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Nowak, J., Noble, A., Gordon, H., Harbord, M., Blad, W., Bergemalm, D., . . . Satsangi, J. (2025). Analysis of the circulating methylome in 155 IBD-discordant twin pairs from UK and Scandinavia highlights differential variance and association with active inflammation. Paper presented at 20th Congress of ECCO, Berlin, Germany, February 19-22, 2025. Journal of Crohn's & Colitis, 19(Suppl. 1), i319-i320, Article ID DOP130.
Open this publication in new window or tab >>Analysis of the circulating methylome in 155 IBD-discordant twin pairs from UK and Scandinavia highlights differential variance and association with active inflammation
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no Suppl. 1, p. i319-i320, article id DOP130Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Consistent alterations in DNA methylation across the genome have been well-characterised in inception cohorts of North European patients with inflammatory bowel disease [1-3]; these data implicate inherited determinants, active inflammation and the exposome in shaping the methylome. We have recruited a unique group of 155 twin pairs discordant for IBD to allow exploration of the interplay between these factors.

Methods: Whole blood from twins discordant for diagnosis of IBD was profiled using methylation microarrays (Figure) in two cohorts (UK-1 & Scandinavia-2). We performed analysis of both cohorts with epigenome-wide association study (EWAS), investigation of methylation Shannon’s entropy, methylation variance, and the epigenetic age. Analysis of the methylation correlates of disease activity in cohort 1 (UK) was performed. Additionally, smoking-related methylation was explored.

Results: The discovery cohort (UK-1) included 64 di- and monozygotic twin pairs while the replication cohort (Scandinavia-2) included 91 sex-matched IBD-discordant twin pairs. The mean age in both cohorts was 53 years and the mean disease duration was 24 years. IBD-discordant twin pairs differed in Shannon’s entropy at individual probes (located in/near IL10RA, IL2RA, IL18RAP, VMP1, CEP72/AHRR), of which three replicated (cg11498228-ARHGEF10, cg07664915-KCTD13/MAPK3, cg20859708-NAA35), and many were located in IBD GWAS regions (such as FOXP1, LPP, MICA). The entropy findings from IBD GWAS regions were partially confirmed in monozygotic twins alone (e.g., TNXB in MHC class III region, bootstrap p.fdr<10-118), despite near-perfect controlling for genetics and early-life exposome. Sites highlighted by differential variance analysis included IBD genes, such as TAS1R3, GALNT2 and CACNA1H (all q-values<5×10-6). No epigenetic age acceleration was identified in patients with IBD. Clinical activity of IBD exhibited a number of associations with the whole blood methylome, including a negative correlation between methylation at a key IBD site RPS6KA2 with faecal calprotectin (Table). In patients with IBD and controls, cross-cohort smoking EWAS replicated multiple smoking-related sites at genome-wide significance, many of which located in AHRR and ALPI loci, both of which are implicated in IBD.

Conclusion: Methylation level at individual probes related to IBD activity and showed IBD-associated differences in methylation entropy and variance between twins despite shared genetics and early-life exposome, adding new context for understanding established IBD loci and strengthening their role.

References:

1. Ventham et al. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease. Nat Commun. 2016;7:13507.

2. Kalla et al. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome. J Crohns Colitis. 2023;17(2):170-184.

3. Ventham et al. Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC). Cell Mol Gastroenterol Hepatol. 2023;16(3):431-450.

Place, publisher, year, edition, pages
Oxford University Press, 2025
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-119279 (URN)10.1093/ecco-jcc/jjae190.0169 (DOI)001407665400016 ()
Conference
20th Congress of ECCO, Berlin, Germany, February 19-22, 2025
Note

Funding: EU's FP7 IBD Character (2858546, JS); Lundbeck (R211-2015-3061), Region of South. Denmark, Univ. of South. Denmark, Univ. Hosp. of South. Denmark Aabenraa (VA).

