Postoperative Complications Are Associated with Long-Term Changes in the Gut Microbiota Following Colorectal Cancer Surgery

Felix C F Schmitt, Martin Schneider, William Mathejczyk, Markus A Weigand, Jane C Figueiredo, Christopher I Li, David Shibata, Erin M Siegel, Adetunji T Toriola, Cornelia M Ulrich, Alexis B Ulrich, Sébastien Boutin, Biljana Gigic, Felix C F Schmitt, Martin Schneider, William Mathejczyk, Markus A Weigand, Jane C Figueiredo, Christopher I Li, David Shibata, Erin M Siegel, Adetunji T Toriola, Cornelia M Ulrich, Alexis B Ulrich, Sébastien Boutin, Biljana Gigic

Abstract

Changes in the gut microbiome have already been associated with postoperative complications in major abdominal surgery. However, it is still unclear whether these changes are transient or a long-lasting effect. Therefore, the aim of this prospective clinical pilot study was to examine long-term changes in the gut microbiota and to correlate these changes with the clinical course of the patient. Methods: In total, stool samples of 62 newly diagnosed colorectal cancer patients undergoing primary tumor resection were analyzed by 16S-rDNA next-generation sequencing. Stool samples were collected preoperatively in order to determine the gut microbiome at baseline as well as at 6, 12, and 24 months thereafter to observe longitudinal changes. Postoperatively, the study patients were separated into two groups-patients who suffered from postoperative complications (n = 30) and those without complication (n = 32). Patients with postoperative complications showed a significantly stronger reduction in the alpha diversity starting 6 months after operation, which does not resolve, even after 24 months. The structure of the microbiome was also significantly altered from baseline at six-month follow-up in patients with complications (p = 0.006). This was associated with a long-lasting decrease of a large number of species in the gut microbiota indicating an impact in the commensal microbiota and a long-lasting increase of Fusobacterium ulcerans. The microbial composition of the gut microbiome shows significant changes in patients with postoperative complications up to 24 months after surgery.

Keywords: 16S rDNA gene sequencing; anastomosis insufficiency; colorectal surgery; gut microbiota; inflammation; postoperative complications; sepsis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Patients with postoperative complications show a stronger reduction in the alpha diversity, which does not resolve even after 24 months. Following symbols were used to represent significance: p < 0.05 was indicated by * p < 0.01 by ** and p < 0.001 by ***.
Figure 2
Figure 2
Heatmap representing the longitudinal changes in the group of patients with postoperative complications. Only significantly differentially abundant ribosomal sequence variants (RSVs) (p-value < 0.05 and log2 (fold change) > 1) compared to the baseline are displayed (Deseq2). Several taxonomical levels were analyzed: (A) RSV, (B) genus, (C) order, and (D) phylum. Taxa enriched in the baseline are displayed in blue, and taxa enriched after complication are in red. The color intensity is relative to the log2 fold change, and nonsignificant taxa are displayed in white.

