Host-bacterial interactions gastrointestinal diseases

There is a clear link between colonization of an individual with Helicobacter pylori and their risk to develop intestinal metaplasia and gastric cancer. While a role for intestinal bacteria in other (intestinal) diseases is emerging, it is as yet unclear whether a causal relationship exists between microbial alterations and intestinal disease. We investigate to what extent microbial changes are present in diverse intestinal diseases, how these changes modulate intracellular signaling in intestinal epithelial cells and how modulation of microbes can affect disease activity.   

The role of the intestinal microbiota in intestinal inflammation in patients with Inflammatory bowel diseases (IBD)
Inflammatory bowel disease is a complex disease, arising as a consequence of impaired interaction between the host immune system in genetically susceptible individuals. We study these different components contributing to IBD pathology, in order to find potential targets for patient stratification, therapy, or diagnosis. In particular, we are interested whether microbial changes induced by diet and pregnancy may affect disease course in these patients. Additionally, we study how genetic factors associated with bacterial handling can contribute to disease. 

The potential use of intestinal microbiome detection for colorectal cancer (CRC) screening
Colorectal cancer is the third most commonly diagnosed cancer in the world, and follows a well-described adenoma to carcinoma sequence which is accompanied by an accumulation of mutations. Identification and treatment of colorectal cancer still requires improvement. We investigate to what extent microbial changes are associated with CRC and whether this may be used to optimize identification of patients.  

The role of Helicobacter pylori interaction with gastric epithelium during gastric metaplasia and the contribution of endoplasmic reticulum stress therein
Intestinal metaplasia of the gastric mucosa is considered a precancerous lesion which may progress to gastric cancer. The primary cause of gastric cancer is considered to be infection with the pathogen Helicobacter pylori. The exact mechanisms of H. pylori induced carcinogenesis, and its role in progression from metaplasia to carcinoma remain to be elucidated. We investigate genetic variants associated with HP infection, and how these can contribute to disease development. 

Other studies 
We have a general interest in gastrointestinal pathology, and the signal transduction mechanisms that contribute therein. Using kinome profiling and phosphatase assays, we associate phosphorylation patterns in fresh tissue and organoids from several intestinal diseases, including colorectal, stomach and pancreatic cancer, as well as inflammatory bowel disease.  

1. Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients. Faria AVS, Andrade SS, Reijm AN, Spaander MCW, de Maat MPM, Peppelenbosch MP, Ferreira-Halder CV, Fuhler GM. J Clin Med. 2019 Jun 28;8(7). pii: E936. doi: 10.3390/jcm8070936.
2. Modulation of cytokine patterns and microbiome during pregnancy in IBD.van der Giessen J, Binyamin D, Belogolovski A, Frishman S, Tenenbaum-Gavish K, Hadar E, Louzoun Y, Peppelenbosch MP, van der Woude CJ, Koren O, Fuhler GM. Gut. 2019 Jun 5. pii: gutjnl-2019-318263. doi: 10.1136/gutjnl-2019-318263
3. HOXA9 mediates and marks premalignant compartment size expansion in colonic adenomas.Janmaat VT, Liu H, da Silva RA, Wisse PHA, Spaander MCW, Ten Hagen TLM, Smits R, Bruno MJ, Fuhler GM, Peppelenbosch MP.Carcinogenesis. 2019 Feb 20. pii: bgz038. doi: 10.1093/carcin/bgz038.
4. Achalasia and associated esophageal cancer risk: What lessons can we learn from the molecular analysis of Barrett's-associated adenocarcinoma? Nesteruk K, Spaander MCW, Leeuwenburgh I, Peppelenbosch MP, Fuhler GM. Biochim Biophys Acta Rev Cancer. 2019 May 4. pii: S0304-419X(19)30028-9. doi: 10.1016/j.bbcan.2019.04.007 
5. A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models.van der Giessen J, van der Woude CJ, Peppelenbosch MP, Fuhler GM. Cells. 2019 Mar 19;8(3). pii: E261. doi: 10.3390/cells803026
6. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response. Grootjans J, Krupka N, Hosomi S, Matute JD, Hanley T, Saveljeva S, Gensollen T, Heijmans J, Li H, Limenitakis JP, Ganal-Vonarburg SC, Suo S, Luoma AM, Shimodaira Y, Duan J, Shih DQ, Conner ME, Glickman JN, Fuhler GM, Palm NW, de Zoete MR, van der Woude CJ, Yuan GC, Wucherpfennig KW, Targan SR, Rosenstiel P, Flavell RA, McCoy KD, Macpherson AJ, Kaser A, Blumberg RS. Science. 2019 Mar 1;363(6430):993-998. doi: 10.1126/science.aat7186.
7. The gastrointestinal microbiota and its role in oncogenesis. Lam SY, Yu J, Wong SH, Peppelenbosch MP, Fuhler GM. Best Pract Res Clin Gastroenterol. 2017 Dec;31(6):607-618. doi: 10.1016/j.bpg.2017.09.010. 
8. Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms. Mommersteeg MC, Yu J, Peppelenbosch MP, Fuhler GM. Biochim Biophys Acta Rev Cancer. 2018 Jan;1869(1):42-52. doi: 10.1016/j.bbcan.2017.11.003. Epub 2017 Nov 24. Review. Pancreatic cyst fluid harbors a unique microbiome. Li S, Fuhler GM, Bn N, Jose T, Bruno MJ, Peppelenbosch MP, Konstantinov SR.
9. Microbiome. 2017 Nov 9;5(1):147. doi: 10.1186/s40168-017-0363-6. Analysis of SHIP1 expression and activity in Crohn's disease patients. Somasundaram R, Fernandes S, Deuring JJ, de Haar C, Kuipers EJ, Vogelaar L, Middleton FA, van der Woude CJ, Peppelenbosch MP, Kerr WG, Fuhler GM. PLoS One. 2017 Aug 2;12(8):e0182308. doi: 10.1371/journal.pone.0182308
10. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R, Saveljeva S, Bhattacharyya J, Flak MB, Shih DQ, Fuhler GM, Parkes M, Kohno K, Iwawaki T, Janneke van der Woude C, Harding HP, Smith AM, Peppelenbosch MP, Targan SR, Ron D, Rosenstiel P, Blumberg RS, Kaser A. J Exp Med. 2017 Feb;214(2):401-422. doi: 10.1084/jem.20160791.
11. Fumarates and Cancer.Fuhler GM, Eppinga H, Peppelenbosch MP. Trends Mol Med. 2017 Jan;23(1):3-5. doi: 10.1016/j.molmed.2016.12.001.
12. Testing for Anti-PBP Antibody Is Not Useful in Diagnosing Autoimmune Pancreatitis. Buijs J, Cahen DL, van Heerde MJ, Hansen BE, van Buuren HR, Peppelenbosch MP, Fuhler GM, Bruno MJ. Am J Gastroenterol. 2016 Nov;111(11):1650-1654. doi: 10.1038/ajg.2016.241. Gut Microbiota Developments With Emphasis on Inflammatory Bowel Disease: Report From the Gut Microbiota for Health World Summit 2016.
13. Eppinga H, Fuhler GM, Peppelenbosch MP, Hecht GA. Gastroenterology. 2016 Aug;151(2):e1-4. doi: 10.1053/j.gastro.2016.06.024.
    Improved intra-array and interarray normalization of peptide microarray phosphorylation for phosphorylome and kinome profiling by rational selection of relevant spots. Scholma J, Fuhler GM, Joore J, Hulsman M, Schivo S, List AF, Reinders MJ, Peppelenbosch MP, Post JN. Sci Rep. 2016 May 26;6:26695. doi: 10.1038/srep26695.

We collaborate with Prof Jun Yu, Dr Siew Ng and Dr Sunny Wong from the Faculty of Medicine, Chinese University of Hong Kong on several projects related to bacterial composition in IBD and cancer.

We collaborate with Prof Carmen Verissima Ferreira Halder from the University of Campinas, UNICAMP, Brazil on several FAPESP-supported studies, including the role of phosphatases in intestinal cancer and the role of platelet in gastrointestinal tumor dissemination.

We collaborate with Prof Willian Fernando Zambuzzi, UNESP, Botucatu, Brazil, on FAPESP supported studies into the signaling pathways contributing to bone formation.

Gwenny Fuhler, PhD, group leader

Janine van der Giessen, MSc, PhD candidate,

Michiel Mommersteeg, MSc, PhD candidate

Suk Yee Lam, MSc, PhD candidate

Kateryna Nesteruk, MSc, PhD candidate

Bingting Yu, PhD candidate

Alessandra Faria, Msc, PhD candidate