Available from: 2025-02-18 Created: 2025-02-18 Last updated: 2025-02-18Bibliographically approved
Pertsinidou, E., Salomon, B., Bergemalm, D., Salihovic, S., Hedin, C. R. H., Ling Lundström, M., . . . Halfvarson, J. (2025). Anti-integrin αvβ6 IgG antibody as a diagnostic and prognostic marker in ulcerative colitis: A cross-sectional and longitudinal study defining a specific disease phenotype. Journal of Crohn's & Colitis, 19(5), Article ID jjaf062.
Open this publication in new window or tab >>Anti-integrin αvβ6 IgG antibody as a diagnostic and prognostic marker in ulcerative colitis: A cross-sectional and longitudinal study defining a specific disease phenotype
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no 5, article id jjaf062Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: The diagnostic and prognostic properties of anti-integrin αvβ6 IgG autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin αvβ6 autoantibodies and examine their association with disease outcomes.

METHODS: Serum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n=473) were analysed using an in-house fluorescence enzyme immunoassay based on EliA™technology. Findings were validated in a Norwegian population-based inception cohort (n=570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals (CIs) and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index.

RESULTS: In the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn's disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC=0.92, 95%CI 0.89-0.95) was superior to hs-CRP (AUC=0.65, 95%CI 0.60-0.70, P<0.001) and faecal calprotectin (fcalpro) (AUC=0.88, 95%CI 0.84-0.92, P=0.09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC=0.97, 95%CI 0.95-0.98) and patient reclassification (P<0.001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P=0.003).

CONCLUSIONS: Anti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

Place, publisher, year, edition, pages
Oxford University Press, 2025
Keywords
Autoantibodies, inflammatory bowel disease, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-120771 (URN)10.1093/ecco-jcc/jjaf062 (DOI)001490503400004 ()40251889 (PubMedID)
Funder
Swedish Foundation for Strategic Research, RB13- 0160Swedish Research Council, 2020-02021Region Örebro County, OLL-890291NordForsk, 90569
Available from: 2025-04-28 Created: 2025-04-28 Last updated: 2025-05-27Bibliographically approved
Salomon, B., Sudhakar, P., Bergemalm, D., Andersson, E., Grännö, O., Carlson, M., . . . Halfvarson, J. (2025). Characterization of Inflammatory Bowel Disease Heterogeneity Using Serum Proteomics: A multicenter study. Journal of Crohn's & Colitis, 19(5), Article ID jjae169.
Open this publication in new window or tab >>Characterization of Inflammatory Bowel Disease Heterogeneity Using Serum Proteomics: A multicenter study
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no 5, article id jjae169Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Recent genetic and transcriptomic data highlight the need for improved molecular characterisation of inflammatory bowel disease (IBD). Proteomics may advance the delineation of IBD phenotypes since it accounts for post-transcriptional modifications. AIM: We aimed to assess the IBD spectrum based on inflammatory serum proteins and identify discriminative patterns of underlying biological subtypes across multiple European cohorts.

METHODS: Using proximity extension methodology, we measured 86 inflammation-related serum proteins in 1551 IBD patients and 312 healthy controls (HC). We screened for proteins exhibiting significantly different levels among IBD subtypes and between IBD and HC. Classification models for differentiating between Crohn's disease (CD) and ulcerative colitis (UC) were employed to explore the IBD spectrum based on estimated probability scores.

RESULTS: Levels of multiple proteins, such as IL-17A, MMP-10, and FGF-19, differed (fold-change>1.2; FDR<0.05) between ileal vs colonic IBD. Using multivariable models, a protein signature reflecting the IBD spectrum was identified, positioning colonic CD between UC and ileal CD, which were at opposite ends of the spectrum. Based on area under the curve (AUC) estimates, classification models more accurately differentiated UC from ileal CD (median AUCs>0.73) than colonic CD (median AUCs<0.62). Models differentiating colonic CD from ileal CD demonstrated intermediate performance (median AUCs 0.67-0.69).

CONCLUSION: Our findings in serum proteins support the presence of a continuous IBD spectrum rather than a clear separation of CD and UC. Within the spectrum, disease location may reflect a more similar disease than CD vs UC, as colonic CD resembled UC more closely than ileal CD.