References

    1. Codner P.A., Herron T.J. The shifting microbiome in surgical stress. Curr. Surg. Rep. 2017;9:4–5. doi: 10.1007/s40137-017-0172-7.
    1. Kamada N., Seo S.-U., Chen G.Y., Núñez G. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 2013;13:321–335. doi: 10.1038/nri3430.
    1. Ley R.E., Turnbaugh P.J., Klein S., Gordon J.I. Microbial ecology: Human gut microbes associated with obesity. Nature. 2006;444:1022–1023. doi: 10.1038/4441022a.
    1. Marteau P., Lepage P., Mangin I., Suau A., Dore J., Pochart P., Seksik P. Review article: Gut flora and inflammatory bowel disease. Aliment Pharmacol. Ther. 2004;20:18–23. doi: 10.1111/j.1365-2036.2004.02062.x.
    1. Schmitt F., Lipinski A., Hofer S., Uhle F., Nusshag C., Hackert T., Dalpke A., Weigand M., Brenner T., Boutin S. Pulmonary microbiome patterns correlate with the course of disease in patients with sepsis-induced ARDS following major abdominal surgery. J. Hosp. Infect. 2020;105:438–446. doi: 10.1016/j.jhin.2020.04.028.
    1. Bartolini I., Risaliti M., Ringressi M.N., Melli F., Nannini G., Amedei A., Muiesan P., Taddei A. Role of gut microbiota-immunity axis in patients undergoing surgery for colorectal cancer: Focus on short and long-term outcomes. World, J. Gastroenterol. 2020;26:2498–2513. doi: 10.3748/wjg.v26.i20.2498.
    1. Koliarakis I., Athanasakis E., Sgantzos M., Mariolis-Sapsakos T., Xynos E., Chrysos E., Souglakos J., Tsiaoussis J. Intestinal Microbiota in Colorectal Cancer Surgery. Cancers. 2020;12:3011. doi: 10.3390/cancers12103011.
    1. Lankelma J.M., Van Vught L.A., Belzer C., Schultz M.J., Van Der Poll T., De Vos W.M., Wiersinga W.J. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: A pilot study. Intensiv. Care Med. 2017;43:59–68. doi: 10.1007/s00134-016-4613-z.
    1. Schmitt F.C.F., Brenner T., Uhle F., Loesch S., Hackert T., Ulrich A., Hofer S., Dalpke A.H., Weigand M.A., Boutin S. Gut microbiome patterns correlate with higher postoperative complication rates after pancreatic surgery. BMC Microbiol. 2019;19:1–13. doi: 10.1186/s12866-019-1399-5.
    1. Pamer E.G. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science. 2016;352:535–538. doi: 10.1126/science.aad9382.
    1. Blaser M.J. Antibiotic use and its consequences for the normal microbiome. Science. 2016;352:544–545. doi: 10.1126/science.aad9358.
    1. Ianiro G., Tilg H., Gasbarrini A. Antibiotics as deep modulators of gut microbiota: Between good and evil. Gut. 2016;65:1906–1915. doi: 10.1136/gutjnl-2016-312297.
    1. Ulrich C.M., Gigic B., Böhm J., Ose J., Viskochil R., Schneider M., Colditz G.A., Figueiredo J.C., Grady W.M., Li C.I., et al. The ColoCare Study: A Paradigm of Transdisciplinary Science in Colorectal Cancer Outcomes. Cancer Epidemiol. Biomark. Prev. 2019;28:591–601. doi: 10.1158/1055-9965.EPI-18-0773.
    1. Gigic B., Boeing H., Toth R., Böhm J., Habermann N., Scherer D. Associations Between Dietary Patterns and Longitudinal Quality of Life Changes in Colorectal Cancer Pa-tients: The ColoCare Study. Nutr. Cancer. 2018;70:51–60. doi: 10.1080/01635581.2018.1397707.
    1. Pettigrew M.M., Gent J.F., Kong Y., Halpin A.L., Pineles L., Harris A.D., Johnson J.K. Gastrointestinal Microbiota Disruption and Risk of Colonization With Carbapenem-resistant Pseudomonas aeruginosa in Intensive Care Unit Patients. Clin. Infect. Dis. 2019;69:604–613. doi: 10.1093/cid/ciy936.
    1. Aardema H., Lisotto P., Kurilshikov A., Diepeveen J.R.J., Friedrich A.W., Sinha B., De Smet A.M.G.A., Harmsen H.J.M. Marked Changes in Gut Microbiota in Cardio-Surgical Intensive Care Patients: A Longitudinal Cohort Study. Front. Cell. Infect. Microbiol. 2020;9:467. doi: 10.3389/fcimb.2019.00467.
    1. McDonald D., Ackermann G., Khailova L., Baird C., Heyland D., Kozar R., Lemieux M., Derenski K., King J., Vis-Kampen C., et al. Extreme Dysbiosis of the Microbiome in Critical Illness. mSphere. 2016;1 doi: 10.1128/mSphere.00199-16.
