Effects of cholecystolithiasis and cholecystectomy on intestinal flora of colorectal cancer patients based on 16S rDNA sequencing_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Jingjing ^1,2 , ZHU Chengzhang ¹ , SHI Xinlong ^1,3 , DU Binbin ^1,3 ,  YANG Xiongfei ^1,3

1. Department of Anorectal Surgery, Gansu Provincial Hospital, Lanzhou 730000, P. R. China;
2. School of Clinical Medicine, Ningxia Medical University, Yinchuan 750004, P. R. China;
3. Clinical Research Center for Anorectal Diseases of Gansu Province, Lanzhou 730000, P. R. China;

Corresponding author：

YANG Xiongfei, Email: XiongfeiYang2022@163.com

Keywords：

colorectal cancer; intestinal flora; cholecystolithiasis; cholecystectomy; 16S rDNA sequencing

DOI：

10.7507/1007-9424.202203003

Video：

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Objective To investigate the effect of cholecystolithiasis with cholecystitis and cholecystectomy on intestinal flora in patients with colorectal cancer. Methods A total of 168 patients with colorectal cancer who admitted to the Department of Anorectal Surgery in Gansu Provincial Hospital from June 2020 to March 2021 were selected, and 29 patients with colorectal cancer who met the criteria were selected as the research objects, including 10 colorectal cancer patients with gallstones and cholecystitis (cholecystolithiasis with cholecystitis+colorectal cancer group), 10 colorectal cancer patients after cholecystectomy (cholecystectomy+colorectal cancer group), and 9 colorectal cancer patients with normal gallbladder (normal gallbladder+colorectal cancer group). Clinical data of the patients in three groups were collected and compared. The fresh fecal samples of the patients included in the study were collected, and the 16S rDNA high-throughput sequencing method was used to determine and analyze the composition and distribution of the intestinal flora in the obtained samples. Results The interleukin-6 level in the cholecystolithiasis with cholecystitis+colorectal cancer group was statistically higher than that in the normal gallbladder+colorectal cancer group and the cholecystectomy+colorectal cancer group (P<0.05). At the phylum level of the fecal flora in three groups patients: ① In the samples of three groups, the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria and Verrucomicrobia phylums were all high, accounting for almost more than 95% of the total intestinal bacteria. ② The relative abundance of Fusobacteria phylum in the cholecystolithiasis with cholecystitis+colorectal cancer group was statistically higher than that in the normal gallbladder+colorectal cancer group (P<0.05). ③ The relative abundance of Verrucomicrobia phylum in the normal gallbladder+colorectal cancer group was statistically higher than that in the cholecystolithiasis with cholecystitis+colorectal cancer group and the cholecystectomy+colorectal cancer group (P<0.05). ④ The relative abundance of Synergistetes phylum in the cholecystectomy+colorectal cancer group was statistically higher than that in the cholecystolithiasis with cholecystitis+colorectal cancer group and the normal gallbladder+colorectal cancer group (P<0.05). At the genus level: ① The relative abundances of Bacteroidetes and Roseburia genus were lower in the gallstone with cholecystitis+colorectal cancer group than those in the cholecystectomy+colorectal cancer group and the normal gallbladder+colorectal cancer group (P<0.05). ② The relative abundance of Shigella genus in the cholecystectomy+colorectal cancer group was higher than that in the cholecystolithiasis with cholecystitis+colorectal cancer group (P<0.05). ③ The relative abundance of the Lachnospira genus in the cholecystolithiasis with cholecystitis+colorectal cancer group was lower than that in the normal gallbladder+colorectal cancer group (P<0.05). ④ The relative abundances of Prevotella and Fusobacteria genus were higher in the cholecystolithiasis with cholecystitis+colorectal cancer group than that in the cholecystectomy+colorectal cancer group and the normal gallbladder+colorectal cancer group (P<0.05). ⑤ The relative abundances of Clostridium and Akkermansia genus were lower in the cholecystolithiasis with cholecystitis+colorectal cancer group and the cholecystectomy+colorectal cancer group than that in the normal gallbladder+colorectal cancer group (P<0.05). ⑥ The relative abundance of Enterococcus genus was higher in the normal gallbladder+colorectal cancer group than that in the cholecystectomy+colorectal cancer group (P<0.05).Conclusions ① Long-term occurrence of cholecystolithiasis with cholecystitis can cause obvious decrease in the abundances of Bacteroides, Roseburia, Lachnospira, etc. ② Cholecystectomy can cause changes in the relative abundances of Clostridium, Enterococcus, Verrucomicrobia, Synergistetes, etc. ③ The relative abundance of Fusobacterium is obviously increased in colorectal cancer patients with gallstones and cholecystitis, then promotes the release of inflammatory cytokines and causes intestinal inflammation, which is conducive to the growth of opportunistic pathogens, thus may affect the occurrence and development of colorectal cancer.

