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  • 1
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    P921 FMT in UC is associated with a decrease in Bacteroides-2 enterotype and response with baseline RNA and microbiota signatures
    Oxford University Press (OUP) ; 2023
    In:  Journal of Crohn's and Colitis Vol. 17, No. Supplement_1 ( 2023-01-30), p. i1029-i1031
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 17, No. Supplement_1 ( 2023-01-30), p. i1029-i1031
    Abstract: The efficacy of faecal microbiota transplantation (FMT) in UC has been reported to be donor-, patient- and procedure-dependent (Rees et al., 2022). The RESTORE-UC trial [NCT03110289] aimed to improve the outcome of FMT in patients with active UC by donor preselection on microbiota level, a strict anaerobic preparation and repeated FMT administration. The trial was prematurely stopped for futility (Caenepeel et al., 2022). We investigated changes in resp. biopsy and faecal samples obtained host transcriptomics and microbiota profiles from baseline to primary endpoint (PE) at week 8 to understand reasons for the observed lack of efficacy. Methods Active UC patients (total Mayo score 4-10 with endoscopic sub-score ³2, n=72) were randomly allocated to receive 4 anaerobic-prepared superdonor (S) FMT or autologous (A) FMT. Primary endpoint was defined as steroid-free clinical remission (Total Mayo ≤ 2, with no sub-score & gt;1). Host RNA extractions were performed from mucosal biopsies collected at week 0 (n=63) and 8 (n=54) using the Qiagen AllPrep DNA/RNA Mini kit, and sequenced using Illumina HiSeq4000. Sequencing data was further processed (read-count filtering, normalization) and further analyzed using DESeq2 package. Corresponding faecal samples (resp. n=62 and n=50) were submitted to DNA extractions using MagAttract PowerMicrobiome DNA/RNA kit on an automated extraction platform, followed by library prep and 16S rDNA-sequencing using Illumina MiSeq. The obtained sequences were subjected to the DADA2 pipeline in R and the Quantitative Microbial Composition (QMP) was quantified by flow cytometry. Results Eight responders were observed: 3 after S-FMT and 5 after A-FMT, as well as 58 non-responders considering the intention-to-treat population. Responders to FMT tended to cluster at baseline (adonis p=0.34) and PCA analysis on the top 500 mucosal genes with the highest variance (Fig.1), showed a significant host effect at week 8 between responders and non-responders (adonis p & lt;0.05). Likewise, PCA analysis of the currently available QMP (Fig.2) showed a trend towards clustering by response at week 0 and 8 resp. adonis p=0.18 and p=0.11). An overall decrease in Bacteroides-2 enterotype prevalence was observed (Fig.3) over both treatment groups and independently from reaching the PE (All McNemar's p=0.077). Conclusion A trend towards clustering of responders on host mRNA level and QMP was observed at baseline as well as at the primary endpoint, showing a potential role for pre-FMT patient selection by phenotype. Moreover, the dysbiotic enterotype Bacteroides-2 seems to be decreased after FMT. However, further analyses are mandatory to identify specific predictors of response and the origin of the microbiota shift.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjac190.1051
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 2
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    P820 An easy and rapid targeted next generation sequencing-based genotyping assay for the validated IBD risk loci
    Oxford University Press (OUP) ; 2020
    In:  Journal of Crohn's and Colitis Vol. 14, No. Supplement_1 ( 2020-01-15), p. S637-S638
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 14, No. Supplement_1 ( 2020-01-15), p. S637-S638
    Abstract: Inflammatory bowel diseases (IBD) are complex genetic diseases for which 242 susceptibility loci have been identified thus far. For translational or functional follow-up studies it can be of interest to know the genotype of specific variants. For other studies a composite genetic risk score–the polygenic risk score–is of value. There currently is a gap in technology to genotype a few hundred variants in a flexible and cost-effective way. We therefore developed a genotyping assay for the 242 validated IBD susceptibility loci. Methods Using MIPgen v.1.1, we designed molecular inversion probes (MIPs) covering 269 independent variants from the 242 IBD loci. MIP libraries were prepared according to Neveling et al. (Clin Chem. 2017), followed by paired-end sequencing using a MiSeq® System (Illumina). In the pilot studies, 16 IBD patients were genotyped, and results were compared with available immunochip (ichip) data. Genotypes for