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Abstract: With the recent upsurge of studies in the field of microbiology, we have learned more about the complexity of the gastrointestinal microecosystem. More than 30 genera and 1000 species of gastrointestinal microflora have been found. The structure of the normal microflora is relatively stable, and is in an interdependent and restricted dynamic equilibrium with the body. In recent years, studies have shown that there is a potential relationship between gastrointestinal microflora imbalance and gastric cancer (GC) and precancerous lesions. So, restoring the balance of gastrointestinal microflora is of great significance. Moreover, intervention in gastric premalignant condition (GPC), also known as precancerous lesion of gastric cancer (PLGC), has been the focus of current clinical studies. The holistic view of traditional Chinese medicine (TCM) is consistent with the microecology concept, and oral TCM can play a two-way regulatory role directly with the microflora in the digestive tract, restoring the homeostasis of gastrointestinal microflora to prevent canceration. However, large gaps in knowledge remain to be addressed. This review aims to provide new ideas and a reference for clinical practice.

胃肠菌群、胃癌及癌前病变与中药防治的最新研究进展

概要：随微生物领域研究热潮的出现，人们了解到胃肠微生态是一个复杂的系统，目前已知的胃肠菌群大概有30个属共1000多种。正常的菌群结构相对稳定，与人体处于一种相互依存及制约的动态平衡状态。近年来研究表明，胃肠菌群失调与胃癌及癌前病变存在潜在联系，有效地修复胃肠菌群的平衡对于防治癌变有着显著意义。对癌前状态的干预治疗一直是临床研究的热点。中医整体观与微生态学统一观在理念上相合，且中药通过口服进入消化道以后，可以直接和胃肠道的菌群起双向调节作用，帮助修复胃肠菌群稳态以防治癌变。基于目前的研究，仍存在较大的空白领域等待探索，鉴此本文进行综述以向临床提供新的思路和借鉴。

关键词：胃癌；胃癌前病变；胃肠菌群；中药防治

[1]Abreu MT, Peek RM, 2014. Gastrointestinal malignancy and the microbiome. Gastroenterology, 146(6):1534-1546.e3.

[2]Alexander JL, Wilson ID, Teare J, et al., 2017. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol, 14(6):356-365.

[3]Andersson AF, Lindberg M, Jakobsson H, et al., 2008. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS ONE, 3(7):e2836.

[4]Arkan MC, 2017. The intricate connection between diet, microbiota, and cancer: a jigsaw puzzle. Semin Immunol, 32:35-42.

[5]Arpaia N, Campbell C, Fan XY, et al., 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature, 504(7480):451-455.

[6]Atarashi K, Nishimura J, Shima T, et al., 2008. ATP drives lamina propria T_H17 cell differentiation. Nature, 455(7214): 808-812.

[7]Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, et al., 2014. Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep, 4:4202.

[8]Bae SE, Jung HY, Kang J, et al., 2014. Effect of Helicobacter pylori eradication on metachronous recurrence after endoscopic resection of gastric neoplasm. Am J Gastroenterol, 109(1):60-67.

[9]Bashir M, Prietl B, Tauschmann M, et al., 2016. Effects of high doses of vitamin D₃ on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract. Eur J Nutr, 55(4):1479-1489.

[10]Bik EM, Eckburg PB, Gill SR, et al., 2006. Molecular analysis of the bacterial microbiota in the human stomach. Proc Natl Acad Sci USA, 103(3):732-737.

[11]Blaser MJ, Atherton JC, 2004. Helicobacter pylori persistence: biology and disease. J Clin Invest, 113(3):321-333.

[12]Braune A, Blaut M, 2016. Bacterial species involved in the conversion of dietary flavonoids in the human gut. Gut Microbes, 7(3):216-234.

[13]Brawner KM, Kumar R, Serrano CA, et al., 2017. Helicobacter pylori infection is associated with an altered gastric microbiota in children. Mucos Immunol, 10(5):1169-1177.

[14]Bultman SJ, 2014. Molecular pathways: gene‍‒‍environment interactions regulating dietary fiber induction of proliferation and apoptosis via butyrate for cancer prevention. Clin Cancer Res, 20(4):799-803.

[15]Cai SR, Kandasamy M, Rahmat JN, et al., 2016. Lactobacillus rhamnosus GG activation of dendritic cells and neutrophils depends on the dose and time of exposure. J Immunol Res, 2016:7402760.

[16]Cai ZW, 2019. Review and prospect of microecology of traditional Chinese medicine in 30 years in China. Chin J Microecol, 31(10):1164-1166, 1210 (in Chinese).

[17]Caunt CJ, Sale MJ, Smith PD, et al., 2015. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer, 15(10):577-592.