Place, publisher, year, edition, pages
Oxford University Press, 2025
Keywords
Biomarkers, Crohn's disease, Montreal classification, Ulcerative colitis, disease location, serum proteins
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-117208 (URN)10.1093/ecco-jcc/jjae169 (DOI)001377184400001 ()39495605 (PubMedID)2-s2.0-105005099584 (Scopus ID)
Funder
Swedish Research Council, 020-02021Swedish Foundation for Strategic Research, B13-016Region Örebro County, LL-986849Region Örebro County, LL-974710Region Örebro County, 936004Region Örebro County, OLL-962042EU, Horizon 2020
Note

This study was supported by the Swedish Research Council (grant number 2020-02021 to Jonas Halfvarson), the Swedish Foundation for Strategic Research (grant number RB13-016 to Jonas Halfvarson), the Örebro University Hospital Research Foundation (grant numbers OLL-986849, OLL-974710, OLL-936004, and OLL-962042 to Jonas Halfvarson). This project has also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 831434 (3TR). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Available from: 2024-11-05 Created: 2024-11-05 Last updated: 2025-06-17Bibliographically approved
Salomon, B., Grännö, O., Bergemalm, D., Strid, H., Carstens, A., Hjortswang, H., . . . Halfvarson, J. (2025). Cohort profile: the Swedish Inception Cohort in inflammatory bowel disease (SIC-IBD). BMJ Open, 15(5), Article ID e099218.
Open this publication in new window or tab >>Cohort profile: the Swedish Inception Cohort in inflammatory bowel disease (SIC-IBD)
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2025 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 15, no 5, article id e099218Article in journal (Refereed) Published
Abstract [en]

Purpose: There is a need for diagnostic and prognostic biosignatures to improve long-term outcomes in inflammatory bowel disease (IBD). Here, we describe the establishment of the Swedish Inception Cohort in IBD (SIC-IBD) and demonstrate its potential for the identification of such signatures.

Participants: Patients aged >= 18 years with gastrointestinal symptoms who were referred to the gastroenterology unit due to suspected IBD at eight Swedish hospitals between November 2011 and March 2021 were eligible for inclusion.

Findings to date: In total, 367 patients with IBD (Crohn's disease, n=142; ulcerative colitis, n=201; IBD-unclassified, n=24) and 168 symptomatic controls were included. In addition, 59 healthy controls without gastrointestinal symptoms were recruited as a second control group. Biospecimens and clinical data were collected at inclusion and in patients with IBD also during follow-up to 10 years. Levels of faecal calprotectin and high-sensitivity C-reactive protein were higher in patients with IBD compared with symptomatic controls and healthy controls. Preliminary results highlight the potential of serum protein signatures and autoantibodies, as well as results from faecal markers, to differentiate between IBD and symptomatic controls in the cohort. During the first year of follow-up, 37% (53/142) of the patients with Crohn's disease, 24% (48/201) with ulcerative colitis and 4% (1/24) with IBD-U experienced an aggressive disease course.

Future plans: We have established an inception cohort enabling ongoing initiatives to collect and generate clinical data and multi-omics datasets. The cohort will allow analyses for translation into candidate biosignatures to support clinical decision-making in IBD. Additionally, the data will provide insights into mechanisms of disease pathogenesis.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2025
Keywords
Inflammatory bowel disease, GASTROENTEROLOGY, Prognosis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-121187 (URN)10.1136/bmjopen-2025-099218 (DOI)001483484200001 ()40328654 (PubMedID)2-s2.0-105004588747 (Scopus ID)
Funder
Swedish Foundation for Strategic Research, RB13-0160Swedish Research Council, 2020-02021
Note

This work was supported by the Swedish Foundation for Strategic Research [RB13-0160 to JH], the Swedish Research Council [2020-02021 to JH], and the Örebro University Hospital research foundation [OLL-962042, OLL-974710, OLL-986849, OLL-1001470 to JH].

