Pathway Paradigms Revealed from the Genetics of Inflammatory Bowel Disease

Overview

Journal Nature

Specialty Science

Date 2020 Feb 28

PMID 32103191

Citations 279

Authors

Daniel B Graham

Ramnik J Xavier

Affiliations

Soon will be listed here.

Abstract

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.

Citing Articles

Microbiota in inflammatory bowel disease: mechanisms of disease and therapeutic opportunities.

Iliev I, Ananthakrishnan A, Guo C Nat Rev Microbiol. 2025; .

PMID: 40065181 DOI: 10.1038/s41579-025-01163-0.

Bile acid 7α-dehydroxylating bacteria accelerate injury-induced mucosal healing in the colon.

Jalil A, Perino A, Dong Y, Imbach J, Volet C, Vico-Oton E EMBO Mol Med. 2025; .

PMID: 40065134 DOI: 10.1038/s44321-025-00202-w.

Zinc Oxide Administration Relieves the Diarrhea of ETEC K88-Infected Piglets by Reducing Ileal Apoptosis and Maintaining Gut Microbial Balance.

Zhang Y, Liu J, Li M, Dong Y, Li Z, Yi D Vet Sci. 2025; 12(2).

PMID: 40005874 PMC: 11861302. DOI: 10.3390/vetsci12020115.

Spleen volume in relation to ulcerative colitis and Crohn's disease: a Mendelian randomization study.

Su Q, Li J, Lu Y, Liang J, Huang S, Wu M Sci Rep. 2025; 15(1):6588.

PMID: 39994250 PMC: 11850802. DOI: 10.1038/s41598-025-90104-1.

Pathogenesis and precision medicine for predicting response in inflammatory bowel disease: advances and future directions.

Little R, Jayawardana T, Koentgen S, Zhang F, Connor S, Boussioutas A eGastroenterology. 2025; 2(1):e100006.

PMID: 39944752 PMC: 11770437. DOI: 10.1136/egastro-2023-100006.

References

Xavier R, Podolsky D . Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448(7152):427-34. DOI: 10.1038/nature06005. View

Kaplan G, Ng S . Understanding and Preventing the Global Increase of Inflammatory Bowel Disease. Gastroenterology. 2016; 152(2):313-321.e2. DOI: 10.1053/j.gastro.2016.10.020. View

Lloyd-Price J, Arze C, Ananthakrishnan A, Schirmer M, Avila-Pacheco J, Poon T . Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019; 569(7758):655-662. PMC: 6650278. DOI: 10.1038/s41586-019-1237-9. View

McKinney E, Lee J, Jayne D, Lyons P, Smith K . T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature. 2015; 523(7562):612-6. PMC: 4623162. DOI: 10.1038/nature14468. View

Hyams J, Davis Thomas S, Gotman N, Haberman Y, Karns R, Schirmer M . Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet. 2019; 393(10182):1708-1720. PMC: 6501846. DOI: 10.1016/S0140-6736(18)32592-3. View

Belarif L, Danger R, Kermarrec L, Nerriere-Daguin V, Pengam S, Durand T . IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease. J Clin Invest. 2019; 129(5):1910-1925. PMC: 6486337. DOI: 10.1172/JCI121668. View

Martins F, Sofiya L, Sykiotis G, Lamine F, Maillard M, Fraga M . Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019; 16(9):563-580. DOI: 10.1038/s41571-019-0218-0. View

Emond B, Ellis L, Chakravarty S, Ladouceur M, Lefebvre P . Real-world incidence of inflammatory bowel disease among patients with other chronic inflammatory diseases treated with interleukin-17a or phosphodiesterase 4 inhibitors. Curr Med Res Opin. 2019; 35(10):1751-1759. DOI: 10.1080/03007995.2019.1620713. View

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

10.

Liu J, van Sommeren S, Huang H, Ng S, Alberts R, Takahashi A . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015; 47(9):979-986. PMC: 4881818. DOI: 10.1038/ng.3359. View

11.

de Lange K, Moutsianas L, Lee J, Lamb C, Luo Y, Kennedy N . Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet. 2017; 49(2):256-261. PMC: 5289481. DOI: 10.1038/ng.3760. View

12.

Huang H, Fang M, Jostins L, Mirkov M, Boucher G, Anderson C . Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017; 547(7662):173-178. PMC: 5511510. DOI: 10.1038/nature22969. View

13.

Dendrou C, Cortes A, Shipman L, Evans H, Attfield K, Jostins L . Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci Transl Med. 2016; 8(363):363ra149. PMC: 5737835. DOI: 10.1126/scitranslmed.aag1974. View

14.

Momozawa Y, Dmitrieva J, Theatre E, Deffontaine V, Rahmouni S, Charloteaux B . IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun. 2018; 9(1):2427. PMC: 6013502. DOI: 10.1038/s41467-018-04365-8. View

15.

Calderon D, Nguyen M, Mezger A, Kathiria A, Muller F, Nguyen V . Landscape of stimulation-responsive chromatin across diverse human immune cells. Nat Genet. 2019; 51(10):1494-1505. PMC: 6858557. DOI: 10.1038/s41588-019-0505-9. View

16.

Finucane H, Reshef Y, Anttila V, Slowikowski K, Gusev A, Byrnes A . Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet. 2018; 50(4):621-629. PMC: 5896795. DOI: 10.1038/s41588-018-0081-4. View

17.

Rivas M, Avila B, Koskela J, Huang H, Stevens C, Pirinen M . Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 2018; 14(5):e1007329. PMC: 5967709. DOI: 10.1371/journal.pgen.1007329. View

18.

Arnadottir G, Norddahl G, Gudmundsdottir S, Agustsdottir A, Sigurdsson S, Jensson B . A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease. Nat Commun. 2018; 9(1):4447. PMC: 6202333. DOI: 10.1038/s41467-018-06964-x. View

19.

Rivas M, Graham D, Sulem P, Stevens C, Desch A, Goyette P . A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun. 2016; 7:12342. PMC: 4980482. DOI: 10.1038/ncomms12342. View

20.

Rivas M, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang C . Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet. 2011; 43(11):1066-73. PMC: 3378381. DOI: 10.1038/ng.952. View