[18]Chang CH, Huang WY, Lai CH, et al., 2011. Development of novel nanoparticles shelled with heparin for berberine delivery to treat Helicobacter pylori. Acta Biomaterialia, 7(2):593-603.

[19]Chen B, Sun J, Liang F, et al., 2018. Regulation of Jianpi Jiedu Recipe on intestinal flora in tumor bearing mice with syndrome of spleen deficiency. Shanghai J Trad Chin Med, 2018, 52(1):81-85 (in Chinese).

[20]Chen DL, Zheng CQ, Yang J, et al., 2017. Immunomodulatory activities of a fungal protein extracted from Hericium erinaceus through regulating the gut microbiota. Front Immunol, 8:666.

[21]Chmiela M, Gonciarz W, 2017. Molecular mimicry in Helicobacter pylori infections. World J Gastroenterol, 23(22):3964-3977.

[22]Coker OO, Dai ZW, Nie YZ, et al., 2018. Mucosal microbiome dysbiosis in gastric carcinogenesis. Gut, 67(6):1024-1032.

[23]Dai JF, Jin HF, Meng LN, et al., 2017. Multi-center randomized clinical study of the effect of curcuma and pseudo-ginseng on chronic atrophic gastritis. Mod Chin Clin Med, 24(6):15-19 (in Chinese).

[24]Delgado S, Cabrera-Rubio R, Mira A, et al., 2013. Microbiological survey of the human gastric ecosystem using culturing and pyrosequencing methods. Microbial Ecology, 65(3):763-772.

[25]Deng WD, Xi DM, Mao HM, et al., 2008. The use of molecular techniques based on ribosomal RNA and DNA for rumen microbial ecosystem studies: a review. Mol Biol Rep, 35(2):265-274.

[26]Dias-Jácome E, Libânio D, Borges-Canha M, et al., 2016. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria—a systematic review. Rev Esp Enferm Dig, 108(9):530-540.

[27]Dong TY, Feng Q, Liu FY, et al., 2017. Alteration of stomach microbiota compositions in the progression of gastritis induces nitric oxide in gastric cell. Exp Ther Med, 13(6):2793-2800.

[28]El-Shouny WA, Ali SS, Hegazy HM, et al., 2020. Syzygium aromaticum L.: traditional herbal medicine against cagA and vacA toxin genes-producing drug resistant Helicobacter pylori. J Tradit Complement Med, 10(4):366-377.

[29]Engstrand L, Lindberg M, 2013. Helicobacter pylori and the gastric microbiota. Best Pract Res Clin Gastroenterol, 27(1):39-45.

[30]Espinoza JL, Matsumoto A, Tanaka L, et al., 2018. Gastric microbiota: an emerging player in Helicobacter pylori-induced gastric malignancies. Cancer Lett, 414:147-152.

[31]Eun CS, Kim BK, Han DS, et al., 2014. Differences in gastric mucosal microbiota profiling in patients with chronic gastritis, intestinal metaplasia, and gastric cancer using pyrosequencing methods. Helicobacter, 19(6):407-416.

[32]Feng H, Zhu XY, Wang CS, 2018. Research progress in mechanism of strengthening spleen medicines for intestinal microecology. Chin J Inf Trad Chin Med, 25(10):‍137-140 (in Chinese).

[33]Ferreira RM, Pereira-Marques J, Pinto-Ribeiro I, et al., 2018. Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota. Gut, 67(2):226-236.

[34]Figueiredo C, Garcia-Gonzalez MA, Machado JC, 2013. Molecular pathogenesis of gastric cancer. Helicobacter, 18(S1):28-33.

[35]Fung KYC, Cosgrove L, Lockett T, et al., 2012. A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr, 108(5):820-831.

[36]Gaffen SL, Jain R, Garg AV, et al., 2014. The IL-23‍‒‍IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol, 14(9):585-600.

[37]Gao R, Li L, Gao HY, 2011. Research on intestinal microflora in patients with gastric cancer. J Jining Med Univ, 34(3):178-179, 182 (in Chinese).

[38]Ge JB, Xu YJ, Wang C, et al., 2019. Inter Medicine. People’s Medical Publishing House (PMPH), Beijing, China, p.366 (in Chinese).

[39]Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Abate D, et al., 2019. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. JAMA Oncol, 5(12):1749-1768.

[40]Gong J, 2019. Study on Microbiota in Patients with Gastric Intestinal Metaplasia Based on High Throughput Sequencing. PhD Thesis, Shandong University, Jinan, China (in Chinese).

[41]Graham DY, Dore MP, 2016. Helicobacter pylori therapy: a paradigm shift. Exp Rev Anti Infect Ther, 14(6):577-585.

[42]He BS, Pan YQ, Xu YF, et al., 2011. Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL-1RN) genes associate with gastric cancer risk in the Chinese population. Dig Dis Sci, 56(7):2017-2023.