Available from: 2025-05-22 Created: 2025-05-22 Last updated: 2025-05-22Bibliographically approved
Visuri, I., Dannenberg, K., Salomon, B., Lundström, M. L., Bergemalm, D., Eriksson, C., . . . Halfvarson, J. (2025). Correlations of clinical characteristics and serum proteins with drug levels: A multicentre cohort study of patients with inflammatory bowel disease starting biologics. Journal of Crohn's & Colitis, 19(Suppl. 1), i1873-i1874, Article ID P1011.
Open this publication in new window or tab >>Correlations of clinical characteristics and serum proteins with drug levels: A multicentre cohort study of patients with inflammatory bowel disease starting biologics
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no Suppl. 1, p. i1873-i1874, article id P1011Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Inter-individual differences in drug clearance are common in inflammatory bowel disease (IBD) patients treated with biologics. Associations between inflammatory markers, clinical features, and drug levels may indicate that the inflammatory immune response influences the pharmacokinetics of biologics. We assessed the impact of inflammatory and immunity-related proteins on drug levels in IBD.

Methods: Serum samples from 144 IBD patients initiating biologics in a prospective multicentre cohort were analysed using AFIAS-3 (Boditech Med Inc. Korea). The primary outcome was drug levels after the end of induction treatment (post-induction), analysed as continuous variables or categorised into high or low groups based on the median. Correlations were assessed using the Pearson’s correlation coefficients with false discovery rate (FDR) adjustment. Predictive capacity of clinical and protein data was evaluated with regularised linear regression models. Analyses were stratified by treatment (infliximab, adalimumab, vedolizumab) and diagnosis (Crohn’s disease (CD), ulcerative colitis (UC)).

Results: Patient demographics and clinical characteristics are provided in Table 1. Median (interquartile range, IQR) post-induction infliximab levels were 5.3 (2.2-9.5) μg/ml in patients with CD (n=34) and 3.8 (1.7-5.6) μg/ml in UC (n=33). The corresponding levels were 12.5 (7.0-16.1) μg/ml (n=36) and 8.8 (5.7-12.7) μg/ml (n=13) for adalimumab, 13.9 (6.4-24.4) μg/ml (n=19) and 17.7 (9.8-22.6) μg/ml (n=9) for vedolizumab. Principal component analyses revealed potential baseline protein profile differences between patients with high vs low post-induction levels for infliximab (p=0.09) and adalimumab (p=0.07) in CD, but no differences for vedolizumab (p=0.78) or UC. Individual protein analyses indicated that patients with higher drug levels post-induction seemed to display lower baseline estimates of inflammatory proteins compared to those with lower drug levels. However, statistical significance after correction for multiple comparisons was only observed for CDCP1 in adalimumab-treated CD patients (PFDR=0.04) (Figure 1). Additionally, baseline Flt31 (r=-0.57, PFDR=0.03) and Wisp1 (r=-0.61, PFDR=0.02) correlated with post-induction s-adali-mumab levels in CD, while Mcp3 (r=-0.89, PFDR=0.04) and Frgamma (r=-0.87, PFDR=0.05) correlated in UC. Integrating baseline protein data in prediction models for post-induction drug levels did not improve their accuracy compared to models based on only clinical and biochemical variables.

Conclusion: Inflammatory protein levels may influence post-induction drug levels in IBD, particularly in adalimumab treated CD patients. This insight could aid in optimising personalised treatment.

Place, publisher, year, edition, pages
Oxford University Press, 2025
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-119426 (URN)10.1093/ecco-jcc/jjae190.1185 (DOI)001407539000045 ()
Available from: 2025-02-26 Created: 2025-02-26 Last updated: 2025-02-26Bibliographically approved
Bergemalm, D., Amcoff, K., Pierik, M. J., Colombel, J. F., Vermeire, S., Bodin, L. & Halfvarson, J. (2025). Environmental factors, genetic predisposition and subclinical inflammation in the development of perinuclear-antineutrophil cytoplasmic antibody (P-ANCA)-positive ulcerative colitis: A European twin study. Paper presented at 20th Congress of ECCO, Berlin, Germany, February 19-22, 2025. Journal of Crohn's & Colitis, 19(Suppl. 1), i787-i787, Article ID P0326.
Open this publication in new window or tab >>Environmental factors, genetic predisposition and subclinical inflammation in the development of perinuclear-antineutrophil cytoplasmic antibody (P-ANCA)-positive ulcerative colitis: A European twin study
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no Suppl. 1, p. i787-i787, article id P0326Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Perinuclear-antineutrophil cytoplasmic antibodies (P-ANCAs) have been identified in familial ulcerative colitis (UC), but the precise mechanism underlying their expression remains elusive. We assessed the role of genetic predisposition, environmental factors and systemic subclinical inflammation in the development of P-ANCA in a twin cohort with UC.