the covered variants were obtained using an in-house developed pipeline, and performance metrics were assessed (incl. genotyping call rate, percentage off-target reads and concordance with ichip-based genotypes). After optimisation, we genotyped 279 individuals (168 IBD patients and 111 non-IBD controls). We also calculated a weighted IBD polygenic risk score (PRSice 2.0) for these. Results Despite a genotyping call rate of 94.3%, the first pilot run suffered from a high rate of off-target reads (52.5%). After redesigning poorly-performing MIPs, off-target reads dropped to 9.4%, and the genotyping call rate increased to 97.5%. Concordance with genotypes previously obtained from ichip was 99.3%. When applying the optimised design on a larger scale (i.e. on the 279 individuals), we obtained similar performance metrics, with 8.0% off-target reads and a genotyping call rate of 97.3%. Moreover, upscaling resulted in a turnaround time of 2.5 working days/96 samples and a cost of €14/sample. The calculated IBD polygenic risk scores showed higher scores in patients as compared with controls (5.5E−03 vs. 4.0E−03, p = 8.80E−10; R² IBD polygenic risk score = 0.15, p = 1.28E−07), however with a large overlap between both groups. Quartile analysis showed that individuals within the highest quartile had an 8.1-fold (95% CI: 3.7–17.5) increase in risk towards IBD compared with individuals in the first quartile. Conclusion We developed a cost-effective genotyping assay for currently known IBD risk loci, with an integrated bioinformatics pipeline from raw sequencing data to individual genotypes and calculation of a polygenic risk score. Furthermore, this assay enables genotyping of individuals on a large scale while remaining flexible to implement newly identified genetic variants.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjz203.948
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 3
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    P005 0190Molecular-based classification of ulcerative colitis and its dynamic
    Oxford University Press (OUP) ; 2023
    In:  Journal of Crohn's and Colitis Vol. 17, No. Supplement_1 ( 2023-01-30), p. i173-i174
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 17, No. Supplement_1 ( 2023-01-30), p. i173-i174
    Abstract: A better characterization of inflammatory bowel disease is needed. We previously developed a molecular classification tool for Crohn’s disease, based on a combination of metagenomics (dysbiosis score - MDI), transcriptomics (barrier integrity score - BIS, autophagy score – ATS, unfolded protein response score - UPRS), serum proteomics (inflammation score - IPS) and genetics (polygenic risk score - GRS)1. We here investigated if this score could also apply for ulcerative colitis (UC) and how the individual components correlate with clinical outcomes. Methods For a total of 173 UC patients and 181 controls (CO), we collected faecal and blood samples, as well as colon biopsies (Table). Faecal microbiota 16S-sequencing, intestinal RNA-sequencing, and serum proteomics (OLINK inflammatory panel) were performed. Using proteomics and RNA expression data, IPS, ATS, UPRS and BIS were calculated. MDI was calculated as previously described1. Based on these findings, patients were categorized into quartiles, ranging from Q1 (the least dysfunctional state) to Q4 (the most dysfunctional state). The individual scores were correlated with time to first biological or biological switch, as well as correlations with C-reactive protein (CRP), faecal calprotectin (FC), and the Montreal classification. The therapeutic value of MDI score was studied in a small dietary intervention pilot study (n=8)2. Results None of the individual components of the score were associated with disease extent. Patients diagnosed at a later age had increased ATS and BIS levels. BIS and UPRS showed a positive correlation with disease duration (r=0.36, r=0.54 respectively, p & lt;0.001) (Figure2). MDI (spearman r=0.27, r=0.44, r=0.46 respectively, all p & lt;0.0001) and IPS (r=0.5, r=0.7, r=0.6 respectively, all p & lt;0.0001) correlated with CRP and FC levels, and time to first biologic. UPRS, ATS, MDI, BIS, and IPS were considerably higher in patients who required a switch in biologic therapy (all p & lt;0.001). Finally, we observed a decreasing trend in MDI in response to dietary modification (Figure3). Conclusion In UC patients, we created a multifaceted scoring system to molecularly describe disease by the degree of dysbiosis, dysregulation of the immune proteome, and intestinal barrier integrity. We also demonstrated the dynamic of MDI of this score in relation to dietary intervention. Therefore, molecular profiling of patients may represent a new, individualized strategy to the management of UC. References: 1. OP30 ECCO 2020, JCC 14(Supplement_1):S028-S0302. 2. P767 ECCO 2017, JCC 11(suppl_1):S473-S473.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjac190.0135
