Research progress of effect of intestinal flora on anastomotic leakage following colorectal cancer surgery_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Chaoyang ¹ , LIN Hao ¹ , ZHANG Haibao ¹ , JU Jiahua ¹ ,  YU Yongjiang ²

1. The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of Gastrointestinal Surgery/Hernia and Abdominal Wall Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding author：

YU Yongjiang, Email: ylongy@163.com

Keywords：

intestinal flora; colorectal cancer; perioperative period; anastomotic leakage

DOI：

10.7507/1007-9424.202205030

Video：

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Objective To understand the changes of intestinal flora during perioperative period of colorectal cancer and the mechanism affecting the occurrence of postoperative anastomotic leakage, so as to improve perioperative management of patients and find possible measures to decrease the incidence rate of anastomotic leakage. Method The literature related to perioperative intestinal flora assessment, anastomotic healing, and anastomotic leakage of colorectal cancer in recent years was comprehensively searched in the CNKI, PubMed, and Embase databases and made an review. Results Due to the various perioperative interventions, the diversity and abundance of intestinal flora had changed after colorectal cancer surgery, and some conditional pathogenic bacteria such as Enterococcus faecalis, Pseudomonas aeruginosa, etc. increased obviously, which led to collagen degradation through the expression of bacterial collagenase or the excessive activation of matrix metalloproteinases in the host intestine, then might lead to the poor anastomotic healing and even the anastomotic leakage. Conclusion Although the evidence of effect of intestinal flora on anastomotic leakage mainly comes from animal experiments, it still shows the potential role of intestinal flora in the occurrence of anastomotic leakage after colorectal cancer surgery, and can be regulated by perioperative intervention, which suggests that it may provide a new strategy for prevention of anastomotic leakage.

Citation： WANG Chaoyang, LIN Hao, ZHANG Haibao, JU Jiahua, YU Yongjiang. Research progress of effect of intestinal flora on anastomotic leakage following colorectal cancer surgery. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(11): 1522-1527. doi: 10.7507/1007-9424.202205030 Copy