Methods: A total of 48 twin pairs (Leuven, Belgium n=4, Maastricht, The Netherlands n=6 and Örebro, Sweden n=38) with UC were included. Among these, 18 were monozygotic (3 concordant and 15 discordant for UC) and 30 were dizygotic (1 concordant and 29 discordant for UC). P-ANCA was detected through standardised ELISA, an indirect immunofluorescence assay and DNase treatment. In addition to high sensitivity C-reactive protein (hs-CRP), 92 inflammatory protein markers were measured in serum by proximity extension assay (Olink proteomics).

Results: P-ANCA was present in 16/52 (31%) of UC twins vs. 4/44 (9%) healthy twin siblings (p=0.01). No agreement in the presence of P-ANCA or their levels was observed between twin siblings in monozygotic pairs discordant for UC [intraclass correlation coefficient (ICC)=0.09] or dizygotic pairs (ICC=-0.20). Female sex was associated with an increased likelihood of P-ANCA (odds ratio, OR 5.49; 95% confidence interval, CI 1.47-20.57) and higher ANCA levels (ratio of geometric means 1.80; 95% CI 1.12-2.88). Active smoking was associated with lower concentrations of ANCA (ratio of geometric means 0.33; 95% CI 0.15-0.75) and potentially reduced the likelihood of P-ANCA (OR 0.23; 95% CI 0.02-2.21) in twins with UC but not in their healthy siblings. In twin siblings without UC, significant correlations between ANCA levels and hs-CRP, CDCP1, IL17A, CXCL9 and IL5 (correlation coefficients 0.36-0.41, p-values <0.05) were observed.

Conclusion: Female sex and tobacco smoking outweighed genetics regarding the generation and levels of P-ANCA and ANCA antibodies. The correlations between ANCA levels and inflammatory markers in healthy twin siblings suggest that P-ANCA may result from subclinical inflammation in these healthy siblings.

Place, publisher, year, edition, pages
Oxford University Press, 2025
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-119424 (URN)10.1093/ecco-jcc/jjae190.0500 (DOI)001404163600038 ()
Conference
20th Congress of ECCO, Berlin, Germany, February 19-22, 2025
Available from: 2025-02-26 Created: 2025-02-26 Last updated: 2025-02-26Bibliographically approved
Bergemalm, D., Baban, B., Ljungqvist, O. & Halfvarson, J. (2025). Insulin sensitivity in moderately severe to acute severe ulcerative colitis. Scandinavian Journal of Gastroenterology, 60(3), 243-247
Open this publication in new window or tab >>Insulin sensitivity in moderately severe to acute severe ulcerative colitis
2025 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 60, no 3, p. 243-247Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Patients hospitalized with moderately severe or acute severe ulcerative colitis (UC) may experience metabolic disturbances, including alterations in insulin resistance due to inflammation and the administration of glucocorticoids (GCs). This pilot study aimed to evaluate insulin sensitivity in patients hospitalized for moderately severe to severe UC.

METHOD: Patients hospitalized for moderately-severely active UC at Örebro University Hospital, Sweden, were eligible for inclusion. Quantification of insulin sensitivity was performed using the hyperinsulinemic euglycemic clamp (HEC) methodology. Assessment of insulin sensitivity was performed during both the index flare and while patients were in steroid-free clinical, biochemical and endoscopic remission during follow-up. Additionally, healthy controls were evaluated using HEC for comparison.

