Multiomic analysis reveals cellular and epigenetic plasticity in intestinal pouches of ulcerative colitis patients.
Journal
medRxiv : the preprint server for health sciences
Titre abrégé: medRxiv
Pays: United States
ID NLM: 101767986
Informations de publication
Date de publication:
13 Nov 2023
13 Nov 2023
Historique:
pubmed:
28
11
2023
medline:
28
11
2023
entrez:
28
11
2023
Statut:
epublish
Résumé
Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the standard of care for patients with severe treatment resistant ulcerative colitis (UC). Despite improvements in patient outcomes, about 50% of patients will develop inflammation of the pouch within 1-2 years following surgery. Establishment of UC pouches is associated with profound histological changes of the mucosa. A detailed characterization of these changes on a cellular and molecular level is crucial for an improved understanding of pouch physiology and diseases management. We generated cell-type-resolved transcriptional and epigenetic atlases of UC pouches using scRNA-seq and scATAC-seq data from paired biopsy samples from the ileal pouch and ileal segment above the pouch (pre-pouch) of UC-IPAA patients (n=6, female=2) without symptoms. We also collected data from paired biopsies of the terminal ileum (TI) and ascending colon (AC) from healthy controls (n=6, female=3). We identified novel populations of colon-like absorptive and secretory epithelial cells, constituting a significant proportion of the epithelial cell fraction in the pouch but not in matched pre-pouch samples. Pouch-specific enterocytes expressed colon-specific genes, including CEACAM5, CA2. However, in contrast to normal colonic epithelium, these cells also expressed a range of inflammatory and secretory genes, similar to previously detected gene expression signatures in IBD patients. Comparison to longitudinal bulk RNA-seq data from UC pouches demonstrated that colon-like epithelial cells are present early after pouch functionalization and independently of subsequent pouchitis. Finally, single cell chromatin accessibility revealed activation colonic transcriptional regulators, including CDX1, NFIA, and EHF. UC pouches are characterized by partial colonic metaplasia of the epithelium. These data constitute a resource of transcriptomic and epigenetic signatures of cell populations in the pouch and provide an anchor for understanding the underlying molecular mechanisms of pouchitis.
Sections du résumé
Background & Aims
UNASSIGNED
Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the standard of care for patients with severe treatment resistant ulcerative colitis (UC). Despite improvements in patient outcomes, about 50% of patients will develop inflammation of the pouch within 1-2 years following surgery. Establishment of UC pouches is associated with profound histological changes of the mucosa. A detailed characterization of these changes on a cellular and molecular level is crucial for an improved understanding of pouch physiology and diseases management.
Methods
UNASSIGNED
We generated cell-type-resolved transcriptional and epigenetic atlases of UC pouches using scRNA-seq and scATAC-seq data from paired biopsy samples from the ileal pouch and ileal segment above the pouch (pre-pouch) of UC-IPAA patients (n=6, female=2) without symptoms. We also collected data from paired biopsies of the terminal ileum (TI) and ascending colon (AC) from healthy controls (n=6, female=3).
Results
UNASSIGNED
We identified novel populations of colon-like absorptive and secretory epithelial cells, constituting a significant proportion of the epithelial cell fraction in the pouch but not in matched pre-pouch samples. Pouch-specific enterocytes expressed colon-specific genes, including CEACAM5, CA2. However, in contrast to normal colonic epithelium, these cells also expressed a range of inflammatory and secretory genes, similar to previously detected gene expression signatures in IBD patients. Comparison to longitudinal bulk RNA-seq data from UC pouches demonstrated that colon-like epithelial cells are present early after pouch functionalization and independently of subsequent pouchitis. Finally, single cell chromatin accessibility revealed activation colonic transcriptional regulators, including CDX1, NFIA, and EHF.
Conclusion
UNASSIGNED
UC pouches are characterized by partial colonic metaplasia of the epithelium. These data constitute a resource of transcriptomic and epigenetic signatures of cell populations in the pouch and provide an anchor for understanding the underlying molecular mechanisms of pouchitis.
