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Inflammatory disease of the colon: ulcerative colitis and Crohn's colitis.

Ulcerative colitis differs from Crohn's colitis in several ways. In ulcerative colitis the disease is limited to the mucosa and, occasionally, the submucosa; Crohn's colitis may involve all layers of the large intestine. Ulcerative colitis almost always begins in the rectum, is diffuse, and spreads proximally. Crohn's colitis may spare the rectum and has a patchy distribution. Perianal fistulas and ulcers are rare in ulcerative colitis but are common in Crohn's colitis. Granulomas and giant cells are not found in ulcerative colitis but are seen in the majority of patients with Crohn's colitis. Colonic and extraintestinal symptoms in the two illnesses may be indistinguishable but growth failure is far more severe in Crohn's colitis and may precede intestinal symptoms by months to years. Cancer of the colon is a risk in patients with either ulcerative or Crohn's colitis but is far more common in the former. It is important to distinguish between ulcerative colitis and Crohn's colitis because response to treatment and prognosis are different. Although neither condition can be cured by medical management, patients with ulcerative colitis may respond more frequently. Unfortunately, in the pediatric age range most cases of ulcerative and Crohn's colitis may be classified as moderate to severe. Fortunately for patients with ulcerative colitis, total colectomy with ileostomy will result in cure of illness. Patients with Crohn's colitis who require surgery may obtain remission of symptoms, but the disease is likely to recur in the small intestine.

Adrenal Cortex Hormones

Integrative multi-omics analyses suggest a candidate microbial metabolite-associated host gene network in ulcerative colitis.

Ulcerative colitis (UC) is associated with gut microbial dysbiosis, but the host molecular alterations potentially linked to microbially derived metabolites remain incompletely understood. We integrated Mendelian randomization (MR), microbial metabolite annotation, computational target prediction, colonic transcriptomics, network analysis, and machine learning. MiBioGen microbiome GWAS data were used as exposures and FinnGen Release 12 ULCERENTER as the outcome. Metabolites linked to MR-prioritized taxa were retrieved from GutMGene, and human targets were predicted using SwissTargetPrediction and SEA. UC-related genes were defined by integrating differential expression analysis and WGCNA and then intersected with predicted metabolite targets. MR prioritized one family and eight genera showing nominal genetically supported associations with UC, but none remained significant after Benjamini-Hochberg FDR correction. Three prioritized genera were linked to 15 microbe-metabolite records, corresponding to 13 unique metabolites; nine were retained for target prediction, yielding 277 unique predicted human targets. Transcriptomic analysis identified 1,530 DEGs and a 312-gene MEgrey60 module, with 273 overlapping genes, producing 1,569 unique UC-related genes. Their intersection with the 277 predicted targets yielded 47 candidate genes. Enrichment analyses highlighted mainly metabolic and lipid-related processes. Random Forest showed the highest mean AUC across the two independent external benchmarking cohorts, and SHAP prioritized EPHX1, HSD17B2, IGFBP5, and MMP10. IBDome analysis showed inflammation-associated expression differences in these genes. This study provides a genomics-informed, hypothesis-generating framework that prioritizes candidate microbe-metabolite-host relationships in UC for future experimental validation.

Humans

Immunological studies in ulcerative colitis. VIII. Antibodies to colon antigen in patients with ulcerative colitis, Crohn's disease, and other diseases.

Sera from patients with ulcerative colitis or Crohn's disease had elevated titers to colon antigen from germ-free rats significantly more often than sera from patients with gastroenteritis, irritable colon, non-gastrointestinal diseases, and healthy controls. Elevated anticolon titers in significant frequency were also found in patients with liver cirrhosis, urinary tract infections, and in polyposis coli and their relatives. Females with ulcerative colitis had, on an average, higher titers than men especially in the age group 30 years and over. In Crohn's disease the antibody titers often increased with time--as opposed to those in ulcerative colitis and non-gastrointestinal diseases. In conjunction with results published earlier, the present work supports the assumption that the antibodies in ulcerative colitis patients react with antigenic determinants distinct from those recognized by the colon antibodies present in other groups, including patients with Crohn's disease and polyposis.