RESULTS: Five patients with moderately-severely active UC, treated with intravenous GCs for ≥2 days, were included and underwent HEC assessment. During the index flare, four patients received second-line treatment with infliximab due to non-response to GC, and one patient was subsequently referred for acute subtotal colectomy. At inclusion, all five patients exhibited significantly reduced insulin sensitivity, and levels appeared similar regardless of the outcome of the index flare. At remission during follow-up, the insulin sensitivity was restored to levels comparable to healthy controls (n = 5).

CONCLUSION: The study demonstrates that patients with moderately severe to severe UC experience significant insulin resistance, irrespective of the outcome of the flare. The reduced insulin sensitivity is likely driven by a combination of active inflammation and GC treatment, as insulin sensitivity returned to normal levels when patients achieved remission during follow-up.

Place, publisher, year, edition, pages
Taylor & Francis, 2025
Keywords
Ulcerative colitis, hyperinsulinemic euglycemic clamp, insulin resistance
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-118995 (URN)10.1080/00365521.2025.2459870 (DOI)001409584200001 ()39882844 (PubMedID)2-s2.0-85216681640 (Scopus ID)
Funder
Bengt Ihres FoundationRegion Örebro County, OLL-709831
Note

Funding Agencies:

The Bengt Ihre research foundation to DB, the Örebro University Hospital Research Foundation, grant number OLL-709831 to DB; Mag-Tarmfonden for DB, Lisa and Johan Grönbergs Stiftelse for DB.

Available from: 2025-01-31 Created: 2025-01-31 Last updated: 2025-03-24Bibliographically approved
Vatn, S. S., Hansen, S. H., Tannæs, T. M., Brackmann, S., Olbjørn, C., Bergemalm, D., . . . Moen, A. E. F. (2025). Microbial Patterns in Newly Diagnosed Inflammatory Bowel Disease Revealed by Presence and Transcriptional Activity-Relationship to Diagnosis and Outcome. Clinical and Experimental Gastroenterology, 18, 103-119
Open this publication in new window or tab >>Microbial Patterns in Newly Diagnosed Inflammatory Bowel Disease Revealed by Presence and Transcriptional Activity-Relationship to Diagnosis and Outcome
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2025 (English)In: Clinical and Experimental Gastroenterology, E-ISSN 1178-7023, Vol. 18, p. 103-119Article in journal (Refereed) Published
Abstract [en]

Background: As part of the IBD Character initiative, we examined an inception cohort and investigated mucosal microbiota composition and transcriptional activity in relation to clinical outcomes.

Methods: A cohort of 237 individuals were included from five countries: Crohn's disease (CD, n = 72), ulcerative colitis (UC, n = 57), symptomatic non-IBD controls (SC, n = 78) and healthy controls (HC, n = 30). Rectal/colonic biopsies were obtained at inclusion, and DNA and RNA were extracted from the same biopsy and examined by sequencing the 16S rRNA V4 region.

Results: Beta diversity measurements separated IBD from both HC and SC. IBD and SC exhibited reduced intra-individual diversity compared with HC. When comparing taxonomy at DNA and RNA level, six bacteria were found to differ in abundance and/or transcriptional activity between IBD and symptomatic control, while there were 14 and three between symptomatic control and CD and UC, respectively. A limited number of bacterial taxa were responsible for the largest difference between presence and activity, separating patients and controls. Multiple bacterial taxa were associated with treatment escalation in both UC and CD. Machine-learning models separated IBD from symptomatic controls and treatment escalators from non-escalators (AUC >0.8). However, the differential effects were mainly driven by clinical biomarkers, such as f-calprotectin, s-albumin, and b-hemoglobin.

Conclusion: Differences between presence and transcriptional activity were found among multiple taxa when assessing 16S rRNA at DNA and RNA level. Symptomatic controls were more similar to the IBD patients compared to HC. The analyses suggest that the mucosal microbiota carries a moderate diagnostic and predictive potential, outcompeted by f-calprotectin.