Citation： LI Jingjing, ZHU Chengzhang, SHI Xinlong, DU Binbin, YANG Xiongfei. Effects of cholecystolithiasis and cholecystectomy on intestinal flora of colorectal cancer patients based on 16S rDNA sequencing. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(12): 1573-1582. doi: 10.7507/1007-9424.202203003 Copy

1.	Bundgaard-Nielsen C, Baandrup UT, Nielsen LP, et al. The presence of bacteria varies between colorectal adenocarcinomas, precursor lesions and non-malignant tissue. BMC Cancer, 2019, 19(1): 399. doi: 10.1186/s12885-019-5571-y.
2.	Zhang Y, Liu H, Li L, et al. Cholecystectomy can increase the risk of colorectal cancer: A meta-analysis of 10 cohort studies. PLoS One, 2017, 12(8): e0181852. doi: 10.1371/journal.pone.0181852.
3.	Lopetuso LR, Petito V, Graziani C, et al. Gut microbiota in health, diverticular disease, irritable bowel syndrome, and inflammatory bowel diseases: time for microbial marker of gastrointestinal disorders. Dig Dis, 2018, 36(1): 56-65.
4.	唐刚, 杜怡, 袁伟杰. 慢性肾脏病状态下肠道菌群失调对免疫及代谢的影响. 中华肾脏病杂志, 2020, 36(11): 881-884.
5.	叶巧园, 丁元林, 朱坚, 等. 基于16S rDNA测序的皮脂溢出患者肠道菌群分析. 广东医科大学学报, 2021, 39(4): 389-394.
6.	Wong SH, Zhao L, Zhang X, et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology, 2017, 153(6): 1621-1633.
7.	Jobin C. Human intestinal microbiota and colorectal cancer: moving beyond associative studies. Gastroenterology, 2017, 153(6): 1475-1478.
8.	Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J, 2012, 6(2): 320-329.
9.	Niccolai E, Russo E, Baldi S, et al. Significant and conflicting correlation of IL-9 with prevotella and bacteroides in human colorectal cancer. Front Immunol, 2021, 11: 573158. doi: 10.3389/fimmu.2020.573158.
10.	Yang J, Li D, Yang Z, et al. Establishing high-accuracy biomarkers for colorectal cancer by comparing fecal microbiomes in patients with healthy families. Gut Microbes, 2020, 11(4): 918-929.
11.	Wu T, Zhang Z, Liu B, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics, 2013, 14: 669. doi: 10.1186/1471-2164-14-669.
12.	Keren N, Konikoff FM, Paitan Y, et al. Interactions between the intestinal microbiota and bile acids in gallstones patients. Environ Microbiol Rep, 2015, 7(6): 874-880.
13.	Wang Q, Hao C, Yao W, et al. Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation. BMC Gastroenterol, 2020, 20(1): 59. doi: 10.1186/s12876-020-01195-1.
14.	臧晓明, 景彩, 肖宁, 等. 基于16S rDNA基因测序技术分析不同身体质量指数人群的肠道菌群结构差异. 中华中医药杂志, 2021, 36(1): 451-455.
15.	Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol, 2013, 108(10): 1620-1630.