1.	Chiarello MM, Fransvea P, Cariati M, et al. Anastomotic leakage in colorectal cancer surgery. Surg Oncol, 2022, 40: 101708. doi: 10.1016/j.suronc.2022.101708.
2.	McDermott FD, Heeney A, Kelly ME, et al. Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks. Br J Surg, 2015, 102(5): 462-479.
3.	刘军广, 陈贺凯, 汪欣, 等. 腹腔镜低位直肠癌经括约肌间切除术后吻合口漏的影响因素分析及预测模型构建. 中华外科杂志, 2021, 59(5): 332-337.
4.	冯永飞, 金相任, 刘洋, 等. 结直肠癌术后吻合口漏预测因素研究进展. 国际外科学杂志, 2021, 48(2): 137-140.
5.	Zarnescu EC, Zarnescu NO, Costea R. Updates of risk factors for anastomotic leakage after colorectal surgery. Diagnostics (Basel), 2021, 11(12): 2382. doi: 10.3390/diagnostics11122382.
6.	Koliarakis I, Athanasakis E, Sgantzos M, et al. Intestinal microbiota in colorectal cancer surgery. Cancers (Basel), 2020, 12(10): 3011. doi: 10.3390/cancers12103011.
7.	Gaines S, Shao C, Hyman N, et al. Gut microbiome influences on anastomotic leak and recurrence rates following colorectal cancer surgery. Br J Surg, 2018, 105(2): e131-e141. doi: 10.1002/bjs.10760.
8.	Bibbò S, Ianiro G, Giorgio V, et al. The role of diet on gut microbiota composition. Eur Rev Med Pharmacol Sci, 2016, 20(22): 4742-4749.
9.	王丽娜, 苏秀兰. 肠道微生物与结直肠癌. 生命的化学, 2021, 41(1): 25-32.
10.	Zhang S, Kong C, Yang Y, et al. Human oral microbiome dysbiosis as a novel non-invasive biomarker in detection of colorectal cancer. Theranostics, 2020, 10(25): 11595-11606.
11.	张明海, 杨依迪, 周诚斌, 等. 结直肠癌与肠道微生物群研究进展. 中国微生态学杂志, 2020, 32(3): 358-363.
12.	Ohigashi S, Sudo K, Kobayashi D, et al. Significant changes in the intestinal environment after surgery in patients with colorectal cancer. J Gastrointest Surg, 2013, 17(9): 1657-1664.
13.	Guyton K, Alverdy JC. The gut microbiota and gastrointestinal surgery. Nat Rev Gastroenterol Hepatol, 2017, 14(1): 43-54.
14.	Shogan BD, Smith DP, Christley S, et al. Intestinal anastomotic injury alters spatially defined microbiome composition and function. Microbiome, 2014, 2: 35. doi: 10.1186/2049-2618-2-35.
15.	Lam A, Fleischer B, Alverdy J. The biology of anastomotic healing-the unknown overwhelms the known. J Gastrointest Surg, 2020, 24(9): 2160-2166.
16.	Karrasch T, Jobin C. Wound healing responses at the gastrointestinal epithelium: a close look at novel regulatory factors and investigative approaches. Z Gastroenterol, 2009, 47(12): 1221-1229.
17.	Lee DS, Ryu JA, Chung CR, et al. Risk factors for acquisition of multidrug-resistant bacteria in patients with anastomotic leakage after colorectal cancer surgery. Int J Colorectal Dis, 2015, 30(4): 497-504.
18.	Komen N, Slieker J, Willemsen P, et al. Polymerase chain reaction for Enterococcus faecalis in drain fluid: the first screening test for symptomatic colorectal anastomotic leakage. The appeal-study: analysis of parameters predictive for evident anastomotic leakage. Int J Colorectal Dis, 2014, 29(1): 15-21.
19.	Neumann PA, Twardy V, Becker F, et al. Assessment of MMP-2/-9 expression by fluorescence endoscopy for evaluation of anastomotic healing in a murine model of anastomotic leakage. PLoS One, 2018, 13(3): e0194249. doi: 10.1371/journal.pone.0194249.
20.	El Bairi K, Jabi R, Trapani D, et al. Can the microbiota predict response to systemic cancer therapy, surgical outcomes, and survival? The answer is in the gut. Expert Rev Clin Pharmacol, 2020, 13(4): 403-421.
21.	Olivas AD, Shogan BD, Valuckaite V, et al. Intestinal tissues induce an SNP mutation in Pseudomonas aeruginosa that enhances its virulence: possible role in anastomotic leak. PLoS One, 2012, 7(8): e44326. doi: 10.1371/journal.pone.0044326.
22.	Gershuni VM, Friedman ES. The microbiome-host interaction as a potential driver of anastomotic leak. Curr Gastroenterol Rep, 2019, 21(1): 4. doi: 10.1007/s11894-019-0668-7.
23.	Shogan BD, Belogortseva N, Luong PM, et al. Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Sci Transl Med, 2015, 7(286): 286ra68. doi: 10.1126/scitranslmed.3010658.
24.	Hyoju SK, Klabbers RE, Aaron M, et al. Oral polyphosphate suppresses bacterial collagenase production and prevents anastomotic leak due to Serratia marcescens and Pseudomonas aeruginosa. Ann Surg, 2018, 267(6): 1112-1118.
25.	Anderson DI, Keskey R, Ackerman MT, et al. Enterococcus faecalis is associated with anastomotic leak in patients undergoing colorectal surgery. Surg Infect (Larchmt), 2021, 22(10): 1047-1051.