Identifiants
pubmed: 38014192
doi: 10.1101/2023.11.11.23298309
pmc: PMC10680893
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK042086
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM142986
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK122394
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007074
Pays : United States
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing interests.
Références
Dis Colon Rectum. 2000 Dec;43(12):1743-8
pubmed: 11156461
Nature. 2015 Jul 23;523(7561):486-90
pubmed: 26083756
Dis Colon Rectum. 2008 May;51(5):554-60
pubmed: 18266037
Lab Invest. 2008 Oct;88(10):1110-20
pubmed: 18711353
Genome Biol. 2015 Apr 08;16:67
pubmed: 25887922
Nat Genet. 2021 Mar;53(3):403-411
pubmed: 33633365
Sci Immunol. 2020 Aug 21;5(50):
pubmed: 32826341
Immunity. 2013 May 23;38(5):958-69
pubmed: 23664832
Gut. 2013 Jul;62(7):967-76
pubmed: 23135761
Gastroenterol Clin North Am. 2001 Mar;30(1):223-41
pubmed: 11394032
Colorectal Dis. 2022 Jan;24(1):27-39
pubmed: 34800326
Gut. 2018 Jan;67(1):36-42
pubmed: 27742763
Cell Tissue Res. 2013 Jun;352(3):639-46
pubmed: 23519454
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Inflamm Bowel Dis. 2017 Mar;23(3):366-378
pubmed: 28221248
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
Bioinformatics. 2021 Apr 19;37(2):192-201
pubmed: 32730587
Cell Stem Cell. 2022 Jan 6;29(1):101-115.e10
pubmed: 34582804
Inflamm Bowel Dis. 2012 Jun;18(6):1146-55
pubmed: 22021180
Gigascience. 2020 Dec 26;9(12):
pubmed: 33367645
Nat Methods. 2017 Nov;14(11):1083-1086
pubmed: 28991892
Gut. 1996 Feb;38(2):234-9
pubmed: 8801203
Cell. 2014 Sep 11;158(6):1431-1443
pubmed: 25215497
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Cell. 2021 Jun 10;184(12):3281-3298.e22
pubmed: 34019796
Ann Surg. 2013 Apr;257(4):679-85
pubmed: 23299522
Nature. 2023 Jul;619(7970):572-584
pubmed: 37468586
Science. 2020 Nov 13;370(6518):
pubmed: 33184180
Nature. 2021 Sep;597(7875):250-255
pubmed: 34497389
Gastroenterology. 2021 Apr;160(5):1679-1693
pubmed: 33359089
Inflamm Bowel Dis. 2011 May;17(5):1177-88
pubmed: 20824812
Gastroenterology. 2020 Aug;159(2):591-608.e10
pubmed: 32428507
Nat Biotechnol. 2018 Dec 03;:
pubmed: 30531897
Nat Commun. 2019 Jan 22;10(1):380
pubmed: 30670690
J Immunol. 2007 Jun 15;178(12):8203-11
pubmed: 17548659
Cell Stem Cell. 2018 Dec 6;23(6):787-793.e6
pubmed: 30526881
Gut. 2017 Dec;66(12):2069-2079
pubmed: 27803115
Gastroenterology. 2022 Jun;162(7):1975-1989
pubmed: 35227778
Sci Rep. 2022 Nov 27;12(1):20361
pubmed: 36437274
Cell Death Differ. 2022 Nov;29(11):2288-2302
pubmed: 35606410
Cell. 2019 Jul 25;178(3):714-730.e22
pubmed: 31348891
Inflamm Bowel Dis. 2021 Aug 19;27(9):1475-1481
pubmed: 33295614
BMC Bioinformatics. 2016 Nov 25;17(1):483
pubmed: 27884101
Immunity. 2023 Feb 14;56(2):444-458.e5
pubmed: 36720220
Cell Genom. 2022 Sep 14;2(9):
pubmed: 36204155