16.	Cao H, Xu M, Dong W, et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int J Cancer, 2017, 140(11): 2545-2556.
17.	Ohigashi S, Sudo K, Kobayashi D, et al. Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer. Dig Dis Sci, 2013, 58(6): 1717-1726.
18.	Sánchez-Alcoholado L, Ramos-Molina B, Otero A, et al. The role of the gut microbiome in colorectal cancer development and therapy response. Cancers (Basel), 2020, 12(6): 1406. doi: 10.3390/cancers12061406.
19.	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.
20.	Huang N, Katz JP, Martin DR, et al. Inhibition of IL-8 gene expression in Caco-2 cells by compounds which induce histone hyperacetylation. Cytokine, 1997, 9(1): 27-36.
21.	Stempelj M, Kedinger M, Augenlicht L, et al. Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate. J Biol Chem, 2007, 282(13): 9797-9804.
22.	张冬冬. 胆囊切除术后肠道菌群改变与结直肠癌的关系. 太原: 山西医科大学, 2020.
23.	Chen YK, Yeh JH, Lin CL, et al. Cancer risk in patients with cholelithiasis and after cholecystectomy: a nationwide cohort study. J Gastroenterol, 2014, 49(5): 923-931.
24.	翟晓, 杨芸, 王文学, 等. 胆囊切除术与结直肠癌发病的关系. 中华消化杂志, 2019, 39(10): 715-717.
25.	Grigor’eva I, Romanova T, Naumova N, et al. Gut microbiome in a russian cohort of pre- and post-cholecystectomy female patients. J Pers Med, 2021, 11(4): 294. doi: 10.3390/jpm11040294.
26.	Wang W, Wang J, Li J, et al. Cholecystectomy damages aging-associated intestinal microbiota construction. front microbiol, 2018, 9: 1402. doi: 10.3389/fmicb.2018.01402.
27.	Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev, 2007, 20(4): 593-621.
28.	Kuwahara T, Yamashita A, Hirakawa H, et al. Genomic analysis of Bacteroides fragilis reveals extensive DNA inversions regulating cell surface adaptation. Proc Natl Acad Sci U S A, 2004, 101(41): 14919-14924.
29.	Sóki J, Gal M, Brazier JS, et al. Molecular investigation of genetic elements contributing to metronidazole resistance in Bacteroides strains. J Antimicrob Chemother, 2006, 57(2): 212-220.
30.	Verma D, Garg PK, Dubey AK. Insights into the human oral microbiome. Arch Microbiol, 2018, 200(4): 525-540.
31.	Hillman ET, Lu H, Yao T, et al. Microbial ecology along the gastrointestinal tract. Microbes Environ, 2017, 32(4): 300-313.
32.	Luo K, Zhang Y, Xv C, et al. Fusobacterium nucleatum, the communication with colorectal cancer. Biomed Pharmacother, 2019, 116: 108988. doi: 10.1016/j.biopha.2019.108988.
33.	Zhou Z, Chen J, Yao H, et al. Fusobacterium and colorectal cancer. Front Oncol, 2018, 8: 371. doi: 10.3389/fonc.2018.00371.