26.	Pasternak B, Rehn M, Andersen L, et al. Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses. Int J Colorectal Dis, 2008, 23(3): 271-276.
27.	Lederer AK, Chikhladze S, Kohnert E, et al. Current insights: the impact of gut microbiota on postoperative complications in visceral surgery—a narrative review. Diagnostics (Basel), 2021, 11(11): 2099. doi: 10.3390/diagnostics11112099.
28.	Watanabe M, Murakami M, Nakao K, et al. Randomized clinical trial of the influence of mechanical bowel preparation on faecal microflora in patients undergoing colonic cancer resection. Br J Surg, 2010, 97(12): 1791-1797.
29.	Gaines S, Williamson A, Pena R, et al. 234–preoperative bowel preparation decreases colonization with collagenase producing bacteria in non-obese patients. Gastroenterology, 2019, 156(6): S1393-S1394. doi: 10.1016/S0016-5085(19)40520-9.
30.	Drago L, Valentina C, Fabio P. Gut microbiota, dysbiosis and colon lavage. Dig Liver Dis, 2019, 51(9): 1209-1213.
31.	Williamson AJ, Alverdy JC. Influence of the microbiome on anastomotic leak. Clin Colon Rectal Surg, 2021, 34(6): 439-446.
32.	De La Cochetière MF, Durand T, Lepage P, et al. Resilience of the dominant human fecal microbiota upon short-course antibiotic challenge. J Clin Microbiol, 2005, 43(11): 5588-5592.
33.	Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut, 2013, 62(11): 1591-1601.
34.	Zimmermann P, Curtis N. The effect of antibiotics on the composition of the intestinal microbiota—a systematic review. J Infect, 2019, 79(6): 471-489.
35.	Golder AM, Steele CW, Conn D, et al. Effect of preoperative oral antibiotics in combination with mechanical bowel preparation on inflammatory response and short-term outcomes following left-sided colonic and rectal resections. BJS Open, 2019, 3(6): 830-839.
36.	Kiran RP, Murray AC, Chiuzan C, et al. Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery. Ann Surg, 2015, 262(3): 416-425.
37.	Klinger AL, Green H, Monlezun DJ, et al. The role of bowel preparation in colorectal surgery: results of the 2012–2015 ACS-NSQIP data. Ann Surg, 2019, 269(4): 671-677.
38.	Ambe PC, Zarras K, Stodolski M, et al. Routine preoperative mechanical bowel preparation with additive oral antibiotics is associated with a reduced risk of anastomotic leakage in patients undergoing elective oncologic resection for colorectal cancer. World J Surg Oncol, 2019, 17(1): 20. doi: 10.1186/s12957-019-1563-2.
39.	van Praagh JB, de Goffau MC, Bakker IS, et al. Mucus microbiome of anastomotic tissue during surgery has predictive value for colorectal anastomotic leakage. Ann Surg. 2019, 269(5): 911-916.
40.	Hartman AL, Lough DM, Barupal DK, et al. Human gut microbiome adopts an alternative state following small bowel transplantation. Proc Natl Acad Sci USA, 2009, 106(40): 17187-17192.
41.	McBrayer DN, Gantman BK, Tal-Gan Y. N-methylation of amino acids in gelatinase biosynthesis-activating pheromone identifies key site for stability enhancement with retention of the Enterococcus faecalis fsr quorum sensing circuit response. ACS Infect Dis, 2019, 5(6): 1035-1041.
42.	Wiegerinck M, Hyoju SK, Mao J, et al. Novel de novo synthesized phosphate carrier compound ABA-PEG20k-Pi20 suppresses collagenase production in Enterococcus faecalis and prevents colonic anastomotic leak in an experimental model. Br J Surg, 2018, 105(10): 1368-1376.
43.	Nichols D, Pimentel MB, Borges FTP, et al. Sustained release of phosphates from hydrogel nanoparticles suppresses bacterial collagenase and biofilm formation in vitro. Front Bioeng Biotechnol, 2019, 7: 153. doi: 10.3389/fbioe.2019.00153.
44.	Hajjar R, Richard CS, Santos MM. The role of butyrate in surgical and oncological outcomes in colorectal cancer. Am J Physiol Gastrointest Liver Physiol, 2021, 320(4): G601-G608. doi: 10.1152/ajpgi.00316.2020.
45.	Bosmans JW, Jongen AC, Boonen BT, et al. Comparison of three different application routes of butyrate to improve colonic anastomotic strength in rats. Int J Colorectal Dis, 2017, 32(3): 305-313.
46.	Hajjar R, Oliero M, Cuisiniere T, et al. Improvement of colonic healing and surgical recovery with perioperative supplementation of inulin and galacto-oligosaccharides. Clin Nutr, 2021, 40(6): 3842-3851.

