Satsangi, Jack

Ho, Gwo-Tzer

Rossi, Adriano

Boyapati, Ray Kiran

2018-10-24T10:22:36Z

2018-10-24T10:22:36Z

2018-11-30

Background The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) are chronic relapsing inflammatory disorders which have a rising incidence and cause significant morbidity. There are currently several treatment options with many more in the drug pipeline, but there are a lack of accurate biomarkers for decisions on treatment choice, assessment of disease activity and prognostication. There is a growing interest and desire for personalised or ‘precision’ medicine in IBD where novel biomarkers may help individualise IBD care in terms of diagnosis, choice of therapy, monitoring of response and detection of relapse. One class of functionally active biomarkers which have yet to be thoroughly investigated in IBD is damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). It has been recently shown that gut mitochondrial dysfunction can result in loss of epithelial barrier function and the development of colitis. Mitochondrial DAMPs have recently been described as elevated in several inflammatory diseases. Hypothesis The primary hypothesis of this thesis is that circulating levels of mtDNA is elevated in IBD. Secondary hypotheses are: (a) levels of other mitochondrial DAMPs are elevated in IBD, (b) circulating mtDNA can be used as a novel biomarker in IBD and (c) mtDNA is released locally at sites of inflammation in IBD. Methods Plasma and serum were collected prospectively from recruited IBD patients and non-IBD controls. Faeces and colonic tissue were collected from a subset of these patients. mtDNA in serum, plasma and faeces was measured using qPCR (amplifying COXIII/ND2 genes). Mass spectrometry was used to detect mitochondrial formylated peptides in the plasma of a subset of patients. IBD tissue was assessed for (a) mitochondrial damage using transmission electron microscopy (TEM) and (b) TLR9 expression, the target for mtDNA. Results 97 patients with IBD (67 UC and 30 CD), and 40 non-IBD controls were recruited. Plasma mtDNA levels were increased in UC and CD (both p<0.0001) compared to non-IBD controls; with significant correlations with blood (CRP, albumin, white cell count), clinical and endoscopic markers of severity; and disease activity. In active UC, we detected significantly higher circulating mitochondrial formylated peptides and faecal mtDNA levels (vs. non-IBD controls [p<0.01 and <0.0001 respectively]) with demonstrable TEM evidence of intestinal mucosal mitochondrial damage. In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC/CD compared to controls (both p<0.05). Conclusions Taken together, the findings suggest mtDNA is released during active inflammation in inflammatory bowel disease and is a potential novel mechanistic biomarker.

http://hdl.handle.net/1842/33169

en

The University of Edinburgh

Boyapati RK et al (2018). Mitochondrial DNA is a pro-inflammatory damage-associated molecular pattern (DAMP) released during active IBD, Inflammatory Bowel Disease, doi: 10.1093/ibd/izy095

Boyapati, R., Satsangi, J. and Ho, GT (2015) ‘Pathogenesis of Crohn’s disease’, F1000Prime Reports, 7(44). doi: 10.12703/P7-44.

Ho, GT., Boyapati, R. and Satsangi, J. (2015) ‘Ulcerative colitis’, Medicine, 43(5):276–281. doi: 10.1016/j.mpmed.2015.02.004.

Boyapati, R.K. et al. (2016) Biomarkers in Search of Precision Medicine in IBD, Am J Gastroenterol, 111(12):1682-1690. doi: 10.1038/ajg.2016.441.

Boyapati, R. et al. (2016) ‘Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications’, Mucosal Immunology, 9(3):567–82. doi: 10.1038/mi.2016.14.

Boyapati, R. K. et al. (2017) ‘Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases’, F1000Research, 6(169). doi: 10.12688/f1000research.10397.1.

Torres, J., Boyapati, R.K. & Kennedy, N.A., Louis, E., Colombel, J.F. & Satsangi, J. (2015). ‘Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease’. Gastroenterology, 149(7)1716-30. doi: 10.1053/j.gastro.2015.08.055

Boyapati, R.K., Ho, GT. and Satsangi J. (2017). ‘Can Thiopurines Prevent Formation of Antibodies Against Tumor Necrosis Factor Antagonists After Failure of These Therapies?’, Clinical Gastroenterology & Hepatology, 15(1):76-78. doi: 10.1016/j.cgh.2016.09.152

Kalla R., Kennedy N.A., Ventham N.T., Boyapati R.K., Adams A.T., Nimmo E.R., Visconti M.R., Drummond H., Ho GT., Pattenden R.J., Wilson D.C, Satsangi J. (2016). ‘Serum Calprotectin: A Novel Diagnostic and Prognostic Marker in Inflammatory Bowel Diseases’. American Journal of Gastroenterology, 111:1796–1805. doi: 10.1038/ajg.2016.342

Ho, G. T., Liu, B., Boyapati, R. K., Kennedy, N. A., Dorward, D. A, Noble, C.L, Shimizu, T, Carter, R.N, Chew, E.T.S, Morton, N.M, Rossi, R.B, Iredale, J.P, Satsangi, J. (2018) ‘MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation’, Mucosal Immunology, 11(1):120-130. doi: 10.1038/mi.2017.31

mitochondria

inflammatory bowel disease

Crohn’s disease

ulcerative colitis

biomarkers

mitochondrial DNA

Mitochondrial damage-associated molecular patterns (DAMPs) in inflammatory bowel disease

Thesis or Dissertation

Doctoral

MD Doctor of Medicine