1. Bundgaard-Nielsen C, Baandrup UT, Nielsen LP, et al. The presence of bacteria varies between colorectal adenocarcinomas, precursor lesions and non-malignant tissue. BMC Cancer, 2019, 19(1): 399. doi: 10.1186/s12885-019-5571-y.
2. Zhang Y, Liu H, Li L, et al. Cholecystectomy can increase the risk of colorectal cancer: A meta-analysis of 10 cohort studies. PLoS One, 2017, 12(8): e0181852. doi: 10.1371/journal.pone.0181852.
3. Lopetuso LR, Petito V, Graziani C, et al. Gut microbiota in health, diverticular disease, irritable bowel syndrome, and inflammatory bowel diseases: time for microbial marker of gastrointestinal disorders. Dig Dis, 2018, 36(1): 56-65.
4. 唐刚, 杜怡, 袁伟杰. 慢性肾脏病状态下肠道菌群失调对免疫及代谢的影响. 中华肾脏病杂志, 2020, 36(11): 881-884.
5. 叶巧园, 丁元林, 朱坚, 等. 基于16S rDNA测序的皮脂溢出患者肠道菌群分析. 广东医科大学学报, 2021, 39(4): 389-394.
6. Wong SH, Zhao L, Zhang X, et al. Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology, 2017, 153(6): 1621-1633.
7. Jobin C. Human intestinal microbiota and colorectal cancer: moving beyond associative studies. Gastroenterology, 2017, 153(6): 1475-1478.
8. Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J, 2012, 6(2): 320-329.
9. Niccolai E, Russo E, Baldi S, et al. Significant and conflicting correlation of IL-9 with prevotella and bacteroides in human colorectal cancer. Front Immunol, 2021, 11: 573158. doi: 10.3389/fimmu.2020.573158.
10. Yang J, Li D, Yang Z, et al. Establishing high-accuracy biomarkers for colorectal cancer by comparing fecal microbiomes in patients with healthy families. Gut Microbes, 2020, 11(4): 918-929.
11. Wu T, Zhang Z, Liu B, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics, 2013, 14: 669. doi: 10.1186/1471-2164-14-669.
12. Keren N, Konikoff FM, Paitan Y, et al. Interactions between the intestinal microbiota and bile acids in gallstones patients. Environ Microbiol Rep, 2015, 7(6): 874-880.
13. Wang Q, Hao C, Yao W, et al. Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation. BMC Gastroenterol, 2020, 20(1): 59. doi: 10.1186/s12876-020-01195-1.
14. 臧晓明, 景彩, 肖宁, 等. 基于16S rDNA基因测序技术分析不同身体质量指数人群的肠道菌群结构差异. 中华中医药杂志, 2021, 36(1): 451-455.
15. Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol, 2013, 108(10): 1620-1630.
16. Cao H, Xu M, Dong W, et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int J Cancer, 2017, 140(11): 2545-2556.
17. Ohigashi S, Sudo K, Kobayashi D, et al. Changes of the intestinal microbiota, short chain fatty acids, and fecal pH in patients with colorectal cancer. Dig Dis Sci, 2013, 58(6): 1717-1726.
18. Sánchez-Alcoholado L, Ramos-Molina B, Otero A, et al. The role of the gut microbiome in colorectal cancer development and therapy response. Cancers (Basel), 2020, 12(6): 1406. doi: 10.3390/cancers12061406.
19. 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.
20. Huang N, Katz JP, Martin DR, et al. Inhibition of IL-8 gene expression in Caco-2 cells by compounds which induce histone hyperacetylation. Cytokine, 1997, 9(1): 27-36.
21. Stempelj M, Kedinger M, Augenlicht L, et al. Essential role of the JAK/STAT1 signaling pathway in the expression of inducible nitric-oxide synthase in intestinal epithelial cells and its regulation by butyrate. J Biol Chem, 2007, 282(13): 9797-9804.
22. 张冬冬. 胆囊切除术后肠道菌群改变与结直肠癌的关系. 太原: 山西医科大学, 2020.
23. Chen YK, Yeh JH, Lin CL, et al. Cancer risk in patients with cholelithiasis and after cholecystectomy: a nationwide cohort study. J Gastroenterol, 2014, 49(5): 923-931.
24. 翟晓, 杨芸, 王文学, 等. 胆囊切除术与结直肠癌发病的关系. 中华消化杂志, 2019, 39(10): 715-717.
25. Grigor’eva I, Romanova T, Naumova N, et al. Gut microbiome in a russian cohort of pre- and post-cholecystectomy female patients. J Pers Med, 2021, 11(4): 294. doi: 10.3390/jpm11040294.
26. Wang W, Wang J, Li J, et al. Cholecystectomy damages aging-associated intestinal microbiota construction. front microbiol, 2018, 9: 1402. doi: 10.3389/fmicb.2018.01402.
27. Wexler HM. Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev, 2007, 20(4): 593-621.
28. Kuwahara T, Yamashita A, Hirakawa H, et al. Genomic analysis of Bacteroides fragilis reveals extensive DNA inversions regulating cell surface adaptation. Proc Natl Acad Sci U S A, 2004, 101(41): 14919-14924.
29. Sóki J, Gal M, Brazier JS, et al. Molecular investigation of genetic elements contributing to metronidazole resistance in Bacteroides strains. J Antimicrob Chemother, 2006, 57(2): 212-220.
30. Verma D, Garg PK, Dubey AK. Insights into the human oral microbiome. Arch Microbiol, 2018, 200(4): 525-540.
31. Hillman ET, Lu H, Yao T, et al. Microbial ecology along the gastrointestinal tract. Microbes Environ, 2017, 32(4): 300-313.
32. Luo K, Zhang Y, Xv C, et al. Fusobacterium nucleatum, the communication with colorectal cancer. Biomed Pharmacother, 2019, 116: 108988. doi: 10.1016/j.biopha.2019.108988.
33. Zhou Z, Chen J, Yao H, et al. Fusobacterium and colorectal cancer. Front Oncol, 2018, 8: 371. doi: 10.3389/fonc.2018.00371.

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Effects of cholecystolithiasis and cholecystectomy on intestinal flora of colorectal cancer patients based on 16S rDNA sequencing

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