About the Project
Antibiotic use prior to and following colorectal surgery is conventional practice, and is aimed at reducing the incidence of postoperative infection which is a major risk of such surgery. However, no standard antibiotic regime is in place and the impact of antibiotics on the resident gut bacteria remains unclear. Indeed, there is currently much debate concerning whether antibiotic treatment is of benefit or causes harm in colorectal-surgery patients1. This gut microbiota has a pivotal role in reducing the risk of enteric infection through competition for nutrients and space, and through suppression of pathogenic organisms by the production of antimicrobial factors2. Oral antibiotics alter the composition and metabolic activity of the microbiota, and also impacts host-microbe co-metabolism which could have longer-term implications for the risk of enteric infection. Prebiotics are non-digestible oligosaccharides that select for specific colonic bacterial groups which are known to be beneficial to health3. Following antibiotic treatment, prebiotic nutritional supplements might aid the re-establishment of the microbiota of colorectal-surgery patients and thus promote recovery. This problem will be addressed by exploring the impact of antibiotics on the composition and metabolic activity of the microbiota colorectal-surgery patients and on host-microbe co-metabolism. We will also employ a series of in vitro gut models to explore the potential of prebiotics to aid the recovery of the gut microbiota following colorectal surgery.
Anastomotic leaks (AL) are potentially fatal complications following colorectal surgery and frequently have significant detrimental impact on the quality of life of those who survive. The clinical manifestations range from fever and pain, and include uncontrolled extravasation and septic shock with multisystem organ failure4, whilst treatment requires applications of antibiotics. Although extensively studied, the rate of incidence has remained at 8-10% for over 30 years5. Thus, there is a need to identify early predictive biomarkers to detect patients at increased risk of developing AL. In the longer term, there is a need to develop strategies to reduce these risks pre-operatively, which should be based on clear understanding of the mechanisms involved.
Following public consultation by the ACPGBI, the Delphi study reported that improving early detection (and thus outcomes) of ALs is the top non-cancer priority6. Clearly, a robust test to identify at risk patients at a preclinical, or early clinical, stage of an AL would be of immense value. Metabolic profiling is the systematic study of small-molecule products of biochemical pathways and such profiling in urine and blood by NMR spectroscopy has accurate predictive and prognostic value for other conditions including decompensated cirrhosis7, CVD8, gestational diabetes militus9 and acute pancreatitis10. Furthermore, metabolic profiling technologies are rapidly becoming established tools for surgical decision making in operating theatres by providing sensitive, specific, and efficient real-time diagnostic information. However, their potential for predicting AL has not yet been explored.
Although the actual causes of AL remain unknown, there is currently renewed interest in the role of the gut microbiota11. Specific commensal bacteria have the potential to contribute to AL, for example by initiating collagen degradation12. Furthermore, there is some evidence of links between the relative abundance of Lachnospiraceae13, mucin-degrading Ruminococcus and AL. However, such bacteria are normal members of the human gut community and it is therefore unlikely that these individual components have a direct causative role in AL. More likely is that they are key components in a microbial profile linked with AL and characterised by a unique metabolic signature. Our previous work demonstrates that metabolic profiling in urine by NMR spectroscopy is the most robust method for gaining insight into the metabolic activity of the microbiota and, importantly, patient-microbe co-metabolism. We will explore the role of the gut microbiota in anastomotic leaks, and determine whether metabolic profiling can identify a signature that is predictive of such leaks.
It is becoming increasingly apparent that the gut microbiota is a pivotal factor of gut health and is likely to play a key role in the outcome of colorectal surgery. However, there is a paucity of knowledge in this field and mechanistic understanding of host-microbe interactions around surgery is extremely limited. This project will generate systems-wide understanding of the links between the gut microbiota and host during recovery from colorectal surgery and thus has the potential to inform the development of preoperative regimes to improve surgical outcomes.
1 Bachmann, R., Leonard, D., Delzenne, N., Kartheuser, A. & Cani, P. D. Novel insight into the role of microbiota in colorectal surgery. Gut 66, 738-749, doi:10.1136/gutjnl-2016-312569 (2017).
2 Harris, V. C., Haak, B. W., Boele van Hensbroek, M. & Wiersinga, W. J. The Intestinal Microbiome in Infectious Diseases: The Clinical Relevance of a Rapidly Emerging Field. Open forum infectious diseases 4, ofx144-ofx144, doi:10.1093/ofid/ofx144 (2017).
3 Slavin, J. Fiber and prebiotics: mechanisms and health benefits. Nutrients 5, 1417-1435, doi:10.3390/nu5041417 (2013).
4 Russ, A. J. & Casillas, M. A. Gut Microbiota and Colorectal Surgery: Impact on Postoperative Complications. Clinics in colon and rectal surgery 29, 253-257, doi:10.1055/s-0036-1584502 (2016).
5 Daams, F., Luyer, M. & Lange, J. F. Colorectal anastomotic leakage: aspects of prevention, detection and treatment. World journal of gastroenterology 19, 2293-2297, doi:10.3748/wjg.v19.i15.2293 (2013).
6 Tiernan, J. et al. Use of a modified Delphi approach to develop research priorities for the Association of Coloproctology of Great Britain and Ireland. Colorectal Disease 16, 965-970, doi:10.1111/codi.12790 (2014).
7 McPhail, M. J. W. et al. Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis. Journal of hepatology 64, 1058-1067, doi:10.1016/j.jhep.2016.01.003 (2016).
8 Ruiz-Canela, M. et al. Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review. Journal of the American Heart Association 6, doi:10.1161/jaha.117.005705 (2017).
9 Bentley-Lewis, R. et al. Metabolomic profiling in the prediction of gestational diabetes mellitus. Diabetologia 58, 1329-1332, doi:10.1007/s00125-015-3553-4 (2015).
10 Battini, S. et al. Metabolomics approaches in pancreatic adenocarcinoma: tumor metabolism profiling predicts clinical outcome of patients. BMC medicine 15, 56, doi:10.1186/s12916-017-0810-z (2017).
11 Gaines, S., Shao, C., Hyman, N. & Alverdy, J. C. Gut microbiome influences on anastomotic leak and recurrence rates following colorectal cancer surgery. The British journal of surgery 105, e131-e141, doi:10.1002/bjs.10760 (2018).
12 Shogan, B. D. et al. Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Science Translational Medicine 7, 286ra268 (2015).
13 van Praagh, J. B. et al. Intestinal microbiota and anastomotic leakage of stapled colorectal anastomoses: a pilot study. Surg Endosc 30, 2259-2265, doi:10.1007/s00464-015-4508-z (2016).
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