (0.6%), had new severe hemorrhagic events during the ensuing 28 days. Subsequent development of severe hemorrhage was unrelated to initial management (P = .82). These results show that severe bleeding is uncommon at diagnosis in children with ITP and rare during the next 4 weeks irrespective of treatment given. We conclude that it would be difficult to design an adequately powered therapeutic trial aimed at demonstrating prevention of severe bleeding during the first 4 weeks after diagnosis. This finding suggests that future studies of ITP management should emphasize other outcomes.
| S-EPMC2581983 | biostudies-literature
Project description:AIMS:Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. METHODS:One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss ] and trough plasma concentration at steady state [Ctrough,ss ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates. RESULTS:Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ?8 were 39% (95% CI: 7-70) and 21% (-2-50), respectively. CONCLUSIONS:Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.
| S-EPMC5980553 | biostudies-literature