1. Chiarello MM, Fransvea P, Cariati M, et al. Anastomotic leakage in colorectal cancer surgery. Surg Oncol, 2022, 40: 101708. doi: 10.1016/j.suronc.2022.101708.
2. McDermott FD, Heeney A, Kelly ME, et al. Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks. Br J Surg, 2015, 102(5): 462-479.
3. 刘军广, 陈贺凯, 汪欣, 等. 腹腔镜低位直肠癌经括约肌间切除术后吻合口漏的影响因素分析及预测模型构建. 中华外科杂志, 2021, 59(5): 332-337.
4. 冯永飞, 金相任, 刘洋, 等. 结直肠癌术后吻合口漏预测因素研究进展. 国际外科学杂志, 2021, 48(2): 137-140.
5. Zarnescu EC, Zarnescu NO, Costea R. Updates of risk factors for anastomotic leakage after colorectal surgery. Diagnostics (Basel), 2021, 11(12): 2382. doi: 10.3390/diagnostics11122382.
6. Koliarakis I, Athanasakis E, Sgantzos M, et al. Intestinal microbiota in colorectal cancer surgery. Cancers (Basel), 2020, 12(10): 3011. doi: 10.3390/cancers12103011.
7. Gaines S, Shao C, Hyman N, et al. Gut microbiome influences on anastomotic leak and recurrence rates following colorectal cancer surgery. Br J Surg, 2018, 105(2): e131-e141. doi: 10.1002/bjs.10760.
8. Bibbò S, Ianiro G, Giorgio V, et al. The role of diet on gut microbiota composition. Eur Rev Med Pharmacol Sci, 2016, 20(22): 4742-4749.
9. 王丽娜, 苏秀兰. 肠道微生物与结直肠癌. 生命的化学, 2021, 41(1): 25-32.
10. Zhang S, Kong C, Yang Y, et al. Human oral microbiome dysbiosis as a novel non-invasive biomarker in detection of colorectal cancer. Theranostics, 2020, 10(25): 11595-11606.
11. 张明海, 杨依迪, 周诚斌, 等. 结直肠癌与肠道微生物群研究进展. 中国微生态学杂志, 2020, 32(3): 358-363.
12. Ohigashi S, Sudo K, Kobayashi D, et al. Significant changes in the intestinal environment after surgery in patients with colorectal cancer. J Gastrointest Surg, 2013, 17(9): 1657-1664.
13. Guyton K, Alverdy JC. The gut microbiota and gastrointestinal surgery. Nat Rev Gastroenterol Hepatol, 2017, 14(1): 43-54.
14. Shogan BD, Smith DP, Christley S, et al. Intestinal anastomotic injury alters spatially defined microbiome composition and function. Microbiome, 2014, 2: 35. doi: 10.1186/2049-2618-2-35.
15. Lam A, Fleischer B, Alverdy J. The biology of anastomotic healing-the unknown overwhelms the known. J Gastrointest Surg, 2020, 24(9): 2160-2166.
16. Karrasch T, Jobin C. Wound healing responses at the gastrointestinal epithelium: a close look at novel regulatory factors and investigative approaches. Z Gastroenterol, 2009, 47(12): 1221-1229.
17. Lee DS, Ryu JA, Chung CR, et al. Risk factors for acquisition of multidrug-resistant bacteria in patients with anastomotic leakage after colorectal cancer surgery. Int J Colorectal Dis, 2015, 30(4): 497-504.
18. Komen N, Slieker J, Willemsen P, et al. Polymerase chain reaction for Enterococcus faecalis in drain fluid: the first screening test for symptomatic colorectal anastomotic leakage. The appeal-study: analysis of parameters predictive for evident anastomotic leakage. Int J Colorectal Dis, 2014, 29(1): 15-21.
19. Neumann PA, Twardy V, Becker F, et al. Assessment of MMP-2/-9 expression by fluorescence endoscopy for evaluation of anastomotic healing in a murine model of anastomotic leakage. PLoS One, 2018, 13(3): e0194249. doi: 10.1371/journal.pone.0194249.
20. El Bairi K, Jabi R, Trapani D, et al. Can the microbiota predict response to systemic cancer therapy, surgical outcomes, and survival? The answer is in the gut. Expert Rev Clin Pharmacol, 2020, 13(4): 403-421.
21. Olivas AD, Shogan BD, Valuckaite V, et al. Intestinal tissues induce an SNP mutation in Pseudomonas aeruginosa that enhances its virulence: possible role in anastomotic leak. PLoS One, 2012, 7(8): e44326. doi: 10.1371/journal.pone.0044326.
22. Gershuni VM, Friedman ES. The microbiome-host interaction as a potential driver of anastomotic leak. Curr Gastroenterol Rep, 2019, 21(1): 4. doi: 10.1007/s11894-019-0668-7.
23. Shogan BD, Belogortseva N, Luong PM, et al. Collagen degradation and MMP9 activation by Enterococcus faecalis contribute to intestinal anastomotic leak. Sci Transl Med, 2015, 7(286): 286ra68. doi: 10.1126/scitranslmed.3010658.
24. Hyoju SK, Klabbers RE, Aaron M, et al. Oral polyphosphate suppresses bacterial collagenase production and prevents anastomotic leak due to Serratia marcescens and Pseudomonas aeruginosa. Ann Surg, 2018, 267(6): 1112-1118.
25. Anderson DI, Keskey R, Ackerman MT, et al. Enterococcus faecalis is associated with anastomotic leak in patients undergoing colorectal surgery. Surg Infect (Larchmt), 2021, 22(10): 1047-1051.