Place, publisher, year, edition, pages
Dove Medical Press, 2025
Keywords
microbiota, RNA, DNA, IBD, biomarkers
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-121422 (URN)10.2147/CEG.S504459 (DOI)001494899700001 ()40491932 (PubMedID)
Note

The study was funded by the following EU FP7 grant: IBD-CHARACTER (contract #2858546). PR, SV and SHH were funded by South-Eastern Norway Regional Health Authority (project numbers 2014011, 2018001 and 2020066) .

Available from: 2025-06-03 Created: 2025-06-03 Last updated: 2025-06-11Bibliographically approved
Grännö, O., Bergemalm, D., Salomon, B., Lindqvist, C. M., Hedin, C. R. H., Carlson, M., . . . Halfvarson, J. (2025). Preclinical protein signatures of Crohn's disease and ulcerative colitis: A nested case-control study within large population-based cohorts. Gastroenterology, 168(4), 741-753
Open this publication in new window or tab >>Preclinical protein signatures of Crohn's disease and ulcerative colitis: A nested case-control study within large population-based cohorts
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2025 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 168, no 4, p. 741-753Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND AIMS: Biomarkers are needed to identify individuals at elevated risk of inflammatory bowel disease (IBD). This study aims to identify protein signatures predictive of IBD.

METHODS: Using large population-based cohorts (n≥180,000), blood samples were obtained from individuals who later in life were diagnosed with IBD and compared to age and sex-matched controls, free from IBD during follow-up. 178 proteins were measured on Olink platforms. We used machine learning methods to identify protein signatures of preclinical disease in the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222) and assessed in an inception cohort (n=144) and a preclinical twin cohort (n=102).

RESULTS: In the discovery cohort, a signature of 29 proteins differentiated preclinical Crohn's disease (CD) cases from controls, with an area under the curve (AUC) of 0.85. Its performance was confirmed in the preclinical validation (AUC=0.87) and the inception cohort (AUC=1.0). In preclinical samples, downregulated (but not upregulated) proteins related to gut barrier integrity and macrophage functionality correlated with time to diagnosis of CD. The preclinical ulcerative colitis (UC) signature had a significant, albeit lower, predictive ability in the discovery (AUC=0.77), validation (AUC=0.67), and inception cohorts (AUC=0.95). The preclinical signature for CD demonstrated an AUC of 0.89 when comparing twins with preclinical CD to matched external healthy twins, but its predictive ability was lower (AUC=0.58; P=.04) when comparing them with their healthy twin siblings, i.e., when accounting for genetic and shared environmental factors.

CONCLUSION: We identified protein signatures for predicting a future diagnosis of CD and UC, validated across independent cohorts. In the context of CD, the signature offers potential for early prediction.

Place, publisher, year, edition, pages
American Gastroenterology Association Institute, 2025
Keywords
Crohn’s disease, Preclinical disease, inflammatory bowel disease, proteomics, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-117660 (URN)10.1053/j.gastro.2024.11.006 (DOI)001467415000001 ()39608683 (PubMedID)2-s2.0-85218876976 (Scopus ID)
Funder
Swedish Research Council, 2020-02021; 2017-00650Swedish Foundation for Strategic Research, RB13-016Bengt Ihres FoundationEU, Horizon Europe, 101095470
Note

This study was supported by the Swedish Research Council (grant number 2020-02021 to Jonas Halfvarson), the Swedish Foundation For Strategic Research (grant number RB13-016 to Jonas Halfvarson), the Örebro University Hospital Research Foundation (grant numbers OLL-986849, OLL-974710, OLL-936004, OLL-890291, OLL-790011, and OLL-962042 to Jonas Halfvarson), the Swedish Foundation for Gastrointestinal Research (Gunilla Falk award 2021 to Jonas Halfvarson), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (grant number OLL-961742 to Olle Grännö and OLL-685051 to Daniel Bergemalm), and the Bengt Ihre research foundation to Daniel Bergemalm. Västerbotten County Council funded the Västerbotten Intervention Program and Biobank Sweden was supported by the Swedish Research Council (grant number VR 2017-00650). This work was funded by the European Union under the Horizon Europe grant 101095470, project miGut-Health, Personalised Blueprint of Intestinal Health.