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 4
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    DOP70 An integrated multi-omics biomarker predicting endoscopic response in ustekinumab treated patients with Crohn's disease
    Oxford University Press (OUP) ; 2019
    In:  Journal of Crohn's and Colitis Vol. 13, No. Supplement_1 ( 2019-01-25), p. S072-S073
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 13, No. Supplement_1 ( 2019-01-25), p. S072-S073
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjy222.104
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 5
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    P820 Molecular changes in non-inflamed terminal ileum in patients with ulcerative colitis
    Oxford University Press (OUP) ; 2019
    In:  Journal of Crohn's and Colitis Vol. 13, No. Supplement_1 ( 2019-01-25), p. S533-S534
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 13, No. Supplement_1 ( 2019-01-25), p. S533-S534
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjy222.944
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 6
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    P004 Microbiota, not host origin drives ex vivo epithelial response in ulcerative colitis patients and non-IBD controls
    Oxford University Press (OUP) ; 2022
    In:  Journal of Crohn's and Colitis Vol. 16, No. Supplement_1 ( 2022-01-21), p. i136-i136
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 16, No. Supplement_1 ( 2022-01-21), p. i136-i136
    Abstract: Host-microbial interactions in inflammatory bowel disease (IBD) are poorly understood. Furthermore, patients with IBD have microbial dysbiosis and their epithelial cells exhibit intrinsic defects. We aimed to unravel the effect of exposure to microbiota on epithelial cells from both patients with ulcerative colitis (UC) and non-IBD controls. Methods Confluent Transwell® organoid-derived monolayers of 8 UC patients and 8 non-IBD controls were co-cultured for 6 hours with microbiota (3.108 cells) derived from active UC patients (n=3, endoscopic Mayo score ≥2) or healthy volunteer (HV, n=1, selected on high microbial cell count and presence of selected phyla1). For this purpose, fresh faecal samples were filtered and frozen in 0.9% NaCl. Inflammation was re-induced with 100 ng/ml TNF-α, 20 ng/ml IL-1β, and 1 µg/ml flagellin in confluent Transwell® cultures, 24 hours prior to microbiota co-culture. Transepithelial electrical resistance (TEER), 4 kDa fluorescein isothiocyanate (FITC) dextran (2 mg/ml) measurements, and RNA sequencing by Truseq were performed on epithelial cells, and 16S rRNA sequencing on microbiota samples before and after co-culture. Results The transcriptomic response of epithelial cells to microbiota was clearly influenced by the type of microbiota stimulation (no, UC or HV microbiota). However, this response was not influenced by the origin of the epithelial cells (UC or non-IBD controls) (Figure 1A). TEER and FITC dextran measurements showed a strong decrease in epithelial integrity (in both UC and non-IBD epithelium) following stimulation with UC microbiota, in contrast to HV microbiota (Figure 1B). In UC epithelial cells, stimulation with microbiota from UC patients induced a stress induced phenotype including activation of EGR1 signalling, AP-1 family, FOSL genes, MAPK and JNK signalling (Figure 2). Activation of stress pathways (MAPK family cascades) and key markers (e.g. FOSB, FOSL1, MYC, EGR1, ATF3, NOTCH1) was lower after HV microbiota stimulation (Figure 3–4). Expression levels of key markers were UC microbiota specific and similar in epithelial cells of UC and non-IBD controls (Figure 4). Conclusion Not the host (UC vs non-IBD epithelial cells) but the microbial donor (UC vs HV) is driving the transcriptomic response. Epithelial cells from UC patients did not show an increased sensitivity towards microbiota stimulation compared to non-IBD epithelial cells. In contrast, exposure of epithelial cells to UC microbiota was sufficient to induce a strong stress response and barrier disruption. Further research on therapies to restore the microbial balance, to remove the constant trigger of dysbiosed microbiota, is required. References 1. Vermeire, JCC, 2015
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjab232.133
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    DOP33 Single-cell analysis identifies pathological fibroblasts as a new therapeutic target to prevent intestinal fibrosis in Crohn’s disease.
