| 1. |
- Amcoff, Karin, 1975-, et al.
(författare)
-
Concordance in Anti-OmpC and Anti-I2 Indicate the Influence of Genetic Predisposition : Results of a European Study of Twins with Crohn's Disease
- 2016
-
Ingår i: Journal of Crohn's & Colitis. - Oxford, United Kingdom : Oxford University Press. - 1873-9946 .- 1876-4479. ; 10:6, s. 695-702
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort.Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Örebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay.Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and -0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA.Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.
|
|
| 2. |
|
|
| 3. |
- Bergemalm, Daniel, 1977-, et al.
(författare)
-
Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
-
Ingår i: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
|
|
| 4. |
|
|
| 5. |
- Hamer, Henrike M., et al.
(författare)
-
Butyrate enemas do not affect human colonic MUC2 and TFF3 expression
- 2010
-
Ingår i: European Journal of Gastroenterology and Hepathology. - 0954-691X .- 1473-5687. ; 22:9, s. 1134-1140
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction The colonic mucus layer plays an important role in the protection of the intestinal epithelium and mainly consists of mucin glycoproteins (primarily MUC2 in the colon) trefoil factor 3 (TFF3) and secretory IgA. Butyrate is a major end product of fermentation of dietary fibres and is associated with beneficial effects on colonic health. Earlier in-vitro and animal studies showed that butyrate modulates MUC2 and TFF3 expression and mucin secretion, although data from human studies are not yet available. Methods Sixteen healthy volunteers and 35 ulcerative colitis (UC) patients in clinical remission self-administered a 60 ml rectal enema containing 100 mmol/l butyrate or placebo once daily for 2 and 3 weeks, respectively. After each treatment, biopsies were taken from the distal sigmoid for quantitative RT-PCR and immunohistochemical analysis of MUC2 and TFF3. In addition, mucosal sections were stained with high iron diamine-alcian blue to distinguish between sialomucins and sulphomucins. To analyse total mucin secretion and secretory IgA concentrations, 24 h faeces were collected during the day before the endoscopic examination. Results The butyrate intervention did not significantly modulate the expression of MUC2 ( fold change: 1.04 and 1.05 in healthy volunteers and ulcerative colitis patients, respectively) or TFF3 (fold change: 0.91 and 0.94 in healthy volunteers and UC patients, respectively). Furthermore, the percentage of sialomucins, mucus secretion and secretory IgA concentrations were not affected by the butyrate intervention in both the groups. Conclusion Butyrate exposure in healthy volunteers and UC patients in remission did not affect the measured parameters of the colonic mucus layer. Eur J Gastroenterol Hepatol 22: 1134-1140 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
|
|
| 6. |
- Hamer, Henrike M., et al.
(författare)
-
Butyrate modulates oxidative stress in the colonic mucosa of healthy humans
- 2009
-
Ingår i: Clinical Nutrition. - Amsterdam : Churchill Livingstone. - 0261-5614 .- 1532-1983. ; 28:1, s. 88-93
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Butyrate, a short-chain fatty acid produced by colonic microbial fermentation of undigested carbohydrates, has been implicated in the maintenance of colonic health. This study evaluates whether butyrate plays a role in oxidative stress in the healthy colonic mucosa. METHODS: A randomized, double blind, cross-over study with 16 healthy volunteers was performed. Treatments consisted of daily rectal administration of a 60 ml enema containing 100 mM sodium butyrate or saline for 2 weeks. After each treatment, a blood sample was taken and mucosal biopsies were obtained from the sigmoid colon. In biopsies, the trolox equivalent antioxidant capacity, activity of glutathione-S-transferase, concentration of uric acid, glutathione (GSH), glutathione disulfide and malondialdehyde, and expression of genes involved in GSH and uric acid metabolism was determined. Secondary outcome parameters were CRP, calprotectin and intestinal fatty acid binding protein in plasma and histological inflammatory scores. RESULTS: Butyrate treatment resulted in significantly higher GSH (p<0.05) and lower uric acid (p<0.01) concentrations compared to placebo. Changes in GSH and uric acid were accompanied by increased and decreased expression, respectively, of their rate limiting enzymes determined by RT-PCR. No significant differences were found in other parameters. CONCLUSIONS: This study demonstrated that butyrate is able to beneficially affect oxidative stress in the healthy human colon.
|
|
| 7. |
- Hamer, Henrike M., et al.
(författare)
-
Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission
- 2010
-
Ingår i: Clinical Nutrition. - Amsterdam, Netherlands : Elsevier. - 0261-5614 .- 1532-1983. ; 29:6, s. 738-744
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Butyrate, produced by colonic fermentation of dietary fibers is often hypothesized to beneficially affect colonic health. This study aims to assess the effects of butyrate on inflammation and oxidative stress in subjects with chronically mildly elevated parameters of inflammation and oxidative stress.Methods: Thirty-five patients with ulcerative colitis in clinical remission daily administered 60 ml rectal enemas containing WO mM sodium butyrate (n = 17) or saline (n = 18) during 20 days (NCT00696098). Before and after the intervention feces, blood and colonic mucosal biopsies were obtained. Parameters of antioxidant defense and oxidative damage, myeloperoxidase, several cytokines, fecal calprotectin and CRP were determined.Results: Butyrate enemas induced minor effects on colonic inflammation and oxidative stress. Only a significant increase of the colonic IL-10/IL-12 ratio was found within butyrate-treated patients (p = 0.02), and colonic concentrations of CCL5 were increased after butyrate compared to placebo treatment (p = 0.03). Although in general butyrate did not affect colonic glutathione levels, the effects of butyrate enemas on total colonic glutathione appeared to be dependent on the level of inflammation.Conclusion: Although UC patients in remission were characterized by low-grade oxidative stress and inflammation, rectal butyrate enemas showed only minor effects on inflammatory and oxidative stress parameters.
|
|
| 8. |
- Kurilshikov, Alexander, et al.
(författare)
-
Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
-
Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
|
|
| 9. |
- Vanhoutvin, Steven A. L. W., et al.
(författare)
-
Butyrate-induced transcriptional changes in human colonic mucosa
- 2009
-
Ingår i: PLoS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:8, s. e6759-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Fermentation of dietary fiber in the colon results in the production of short chain fatty acids (mainly propionate, butyrate and acetate). Butyrate modulates a wide range of processes, but its mechanism of action is mostly unknown. This study aimed to determine the effects of butyrate on the transcriptional regulation of human colonic mucosa in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Five hundred genes were found to be differentially expressed after a two week daily butyrate administration with enemas. Pathway analysis showed that the butyrate intervention mainly resulted in an increased transcriptional regulation of the pathways representing fatty acid oxidation, electron transport chain and oxidative stress. In addition, several genes associated with epithelial integrity and apoptosis, were found to be differentially expressed after the butyrate intervention. CONCLUSIONS/SIGNIFICANCE: Colonic administration of butyrate in concentrations that can be achieved by consumption of a high-fiber diet enhances the maintenance of colonic homeostasis in healthy subjects, by regulating fatty acid metabolism, electron transport and oxidative stress pathways on the transcriptional level and provide for the first time, detailed molecular insight in the transcriptional response of gut mucosa to butyrate.
|
|
| 10. |
- Zheng, Tenghao, et al.
(författare)
-
Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
- 2024
-
Ingår i: Journal of Crohn's and Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 18:3, s. 349-359
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
|
|