[43]He XJ, Li XQ, Luo W, 2020. Effect observation on allicin in adjuvant treatment of Helicobacter pylori infection. Chin Nurs Res, 34(8):1484-1486 (in Chinese).

[44]Herrera V, Parsonnet J, 2009. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect, 15(11):971-976.

[45]Ianiro G, Molina-Infante J, Gasbarrini A, 2015. Gastric microbiota. Helicobacter, 20(S1):68-71.

[46]Ivanov II, de Llanos Frutos R, Manel N, et al., 2008. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe, 4(4):337-349.

[47]Jackson MA, Goodrich JK, Maxan ME, et al., 2016. Proton pump inhibitors alter the composition of the gut microbiota. Gut, 65(5):749-756.

[48]Jia ET, Liu ZY, Pan M, et al., 2019. Regulation of bile acid metabolism-related signaling pathways by gut microbiota in diseases. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(10):781-792.https://doi/org/10.1631/jzus.B1900073

[49]Jiang HT, Liu HY, Zhang BL, 2005. Effect of Weizhuan’an recipe on telomerase activity of rats before occurrence of gastric carcinoma. Jiangsu J Trad Chin Med, 26(6):50-51 (in Chinese).

[50]Jo HJ, Kim J, Kim N, et al., 2016. Analysis of gastric microbiota by pyrosequencing: minor role of bacteria other than Helicobacter pylori in the gastric carcinogenesis. Helicobacter, 21(5):364-374.

[51]Johnson CH, Dejea CM, Edler D, et al., 2015. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metabol, 21(6):891-897.

[52]Khosravi Y, Dieye Y, Poh BH, et al., 2014. Culturable bacterial microbiota of the stomach of Helicobacter pylori positive and negative gastric disease patients. Sci World J, 2014:610421.

[53]Kobayashi, 1995. Relationship between effective components of traditional Chinese medicine and intestinal microflora. Med Phil, 16(11):598 (in Chinese).

[54]Kolho KL, Korpela K, Jaakkola T, et al., 2015. Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation. Am J Gastroenterol, 110(6):921-930.

[55]Landy J, Walker AW, Li JV, et al., 2015. Variable alterations of the microbiota, without metabolic or immunological change, following faecal microbiota transplantation in patients with chronic pouchitis. Sci Rep, 5:12955.

[56]Lertpiriyapong K, Whary MT, Muthupalani S, et al., 2014. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis. Gut, 63(1):54-63.

[57]Li FF, Du WH, Yang JB, 2014. The expression and alteration of ATP4B induced by Helicobacter pylori infection in the development of gastric mucosa lesions. Beijing Med J, 36(1):12-14 (in Chinese).

[58]Li SH, Liu HY, Tang YP, 2016. Clinical observation on 48 cases of peptic ulcer of spleen and stomach deficiency type caused by Helicobacter pylori infection treated by Xiangsha Liujunzi Decoction combined with quadruple therapy. J Tradit Chin Med, 57(21):1854-1857, 1863 (in Chinese).

[59]Li TH, Qin Y, Sham PC, et al., 2017. Alterations in gastric microbiota after H. pylori eradication and in different histological stages of gastric carcinogenesis. Sci Rep, 7:44935.

[60]Lian DW, Xu YF, Ren WK, et al., 2017. Mechanism of anti-Helicobacter pylori urease activity of patchouli alcohol. China J Chin Mat Med, 42(3):562-566 (in Chinese).

[61]Liu J, He LH, Haesebrouck F, et al., 2015. Prevalence of coinfection with gastric non-Helicobacter pylori Helicobacter (NHPH) species in Helicobacter pylori-infected patients suffering from gastric disease in Beijing, China. Helicobacter, 20(4):284-290.

[62]Liu SM, Dong CY, Wang LL, et al., 2015. The impact of Lactobacillus in gastric mucosa on Helicobacter pylori infection. Chin J Microecol, 27(11):1276-1280 (in Chinese).

[63]Llorca L, Pérez-Pérez G, Urruzuno P, et al., 2017. Characterization of the gastric microbiota in a pediatric population according to Helicobacter pylori status. Pediatric Infect Dis J, 36(2):173-178.

[64]Ma JL, Zhang L, Brown LM, et al., 2012. Fifteen-year effects of Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence and mortality. J Natl Cancer Inst, 104(6):488-492.

[65]Malfertheiner P, Megraud F, O'Morain CA, et al., 2012. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut, 61(5):646-664.

[66]Mazmanian SK, Liu CH, Tzianabos AO, et al., 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell, 122(1): 107-118.