Adolescent

Genome-wide Association Studies of the Pathogenic Sphingosine-1-Phosphate Gene in Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can lead to malignancies over time. Sphingosine-1-phosphate (S1P) receptor signaling affects lymphocyte trafficking and vascular integrity, influencing intestinal inflammation. This study aimed to identify S1P-related key genes in UC. METHODS: Differentially expressed genes (DEGs) between the UC and control groups were analyzed in the GSE87473 (training) dataset. Genes overlapping between the DEGs and S1P-related genes were considered candidate genes. These genes were incorporated into machine learning algorithms and subjected to expression analysis to identify key genes. Gene functions were determined through a gene–gene interaction network, enrichment analysis, and immune cell infiltration analysis. In addition, transcription factor–mRNA and mRNA–miRNA–lncRNA networks were constructed. Finally, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was performed to evaluate the expression of key candidate genes in UC and control tissues. RESULTS: This study identified two key genes (SPHK2 and SPNS2) associated with UC. Notably, SPHK2 expression was lower and SPNS2 expression was higher in the UC group in both training and validation datasets and in clinical UC tissues (RT-qPCR). The area under the curve values of SPHK2 and SPNS2 exceeded 0.7 in both datasets, indicating that the genes had good diagnostic efficacy for UC. Consistently, the nomogram showed that the two genes had promising diagnostic value in UC. SPHK2 and SPNS2 were found to be localized to the plasma membrane. The correlations of the two genes with different immune cells showed significantly opposite trends. In particular, SPHK2 had the strongest positive correlation with M2 macrophages (r = 0.6) and the strongest negative correlation with neutrophils. Moreover, mRNA–miRNA–lncRNA and transcription factor– mRNA networks of the key genes were constructed. CONCLUSION: This study suggests that SPHK2 and SPNS2 are key genes associated with UC, highlighting their potential as effective diagnostic biomarkers.

Humans

Comparative trial of sulphasalazine and oral sodium cromoglycate in the maintenance of remission in ulcerative colitis.

Patients with ulcerative colitis in remission were randomly allocated to treatment with sulphasalazine (2 g/day) or oral sodium cromoglycate (160 mg/day or 2 g/day), and the relapse rates in these treatment groups were compared during continued treatment for one year. The percentage cumulative relapse rate after 12 months' treatment was 30% in the 33 patients treated with sulphasalazine compared with 71% in the 25 treated with high dose sodium cromoglycate, a highly significant difference (P less than 0.01). Patients allocated low dose sodium cromoglycate were only treated for a maximum of six months, and the relapse rate in these 12 patients was similar to that in patients on the high dose. These results suggest that oral sodium cromoglycate is considerably less effective than sulphasalazine in maintaining remission, and by analogy with results in other trials may be no more effective than placebo tablets.

Adult

IgA-related defective neutrophil chemotaxis in ulcerative colitis.

A case of ulcerative colitis with defective neutrophil chemotaxis, improved after short sulfasalazine therapy, is reported. This is the first case of this disease in which the chemotactic defect was characterized as a serum inhibitor, directed toward autologous and homologous neutrophils and associated with circulating IgA. Preincubation of normal neutrophils with increasing concentrations of patient's serum resulted in a dose-related inhibition, suggesting a stoichiometric relationship between humoral inhibitory power and neutrophils.

Adult

HLA antigens and ulcerative colitis in Japan.

The HLA antigens in 44 cases of ulcerative colitis and 271 control individuals in Japan were studied. The NIH tissue typing method was used according to the new leukocyte nomenclature adapted by the WHO Committee. In normal Japanese populations, the HLA antigens, which were of high frequency, were HLA A2(37.3%), A9(60.9%) and B5 (40.6%). On the contrary, the significantly high frequency of HLA B5 was demonstrated in ulcerative colitis, compared with that in control. Moreover, HLA B5 in cases with ulcerative colitis excluding those with proctitis only, was found with higher frequency than that in total cases. Although the most frequent haplotype was HLA A9-B5 in control, so frequent haplotype was not found in ulcerative colitis. A family study revealed no significant diathesis on the hapolytpe of HLA in ulcerative colitis. The relationship between MLC locus and ulcerative colitis was not yet clarified from the study of one family whose two members suffered from ulcerative colitis.

Adult

Isolation and characterization of colonic tissue-bound antibodies from patients with idiopathic ulcerative colitis.

To determine if specific anticolon antibodies bound to colonic mucosa occur in ulcerative colitis, we obtained surgical specimens of colon from five patients with ulcerative colitis, one patient with diverticulitis, and three control subjects with carcinoma. Two specimens of ileum and cecum were also obtained from patients with Crohn ileocolitis. Tissue was homogenized and washed and bound Ig was eluted by citrate buffer, pH 3.2. Concentrated eluates of all specimens from patients with ulcerative colitis reacted with antisera to kappa and gamma and not with antisera to alpha and mu chains. Corresponding eluates from all other specimens did not react with these antisera, but did react with antialbumin. The presence of IgG in ulcerative colitis eluates was also determined by immunoelectrophoresis, immunocoprecipitation, and affinity chromatography with antisera against human IgG. Indirect immunofluorescence and uptake of radiolabeled antibody demonstrated antigenic sites in diseased colonic epithelium of biopsy specimens obtained from six additional patients with ulcerative colitis and three patients with idiopathic proctitis, but not in patients with Crohn disease, nonspecific diarrhea, and bacillary dysentery and control subjects. Although the role of colitis colon-bound antibody in the pathogenesis of ulcerative colitis is unclear, local antibody-antigen complexes may initiate colonic epithelial cytolysis by various immunologically mediated mechanisms.