    Oxford University Press (OUP) ; 2023
    In:  Journal of Crohn's and Colitis Vol. 17, No. Supplement_1 ( 2023-01-30), p. i96-i97
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 17, No. Supplement_1 ( 2023-01-30), p. i96-i97
    Abstract: Recurrent episodes of intestinal inflammation and tissue remodeling progressively result in fibro-stenosis and bowel obstruction in Crohn’s disease (CD). This irreversible end-stage complication is the main indication for surgical intervention but is often associated with postoperative recurrence of inflammation and repeated tissue resection. Methods To understand transmural inflammation-induced fibro-stenosis, full-thickness ileum from CD patients (n=10) undergoing ileocecal resection were profiled using single-cell RNA sequencing (scRNA seq) on 10x Genomics platform. Our tissue sampling strategy aimed at recapitulating different disease stages from the same patient including normal ileum, chronic active inflammation and stenotic ileum, allowing a better definition of cell heterogeneity, inter-cellular communication, and tissue organization in CD. Healthy ileum from CRC patients (n=5) undergoing right hemicolectomy were included as external control. Flow cytometry (FACS) was carried out to confirm scRNA seq findings. For functional validation, intestinal fibroblasts were co-cultured with NicheNet-predicted cytokines and FACS-sorted myeloid supernatants. Finally, the chronic dextran sulfate sodium (DSS)-induced colitis model was used to validate the transcription regulation in activated fibroblasts. Results Using scRNA seq, we identified a specific subset of activated fibroblasts during chronic inflammation and fibrosis. FACS showed increasing FAP+ fibroblasts in both inflamed and stenotic ileum, compared to control ileum and proximal ileum (p & lt;0.01). Computational methods predicting ligand-receptor signaling suggest that fibroblast activation is mostly mediated by myeloid cell-derived inflammatory signals resulting in collagen deposition and tissue fibrosis. Intestinal fibroblasts co-cultured with inflammatory monocyte supernatant and predicted ligands expressed higher protein levels of FAP, COL3A1 and showed signs of EMT transformation. Furthermore, stimulated intestinal fibroblasts secreted higher levels of ECM proteins, including COL1 (p & lt;0.001), and COL3A1 (p & lt;0.005). After inhibiting an EMT-related transcription factor identified in the activated fibroblasts, collagen expression and extracellular matrix accumulation were decreased in fibroblasts. Finally, inhibition of EMT transformation in chronic DSS colitis resulted in reduced ECM deposition, compared to vehicle mouse (p & lt;0.05). Conclusion Our findings suggest that inflammatory monocytes mediate local activation of fibroblasts promoting excessive collagen deposition. We furthermore show that targeting activated fibroblasts was able to reduce tissue remodeling and may therefore prevent fibrostenosis in CD.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjac190.0073
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    OP30 The interplay of microbiome dysbiosis and immune system deregulation in patients with Crohn’s disease
    Oxford University Press (OUP) ; 2020
    In:  Journal of Crohn's and Colitis Vol. 14, No. Supplement_1 ( 2020-01-15), p. S028-S030
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 14, No. Supplement_1 ( 2020-01-15), p. S028-S030
    Abstract: The perturbation of composition, function, and structure of the gut microbiota known as dysbiosis is a key factor in inflammatory bowel disease (IBD) pathogenesis. There is a crosstalk between the microbiota and the gut immunological niche. To better understand this interaction, we characterised the degree of dysbiosis and dysregulation of the immune proteome in Crohn’s disease (CD) patients to see whether subtypes of patients could be identified. Methods We collected faecal and serum samples of 146 CD patients and 63 healthy controls (HC) (Figure 1), and studied microbiota phylogenetic (16S rRNA gene sequencing) and serum proteomic (91 inflammatory proteins OLINK). Microbial dysbiotic index (MDI), defined as the logarithm of the sum of [abundance in organisms increased in CD] over the [abundance of organisms decreased in CD] was calculated and patients were ranked from Q1 (the least dysbiotic state) to Q4 (the most dysbiotic state). For the proteomic score, 32 proteins that correlated (adj. p ≤ 0.01) with faecal calprotectin (FC) were selected. A penalised logistic regression model was trained on these proteins, to distinguish HC from super active (defined as FC ≥ 1800 μg/g). We next developed an inflammatory proteomic score (IPS) defined as the weighted sum of the serum level of inflammatory proteins, using the coefficient value of the regression model as the protein’s weight. Using the IPS score, patients were clustered from Q1 (the least inflammatory state) to Q4 (the most inflammatory state). Statistical analyses were performed in R 3.5.2. Results The MDI did not correlate with standard phenotypic subgroups based on the Montreal classification but did positively correlate with C-reactive protein (CRP) and FC level (p ≤ 0.001). The regression model identified 14 proteins [including CCL20, CXCL1, IL-7, IL-17A, FGF-19] distinguishing super active CD patients from HC with accuracy, sensitivity, and specificity of 95.6%, 92.3%, 100%, respectively. IPS positively correlated with CRP and FC level (p ≤ 0.001). Likewise, MDI and IPS-based clusters were significantly different in CRP and FC levels. Different components of the microbiome correlated with the proteome in a subset of samples. For example, fibroblast growth factor 19 (FGF-19) positively correlated with Faecalibacterium and negatively with Fusicatenibacterium. Of note, we observed a significant positive correlation between MDI and IPS (r = 0.33, p ≤ 0.001) (Figure 2). Conclusion We were able to define clusters of patients based on molecular characterisation of different players in IBD pathogenesis such as microbiota and proteome. This molecular clustering in a given patient could be considered as a novel therapeutic and personalised approach to IBD. Further validation in larger cohorts is required.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjz203.029
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 9
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    DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease
    Oxford University Press (OUP) ; 2021
    In:  Journal of Crohn's and Colitis Vol. 15, No. Supplement_1 ( 2021-05-27), p. S061-S062
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 15, No. Supplement_1 ( 2021-05-27), p. S061-S062
    Abstract: Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients. Methods Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of & gt; 2 and Q-value & lt; 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation. Results Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively. Conclusion Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjab073.061
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 10
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    P030 Distinct molecular profiles between idiopathic cryptoglandular and Crohn-related perianal fistulas
    Oxford University Press (OUP) ; 2022
    In:  Journal of Crohn's and Colitis Vol. 16, No. Supplement_1 ( 2022-01-21), p. i151-i151
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 16, No. Supplement_1 ( 2022-01-21), p. i151-i151
    Abstract: Perianal fistula can originate idiopathically (cryptoglandular fistula) or can be a representation of underlying Crohn’s disease (CD). In case of idiopathic fistula, the cryptoglandular theory suggests their development from the anal glands. In contrast, the pathophysiology of CD-related fistula is very poorly understood. Hence, we molecularly characterised and compared the fistula tract in both conditions. Methods We collected surgical biopsies from the fistula tract in 70 CD patients with active draining perianal fistula and in 12 patients with cryptoglandular non-CD related, active draining fistula, all requiring surgical examination under anaesthesia. RNA was sequenced using Illumina HiSeq4000, and these data were analysed through differential gene expression analysis (DESeq2). A false discovery rate (FDR) of 0.05 and a |log 2-fold change (log2FC)| & gt;1 was considered significant. Pathway analysis was performed using IPA (Qiagen). In addition, cellular deconvolution methods (xCell) were applied to study the cellular composition. Results Gene expression analysis identified 1087 genes being differentially expressed between CD-related and cryptoglandular fistula (716 up, 371 down). Top differentially expressed genes encode proteins implicated in IBD pathogenesis including CARD18 (log2FC= 23.2, p=3.9E-21), BATF2 (log2FC=2.8, p=1.8E-8), ETV7 (log2FC=2.1, p=2.0E-7), DSG1 (log2FC=7.8, p=2.7E-6) and IL22RA1 (log2FC=5.3, p=4.6E-6). Additional pathway analysis highlighted various proinflammatory processes in CD fistula (as compared to cryptoglandular fistula), including upregulation of antigen presentation and Th1/Th2 activation (p & lt;1.0E-9). Intriguingly, CD fistula showed a significant downregulation of wound healing signaling pathways (p=6.5E-6), emphasising the refractory character of this debilitating condition. Upstream analyses showed an increased activation of top regulators IFNγ, TNF, LPS and STAT1 (p & lt;1.0E-24). Cellular deconvolution identified significant differences between both fistula types, with a predominance of inflammatory cells in CD including Th1 cells, dendritic cells, naïve CD4 T cells, memory B cells and central memory CD8 and CD4 T cells (p & lt;5.0E-2). In contrast, cryptoglandular fistula were characterised by a significant enrichment of myocytes, smooth muscle cells and neurons (p & lt;3.0E-3). Presence of neutrophils, wound healing and pro-inflammatory macrophages did not differ between both fistula types. Conclusion CD fistulas have a strong proinflammatory fingerprint, but seem to have lower wound healing capacity as compared to cryptoglandular fistula. An aggressive medical and surgical treatment is therefore required, including the search for novel, powerful anti-inflammatory and wound healing compounds.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjab232.159
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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