Available from: 2024-12-11 Created: 2024-12-11 Last updated: 2025-04-28Bibliographically approved
Wong, S. Y., Moran, H. R., Rajauria, P., Giselbrecht, E., Wellens, J., Vermiere, S., . . . Satsangi, J. (2025). Trans-continental analysis of determinants of response to COVID-19 vaccination in 2268 patients with Inflammatory Bowel Disease. Paper presented at 20th Congress of ECCO, Berlin, Germany, February 19-22, 2025. Journal of Crohn's & Colitis, 19(Suppl. 1), I1369-I1371, Article ID P0701.
Open this publication in new window or tab >>Trans-continental analysis of determinants of response to COVID-19 vaccination in 2268 patients with Inflammatory Bowel Disease
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2025 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 19, no Suppl. 1, p. I1369-I1371, article id P0701Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Little is known about the relative efficacy of available COVID-19 vaccine types around the world in immune-compromised patients with inflammatory bowel disease (IBD).1,2 We aimed to compare antibody responses to SARS-CoV-2 in patients with IBD who had received mRNA, vector, and inactivated virus vaccines and the impact of medications thereof among multinational sites.

Methods: Serum samples taken after 1st, 2nd, and 3rd doses of COVID-19 vaccines from patients with IBD seen at 13 sites across Europe, Asia, and North America were prospectively collected between January 2021 and November 2022. We measured anti-Spike (S) and anti-nucleocapsid (N) antibody levels. To identify determinants of serological responses to vaccination, both univariate and multivariate analyses were conducted.

Results: There were a total of 2,268 patients, including 1,279 Crohn’s disease (CD) and 868 ulcerative colitis (UC) (Table 1). 1552 patients had an mRNA vaccine, 590 an adenovirus vaccine, and 98 an inactivated virus vaccine. At 14-84 days, 85-168 days, and 169+ days after completing a full vaccination series, the proportion of patients who were positive for anti-S antibodies were 98% (n=922/939), 96% (n=700/731), and 98% (n=677/692) for mRNA, 95% (n=378/396), 89% (n=55/62), and 97% (n=33/34) for adenovirus, and 72% (n=21/29), 84% (n=31/37), and 95% (n=55/58) for inactivated virus vaccine, respectively.

On univariate analysis, rates of serological response were highest in those who received mRNA vaccines at all six time periods (Figure 1a). Adenovirus vaccine response rates closely resembled the rate of seropositivity in mRNA vaccinated patients. In contrast, inactivated vaccines had a significantly lower percent of patients reaching seropositivity until 169 days or more after the second vaccine dose (p<0.001). Anti-TNF mono-therapy and immunomodulator monotherapy were associated with the ability to obtain maximum antibody titres. However, this difference is ablated after the 3rd dose (Figure 1c).

Univariate analysis also implicated geographical site, male sex, and a diagnosis of ulcerative colitis as determinants of serological responses.

On multi-variable analysis, vaccine type (p < 0.001 at every time point analysed) and the use of immunomodulators (p <0.001 at time points 1 and 3) were confirmed as independent determinants of vaccine responsiveness across the study populations.

Conclusion: Our data suggests that while there is variability between geographical centers, the response rates are high worldwide, and the key determinants of serological response to vaccines are the use of immunosuppressive agents and vaccine class.3 These data are important considerations for better pandemic preparedness in the IBD community worldwide.

References:

(1) Wong SY, Wellens J, Helmus D, et al. Geography Influences Susceptibility to SARS-CoV-2 Serological Response in Patients With Inflammatory Bowel Disease: Multinational Analysis From the ICARUS-IBD Consortium. Inflamm Bowel Dis. 2023;29(11):1693-1705. doi:10.1093/ibd/izad097Figure(s)/Table(s): see ne

Place, publisher, year, edition, pages
Oxford University Press, 2025
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-119286 (URN)10.1093/ecco-jcc/jjae190.0875 (DOI)001404189500022 ()
Conference
20th Congress of ECCO, Berlin, Germany, February 19-22, 2025
Available from: 2025-02-17 Created: 2025-02-17 Last updated: 2025-02-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1906-0746

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