Autoantibodies

Immunohistochemical and electronmicroscopic observations on the local immune response in ulcerative colitis.

Inflammatory cell infiltrates in ulcerative colitis have been investigated by means of the immunoperoxidase method and by electronmicroscopy. Considerable morphological and functional changes of the local plasma cell population have been found. The absolute number of plasma cells is raised with a marked increase of IgG-cells and a relative decrease of IgA-cells. In particular complement (C3) has been demonstrated at the basement membrane of the surface epithelium and between epithelial cells. The significance of these findings, as a local humoral immune response, is briefly considered, with regard to their possible pathogenetic importance in aggravating and perpetuating the disease.

Colitis, Ulcerative

Immunohistochemical identification of lysozyme in intestinal lesions in ulcerative colitis and Crohn's disease.

Lysozyme (LZM) was identified in ulcerative colitis in granulocytes, monocytes, and macrophages of the intestinal lamina propria. In contrast with findings in normal colon or rectum, in ulcerative colitis LZM was also detected in some mucosal crypt cells and metaplastic Paneth cells. In both ulcerative colitis and Crohn's disease LZM was present in inflammatory cells of crypt abscesses. In Crohn's disease intense LZM staining was seen in epitheloid cell granulomas. The present observations permit one explanation for the raised concentration of serum-LZM in patients with ulcerative colitis and Crohn's disease.

Colitis, Ulcerative

Intercurrent cytomegalovirus colitis in a patient with ulcerative colitis.

Acute intercurrent CMV colitis developed in a patient with UC who was receiving prednisone. CMV infection was suggested by light and electron microscopic study of a rectal biopsy taken during the acute episode and was confirmed by serology done nine months later. The microscopic studies of plastic-embedded tissues demonstrated that infected cells were concentrated in a subendothelial location and were presumably macrophages. Epithelial and endothelial cells were not involved. Steroid therapy and the inflammation and repair process (granulartion tissue) of active UC may have predisposed the present patient to CMV colitis. CMV infection has been reported to be more common in patients with UC than in the general population. Detection of CMV colitis in patients with UC could be of special importance since alteration of immunosuppressive therapy may be indicated.

Acute Disease

Clinical outcome of the first ten years of ulcerative colitis and proctitis.

269 patients with ulcerative colitis and a history of less than 6 months when first seen at St. Mark's Hospital in the decade 1966--75 have been followed for up to 11 years. The outcome has been correlated with the maximum extent of the disease observed within 3 months of presentation. 75 patients required hospital admission, 56 within a year of presentation. Extensive colitis developed in 60 patients. The cumulative probability of the disease being extensive was 21% +/- 3% at 5 years and 29% +/- 4% at 10 years. 25 patients required surgical treatment. The cumulative probability of operation was 8% +/- 2% at 5 years and 15% +/- 4% at 10 years. 19 patients are known to have died. The expected number of deaths was 19.2.

Adolescent

Further studies of sulphasalazine metabolism in the treatment of ulcerative colitis.

Sixty-four outpatients with ulcerative colitis receiving maintenance treatment with sulphasalazine were studied to relate disease activity to serum concentrations of sulphapyridine. Of 43 patients in remission, 32 had serum sulphapyridine levels over 20 microgram/ml. Ten of the 21 patients with active disease were for various reasons taking inadequate doses of sulphasalazine, as indicated by low serum sulphapyridine levels, and of the remaining 11 patients, who had serum levels over 20 microgram/ml, nine had faecal stasis proximal to active distal colitis and went into remission when treated with hydrophilic colloid or bran and an unchanged sulphasalazine dosage. This suggests that to be effective the metabolites of sulphasalazine must be delivered in the faeces to the lumen of the diseased distal segment of the colon. High serum concentrations of sulphapyridine produce side effects; therefore slow acetylators of sulphapyridine need lower doses of sulphasalazine. Estimations of serum sulphapyridine concentrations, as well as identifying the patient's acetylation phenotype, can also be useful in assessing his compliance with treatment.