    1. Ojima M., Motooka D., Shimizu K., Gotoh K., Shintani A., Yoshiya K., Nakamura S., Ogura H., Iida T., Shimazu T. Metagenomic Analysis Reveals Dynamic Changes of Whole Gut Microbiota in the Acute Phase of Intensive Care Unit Patients. Dig. Dis. Sci. 2016;61:1628–1634. doi: 10.1007/s10620-015-4011-3.
    1. Zaborin A., Smith D., Garfield K., Quensen J., Shakhsheer B., Kade M. Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during pro-longed critical illness. mBio. 2014;5:e01361-14. doi: 10.1128/mBio.01361-14.
    1. Brahe L.K., Le Chatelier E., Prifti E., Pons N., Kennedy S., Blaedel T., Håkansson J., Dalsgaard T.K., Hansen T., Pedersen O., et al. Dietary modulation of the gut microbiota—A randomised controlled trial in obese postmenopausal women. Br. J. Nutr. 2015;114:406–417. doi: 10.1017/S0007114515001786.
    1. Matsumoto T., Ishikawa H., Tateda K., Yaeshima T., Ishibashi N., Yamaguchi K. Oral administration of Bifidobacterium longum prevents gut-derived Pseudomonas aeruginosa sepsis in mice. J. Appl. Microbiol. 2008;104:672–680. doi: 10.1111/j.1365-2672.2007.03593.x.
    1. Buffie C.G., Bucci V., Stein R.R., McKenney P.T., Ling L., Gobourne A., No D., Liu H., Kinnebrew M., Viale A., et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nat. Cell Biol. 2015;517:205–208. doi: 10.1038/nature13828.
    1. Adriaans B., Shah H. Fusobacterium ulcerans sp. nov. from Tropical Ulcers. Int. J. Syst. Bacteriol. 1988;38:447–448. doi: 10.1099/00207713-38-4-447.
    1. Claros M.C., Papke Y., Kleinkauf N., Adler D., Citron D.M., Hunt-Gerardo S. Characteristics of Fusobacterium ulcerans, a new and unusual species compared with Fusobacterium varium and Fusobacterium mortiferum. Anaerobe. 1999;5:137–140. doi: 10.1006/anae.1999.0201.
    1. Citron D.M. Update on the Taxonomy and Clinical Aspects of the GenusFusobacterium. Clin. Infect. Dis. 2002;35:S22–S27. doi: 10.1086/341916.
    1. Miniet A.A., Grunwell J.R., Coopersmith C.M. The microbiome and the immune system in critical illness. Curr. Opin. Crit. Care. 2021;27:157–163. doi: 10.1097/MCC.0000000000000800.
    1. Krezalek M.A., DeFazio J., Zaborina O., Zaborin A., Alverdy J.C. The Shift of an Intestinal “Microbiome” to a “Pathobiome” Governs the Course and Outcome of Sepsis Following Surgical Injury. Shock. 2016;45:475–482. doi: 10.1097/SHK.0000000000000534.
    1. Liang W., Yang Y., Wang H., Wang H., Yu X., Lu Y., Shen S., Teng L. Gut microbiota shifts in patients with gastric cancer in perioperative period. Medicine. 2019;98:e16626. doi: 10.1097/MD.0000000000016626.
    1. Van Passel M.W., Kant R., Zoetendal E.G., Plugge C.M., Derrien M., Malfatti S.A. The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intes-tinal metagenomes. PLoS ONE. 2011;6:e16876.
    1. Borchers M.T., Carty M.P., Leikauf G.D. Regulation of human airway mucins by acrolein and inflammatory mediators. Am. J. Physiol. Content. 1999;276:L549–L555. doi: 10.1152/ajplung.1999.276.4.L549.
    1. Moal V.L.-L., Servin A.L. Anti-Infective Activities of Lactobacillus Strains in the Human Intestinal Microbiota: From Probiotics to Gastrointestinal Anti-Infectious Biotherapeutic Agents. Clin. Microbiol. Rev. 2014;27:167–199. doi: 10.1128/CMR.00080-13.
    1. Derrien M., Van Baarlen P., Hooiveld G., Norin E., Müller M., De Vos W.M. Modulation of Mucosal Immune Response, Tolerance, and Proliferation in Mice Colonized by the Mucin-Degrader Akkermansia muciniphila. Front. Microbiol. 2011;2:166. doi: 10.3389/fmicb.2011.00166.
    1. Reunanen J., Kainulainen V., Huuskonen L., Ottman N., Belzer C., Huhtinen H., De Vos W.M., Satokari R. Akkermansia muciniphila Adheres to Enterocytes and Strengthens the Integrity of the Epithelial Cell Layer. Appl. Environ. Microbiol. 2015;81:3655–3662. doi: 10.1128/AEM.04050-14.
    1. Blander J.M., Longman R.S., Iliev I.D., Sonnenberg G.F., Artis D. Regulation of inflammation by microbiota interactions with the host. Nat. Immunol. 2017;18:851–860. doi: 10.1038/ni.3780.

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