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Multimodal single cell analyses reveal mechanisms of perianal fistula in diverse Crohn’s disease [scRNA-seq]

ABSTRACT: Crohn’s disease (CD) is a chronic inflammatory condition that can affect any part of the gastrointestinal tract. African ancestry (AA) populations have been substantially under-represented in genome-wide association studies (GWAS) of CD and inflammatory bowel disease (IBD), reflecting in part the lower prevalence of CD in AA compared to European ancestry (EA) populations. Importantly, CD complicated by perianal fistulae has been found to be more prevalent and severe in African-ancestry patients. Perianal fistulae arise from the distal rectal mucosa and can course to a cutaneous surface, resulting in highly morbid complications. Monoclonal antibodies against anti-TNF are the mainstay of treatment, but recurrence and secondary loss-of-response is common. In severe, uncontrolled cases, complete proctectomy is required. The intestine is unique among adult tissues in that under homeostasis, residential macrophages are continually replenished from recruited blood monocytes. In EA cohorts, we established that chronic monocyte cultures stimulated with NOD2 agonists result in aberrant myeloid-stromal differentiation stratified by risk allele carrier status. NOD2 risk alleles are not associated with perianal fistulae; African-American patients with CD do not carry them (except via recent European ancestry admixture). There is no direct association between known CD GWAS risk loci and the risk of developing perianal fistula. Here, we present direct ex-vivo, single cell multiomic analyses of colorectal tissues and perianal fistulous tracts in AA and EA cases to define mechanisms of perianal fistula development. We implicate myeloid-stromal crosstalk and define cell subtypes using single cell RNA (scRNASeq), ATAC sequencing, and chronic, unstimulated monocyte cultures. Transcription factor motifs and ATAC signals co-localized with fine-mapped GWAS loci provide insight to cell-specific and transcriptional network regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260842 | GEO | 2024/05/16

REPOSITORIES: GEO

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Project description:Background: CrohnM-bM-^@M-^Ys disease is presently an incurable inflammatory bowel disease. Fistulae are extensions of the intestinal tract that may form connections with other organs. These are a common complication of CrohnM-bM-^@M-^Ys disease affecting up to 50% of patients with the most common including perianal and rectovaginal fistulae. The dysregulated growth observed in fistulae shares several major characteristics seen in the development of tumours. These similarities include epithelial-to-mesenchymal transition (EMT), invasive cell growth, increased extracellular matrix production and remodelling, up-regulated local expression of growth factors such as IGF-1 and the down-regulation of apoptosis pathways. Although several susceptibility loci have been described within CrohnM-bM-^@M-^Ys disease there is no individual gene or mutation that identifies susceptibility or the subsequent formation of fistulae within all people. Copy-number variation (CNV) is one mechanism that may explain much of this genetic complexity. CNV may be caused by a variety of mechanisms such as cycles of chromosomal breakage/fusion/bridging that are typical within chronically inflamed tissue. Interestingly CNV shows locus-specific mutation rates between individuals higher than that of SNPs and has been associated with complex Mendelian traits including disease susceptibility. In this current study we performed array comparative genomic hybridisation (aCGH) analysis of active fistulae resected from patients as part of a previous surgical intervention. As the control for comparison we employed tissue taken from the same patient within the same surgery at an uninvolved site of the gastrointestinal tract. This matched control was employed to better investigate CNV specific to the fistula tissue of each individual avoiding complications associated with the large number of CNV present within the healthy population. Major question addressed by the work: What are the differences in genetic copy-number within localised intestinal fistula tissue of individuals with CrohnM-bM-^@M-^Ys disease compared to healthy intestinal tissue from the same individual? Samples were selected from patients presenting with CrohnM-bM-^@M-^Ys Disease fistulae at Eastern Health Department of Gastroenterology and Hepatology (Arnold Street, Box Hill, Victoria, Australia). The 8 samples used in this study were formalin-fixed paraffin-embedded (FFPE) specimens following a surgical intervention to remove fistula tissue. To focus on changes within the individual patient we used tissue taken from the same surgery at an uninvolved region of the intestine as the matched control for CNV analysis.

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Multimodal single cell analyses reveal mechanisms of perianal fistula in diverse Crohn’s disease [scRNA-seq]

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