Adolescent

Shared CD4+ T cell receptor specificity groups in Crohn's disease and ulcerative colitis.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is marked by chronic intestinal inflammation and dysregulated immunity. Although UC and CD affect different areas of the gastrointestinal tract, both diseases share aberrant CD4+ memory T cell responses, with HLA-DRB1 as a major genetic risk factor. HLA-DRB1 encodes MHC class II molecules that influence the CD4+ T cell receptor (TCR) repertoire, yet how these genotypes shape TCR specificity in IBD remains unclear. Here, we genotyped HLA-DRB1 and profiled 3.13 million TCRβ sequences from circulating memory CD4+ T cells in 33 IBD patients (20 UC, 13 CD) and 14 healthy controls. Using the GLIPH2 algorithm, we distilled 468,441 candidates based on CDR3 amino acid motifs into 440 high-confidence TCR specificity groups significantly enriched among individuals sharing HLA-DRB1 alleles. Notably, 5 specificity groups were IBD-enriched and were shared between UC and CD, suggesting common antigen targets in both diseases. We also observed increased frequencies of clonally expanded cytotoxic GZMB+PRF1+ memory CD4+ T cells and KIR+CD8+ T cells in a subset of risk-allele carriers with IBD. These findings elucidate distinct, HLA-linked TCR specificity groups in IBD and provide mechanistic insights that may advance antigen discovery and personalized medicine.

Humans

Growth retardation in children with ulcerative colitis: the effect of medical and surgical therapy.

The growth of 37 children with ulcerative colitis have been analyzed. While conventional growth charts showed only percentile changes in height, height data plotted on Tanner et al.'s growth charts showed increases and decreases in growth velocity. Growth retardation is a prominent complication of ulcerative colitis with onset on bowel symptoms. Both ulcerative colitis and "high-dose" steroid therapy (greater than 12 mg/sq m/day of cortisol) can hinder growth but in some instances there is a growth spurt after high-dose steroid therapy. "Low-dose" steroid therapy does not retard growth. Colectomy is more effective than high-dose steroid therapy in reversing the growth retardation caused by ulcerative colitis and is of greatest value if not delayed too long. Growth following subtotal colectomy with ileorectal anastomosis (Aylett procedure) is not likely to be as much as that after subtotal colectomy with ileostomy. Growth retardation is infrequently the only indication for surgical intervention but ileostomy and colectomy are appropriate for this complication of ulcertive colitis in itself when not improved by adequate medical treatment.

Adolescent

Long-term prognosis of ulcerative colitis with onset in childhood or adolescence.

From 1955 through 1974, 336 patients with ulcerative colitis diagnosed before age 21 years were studied. In 93 patients (29%), a blood relative had ulcerative colitis, one case of Crohn's disease being found. The total colon was involved in 63% of patients; the entire colon or all but the rectal stump was removed in 35%. Eighteen patients died, nine of carcinoma of the colon. Sixty-five percent of patients had symptoms for longer than 6 months before the diagnosis of ulcerative colitis. If the diagnosis was delayed more than 24 months, there was a statistically significant correlation with increased rate of operations and complications and less good quality of life. When the 20-year study period was divided into two 10-year periods, the operative and complication rates were significantly different. Early diagnosis and treatment appear to improve the long-term prognosis of young patients with ulcerative colitis.

Acute Disease

Multicentric colonic lymphoma complicating ulcerative colitis.

A 72-year-old female with ulcerative colitis of 30 years duration underwent total proctocolectomy for a cecal mass thought to be an adenocarcinoma. Pathologic examination of the colon revealed 22 tumors, all of which proved to be malignant lymphoma, histiocytic type. Thirteen cases of non-Hodgkins malignant lymphoma and 2 cases of Hodgkins disease of the colon arising in ulcerative colitis are reviewed and discussed.

Aged

Fecal bile acids and cholesterol metabolites of patients with ulcerative colitis, a high-risk group for development of colon cancer.

Patients with chronic ulcerative colitis are at increased risk of developing carcinoma of the colon. It has been shown that the concentration of fecal bile acids and neutral sterols was higher in cancer patients than in the comparable healthy controls. Fecal neutral steroids and bile acids were measured in patients with ulcerative colitis, family controls who were immediate relatives of patients, patients with other digestive diseases, and healthy unrelated controls. The fecal excretion of cholesterol, coprostanol, and cholestane-3beta, 5alpha, 6beta-triol was higher in patients with ulcerative colitis than in other groups. Patients with other diseases, family controls, and unrelated controls excreted comparable levels of neutral sterols. Patients with ulcerative colitis excreted levels of bile acids in their feces comparable to those excreted by other groups. These findings suggest that possible interactions between cholesterol metabolites and colonic epithelial cells may be relevant in colon carcinogenesis.

Adult