Gastroenterology and Hepatology

Research

Research in this Division focuses on immunity and inflammation and its consequences, and the genetic underpinning of gastrointestinal diseases.

Professor Kaser’s group investigates the mechanisms that underlie inflammation at mucosal surfaces.  A single layer of intestinal epithelial cells – which may be considered the evolutionary most ancient innate immune cell type – separates the complex and densely populated habitat of the microbiota from the sterile host tissue of the gut, which itself harbours the majority of the host’s bona fide immune cells.  A loss of the mutualistic relationship between host and microbiota is thought to be at the basis of the inflammatory bowel diseases Crohn’s disease and ulcerative colitis. Using a variety of techniques, including complex genetic models, we explore the major biological mechanisms that are affected by risk genes of inflammatory bowel disease.  This approach opens up a window to explore the environmental factors that may trigger disease in genetically susceptible individuals, and which are the cause for the steep increase in incidence and prevalence of these diseases around the world. Following this path, we have reported mechanisms of how hypomorphic autophagy and mediators of the unfolded protein response lead to inflammatory bowel disease, defining a key pathway of Crohn’s disease pathogenesis.

Dr Parkes investigates the genetic basis of inflammatory bowel disease through genome-wide association studies, which are performed in collaboration with the Wellcome Trust Sanger Centre.  He leads the UK IBD Genetics consortium and is the past founding chair of the international consortium, which has driven the discovery of now > 150 genetic loci associated with risk for IBD.

Professor Fitzgerald investigates methods of early detection of cancer of the oesophagus. Oesophageal cancers are the 8th most common cancer worldwide and the 6th most common cause of cancer death with only 15% surviving 5 years, and frequently develops from an inflammatory condition of the oesophagus, Barrett’s oesophagus. The laboratory develops methods to allow for efficient ways of screening for patients at risk for malignant transformation that overcomes the limitations associated with the currently available screening methods. Professor Fitzgerald holds her primary affiliation with the Dept of Oncology and the MRC Cancer Unit.

Further research topics covered in the Division are the genetic basis of chronic liver disease (primary sclerosing cholangitis and primary biliary cirrhosis), and the role of senescence in liver disease (Dr Alexander), liver transplantation (Dr Gimson), small bowel transplantation and intestinal failure (Dr Middleton and Dr Woodward), non-alcoholic fatty liver disease (Dr Allison), inherited liver disease (Dr Griffiths), and endoscopy (Dr Metz).

In translational research, multi-centre trials of novel biological therapies for IBD, which target specific immune functions, are pursued within the Division.

Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon MN, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A*, Blumberg RS* (* denotes shared senior and corresponding authors). Paneth cells as a site of origin for intestinal inflammation. Nature 2013;503:272-6.

Niederreiter L, Fritz TM, Adolph TE, Krismer AM, Offner FA, Tschurtschenthaler M, Flak MB, Hosomi S, Tomczak MF, Kaneider NC, Sarcevic E, Kempster SL, Raine T, Esser D, Rosenstiel P, Kohno K, Iwawaki T, Tilg H, Blumberg RS, Kaser A.  ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med. 2013 Sep 23;210(10):2041-56

Tschurtschenthaler M, Wang J, Fricke C, Fritz TM, Niederreiter L, Adolph TE, Sarcevic E, Künzel S, Offner FA, Kalinke U, Baines JF, Tilg H, Kaser A. Type I interferon signalling in the intestinal epithelium affects Paneth cells, microbial ecology and epithelial regeneration. Gut. 2014 Feb 20. doi: 10.1136/gutjnl-2013-305863.

Raine T, Liu JZ, Anderson CA, Parkes M*, Kaser A* (*denotes shared senior author). Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease. Gut. 2014 May 5. doi: 10.1136/gutjnl-2013-306657. [Epub ahead of print]

Parkes M, Cortes A, van Heel D, Brown M. Analysis Article: Genetic insights into common pathways and complex relationships among immune mediated diseases. Nature Reviews Genetics 2013;14(9):661-73

Ellinghaus D, Zhang H, Zeissig S, Lipinski S, Till A, .., Annese V, Halfvarson J, D’Amato M, Daly MJ, Nothnagel M, Karlsen TH, Subramani S, Rosenstiel P, Schreiber S, Parkes M*, Franke A* (*denotes shared senior author). Association Between Variants of PRDM1 and NDP52 and Crohn’s Disease, Based on Exome Sequencing and Functional Studies. Gastroenterology. 2013 Aug;145(2):339-47

Aravinthan A, Pietrosi G, Hoare M, Jupp J, Marshall A, Verrill C, Davies S, Bateman A, Sheron N, Allison M, Alexander GJ. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS One. 2013 Sep 23;8(9):e72904. doi: 10.1371/journal.pone.0072904.

Weaver JM, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong CA, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O’Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavare S, Fitzgerald RC, the OCCAMS Consortium.  Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.  Nat Genet. 2014 June 22 (Epub ahead of print).

Ong CA, Shannon NB, Ross-Innes CS, O’Donovan M, Rueda OM, Hu DE, Kettunen MI, Walker CE, Noorani A, Hardwick RH, Brindle K, Fitzgerald RC.  Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy.  J Natl Cancer Inst. 2014 April 28;106(5).

Kaser A, Zeissig S, Blumberg RS.  Inflammatory Bowel Disease.  Annu Rev Immunol 2010; 28: 573-621.

Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS.  XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.  Cell 2008; 134:743-56.

 Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D’Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, Verspaget HW, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panés J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Rioux JD, D’Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, Parkes M.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci.  Nat Genet. 2010; 42:1118-25.

 Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM; Wellcome Trust Case Control Consortium, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M.  Investigation of Crohn’s disease risk loci in ulcerative colitis further defines their molecular relationship.  Gastroenterology 2009; 136:523-9.

 Saadi A, Shannon NB, Lao-Sirieix P, O’Donovan M, Walker E, Clemons NJ, Hardwick JS, Zhang C, Das M, Save V, Novelli M, Balkwill F, Fitzgerald RC.  Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers.  Proc Natl Acad Sci USA 2010; 107:2177-82.

 Bird-Lieberman EL, Neves AA, Lao-Sirieix P, O’Donovan M, Novelli M, Lovat L, Mahal DLK, Eng WS, Brindle KM, Fitzgerald RC.  Molecular imaging via novel application of fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett’s esophagus.  Nat Med 2011 in press.

Legend

Crypt abscess in the intestinal mucosa as a consequence of unresolved endoplasmic reticulum stress due to hypomorphic XBP1 function.