26. Pasternak B, Rehn M, Andersen L, et al. Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses. Int J Colorectal Dis, 2008, 23(3): 271-276.
27. Lederer AK, Chikhladze S, Kohnert E, et al. Current insights: the impact of gut microbiota on postoperative complications in visceral surgery—a narrative review. Diagnostics (Basel), 2021, 11(11): 2099. doi: 10.3390/diagnostics11112099.
28. Watanabe M, Murakami M, Nakao K, et al. Randomized clinical trial of the influence of mechanical bowel preparation on faecal microflora in patients undergoing colonic cancer resection. Br J Surg, 2010, 97(12): 1791-1797.
29. Gaines S, Williamson A, Pena R, et al. 234–preoperative bowel preparation decreases colonization with collagenase producing bacteria in non-obese patients. Gastroenterology, 2019, 156(6): S1393-S1394. doi: 10.1016/S0016-5085(19)40520-9.
30. Drago L, Valentina C, Fabio P. Gut microbiota, dysbiosis and colon lavage. Dig Liver Dis, 2019, 51(9): 1209-1213.
31. Williamson AJ, Alverdy JC. Influence of the microbiome on anastomotic leak. Clin Colon Rectal Surg, 2021, 34(6): 439-446.
32. De La Cochetière MF, Durand T, Lepage P, et al. Resilience of the dominant human fecal microbiota upon short-course antibiotic challenge. J Clin Microbiol, 2005, 43(11): 5588-5592.
33. Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut, 2013, 62(11): 1591-1601.
34. Zimmermann P, Curtis N. The effect of antibiotics on the composition of the intestinal microbiota—a systematic review. J Infect, 2019, 79(6): 471-489.
35. Golder AM, Steele CW, Conn D, et al. Effect of preoperative oral antibiotics in combination with mechanical bowel preparation on inflammatory response and short-term outcomes following left-sided colonic and rectal resections. BJS Open, 2019, 3(6): 830-839.
36. Kiran RP, Murray AC, Chiuzan C, et al. Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery. Ann Surg, 2015, 262(3): 416-425.
37. Klinger AL, Green H, Monlezun DJ, et al. The role of bowel preparation in colorectal surgery: results of the 2012–2015 ACS-NSQIP data. Ann Surg, 2019, 269(4): 671-677.
38. Ambe PC, Zarras K, Stodolski M, et al. Routine preoperative mechanical bowel preparation with additive oral antibiotics is associated with a reduced risk of anastomotic leakage in patients undergoing elective oncologic resection for colorectal cancer. World J Surg Oncol, 2019, 17(1): 20. doi: 10.1186/s12957-019-1563-2.
39. van Praagh JB, de Goffau MC, Bakker IS, et al. Mucus microbiome of anastomotic tissue during surgery has predictive value for colorectal anastomotic leakage. Ann Surg. 2019, 269(5): 911-916.
40. Hartman AL, Lough DM, Barupal DK, et al. Human gut microbiome adopts an alternative state following small bowel transplantation. Proc Natl Acad Sci USA, 2009, 106(40): 17187-17192.
41. McBrayer DN, Gantman BK, Tal-Gan Y. N-methylation of amino acids in gelatinase biosynthesis-activating pheromone identifies key site for stability enhancement with retention of the Enterococcus faecalis fsr quorum sensing circuit response. ACS Infect Dis, 2019, 5(6): 1035-1041.
42. Wiegerinck M, Hyoju SK, Mao J, et al. Novel de novo synthesized phosphate carrier compound ABA-PEG20k-Pi20 suppresses collagenase production in Enterococcus faecalis and prevents colonic anastomotic leak in an experimental model. Br J Surg, 2018, 105(10): 1368-1376.
43. Nichols D, Pimentel MB, Borges FTP, et al. Sustained release of phosphates from hydrogel nanoparticles suppresses bacterial collagenase and biofilm formation in vitro. Front Bioeng Biotechnol, 2019, 7: 153. doi: 10.3389/fbioe.2019.00153.
44. Hajjar R, Richard CS, Santos MM. The role of butyrate in surgical and oncological outcomes in colorectal cancer. Am J Physiol Gastrointest Liver Physiol, 2021, 320(4): G601-G608. doi: 10.1152/ajpgi.00316.2020.
45. Bosmans JW, Jongen AC, Boonen BT, et al. Comparison of three different application routes of butyrate to improve colonic anastomotic strength in rats. Int J Colorectal Dis, 2017, 32(3): 305-313.
46. Hajjar R, Oliero M, Cuisiniere T, et al. Improvement of colonic healing and surgical recovery with perioperative supplementation of inulin and galacto-oligosaccharides. Clin Nutr, 2021, 40(6): 3842-3851.

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Research progress of effect of intestinal flora on anastomotic leakage following colorectal cancer surgery

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