[67]Meng CT, Bai CM, Brown TD, et al., 2018. Human gut microbiota and gastrointestinal cancer. Genom Proteom Bioinform, 16(1):33-49.

[68]Meng LK, Yang JW, Yang K, et al., 2020. Clinical observation of Weizhuan’an granules in treating gastric precancerous lesions of Qi deficiency and blood stasis type. World J Integr Trad Western Med, 15(6):‍1122-1125, 1129 (in Chinese).

[69]Morrison WB, 2012. Inflammation and cancer: a comparative view. J Vet Int Med, 26(1):18-31.

[70]Musso G, Gambino R, Cassader M, 2011. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med, 62:361-380.

[71]Nakamoto N, Amiya T, Aoki R, et al., 2017. Commensal Lactobacillus controls immune tolerance during acute liver injury in mice. Cell Rep, 21(5):1215-1226.

[72]Nardone G, Compare D, 2015. The human gastric microbiota: is it time to rethink the pathogenesis of stomach diseases? United European Gastroenterol J, 3(3):255-260.

[73]Noverr MC, Huffnagle GB, 2004. Does the microbiota regulate immune responses outside the gut? Trends Microbiol, 12(12):562-568.

[74]Palm NW, de Zoete MR, Flavell RA, 2015. Immune—microbiota interactions in health and disease. Clin Immunol, 159(2):122-127.

[75]Peng XH, Zhou LY, Gong YN, et al., 2017. Non-pylori Helicobacters (NHPHs) induce shifts in gastric microbiota in Helicobacter pylori-infected patients. Front Microbiol, 8:1038.

[76]Plummer M, de Martel C, Vignat J, et al., 2016. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health, 4(9):e609-e616.

[77]Rodríguez-Hernández E, Quintas-Granados LI, Flores-Villalva S, et al., 2020. Application of antigenic biomarkers for Mycobacterium tuberculosis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(11):856-870.

[78]Rokkas T, Rokka A, Portincasa P, 2017. A systematic review and meta-analysis of the role of Helicobacter pylori eradication in preventing gastric cancer. Ann Gastroenterol, 30(4):414-423.

[79]Saber A, Alipour B, Faghfoori Z, et al., 2017. Cellular and molecular effects of yeast probiotics on cancer. Crit Rev Microbiol, 43(1):96-115.

[80]Saeki N, Ono H, Sakamoto H, et al., 2013. Genetic factors related to gastric cancer susceptibility identified using a genome-wide association study. Cancer Sci, 104(1):1-8.

[81]Salminen MK, Rautelin H, Tynkkynen S, et al., 2004. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis, 38(1):62-69.

[82]Samarth AR, 2017. Prevalence of oral Helicobacter pylori infection in dyspeptic patients with gastric Helicobacter pylori infection. J Med Sci Clin Res, 5(9):28129-28134.

[83]Samuel BS, Shaito A, Motoike T, et al., 2008. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA, 105(43):16767-16772.

[84]Schulz C, Koch N, Schütte K, et al., 2015. H. pylori and its modulation of gastrointestinal microbiota. J Dig Dis, 16(3): 109-117.

[85]Sgambato D, Miranda A, Romano L, et al., 2017. Gut microbiota and gastric disease. Minerva Gastroenterol Dietol, 63(4):345-354.

[86]Shen WC, Wang X, Qin WT, et al., 2014. Exogenous carbon monoxide suppresses Escherichia coli vitality and improves survival in an Escherichia coli-induced murine sepsis model. Acta Pharmacol Sin, 35(12):1566-1576.

[87]Shi N, Li N, Duan XW, et al., 2017. Interaction between the gut microbiome and mucosal immune system. Mil Med Res, 4:14.

[88]Shiotani A, Iishi H, Uedo N, et al., 2004. Hypoacidity combined with high gastric juice nitrite induced by Helicobacter pylori infection is associated with gastric cancer. Aliment Pharmacol Ther, 20:48-53.

[89]Shirokawa T, Nakajima J, Hirose K, et al., 2014. Spontaneous meningitis due to Streptococcus salivarius subsp. salivarius: cross-reaction in an assay with a rapid diagnostic kit that detected Streptococcus pneumoniae antigens. Intern Med, 53(3):279-282.

[90]Sivaprakasam S, Prasad PD, Singh N, 2016. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther, 164:144-151.

[91]Smith PM, Howitt MR, Panikov N, et al., 2013. The microbial metabolites, short-chain fatty acids, regulate colonic T_reg cell homeostasis. Science, 341(6145):569-573.

[92]Sohn SH, Kim N, Jo HJ, et al., 2017. Analysis of gastric body microbiota by pyrosequencing: possible role of bacteria other than Helicobacter pylori in the gastric garcinogenesis. J Cancer Prev, 22(2):115-125.

[93]Song CY, Xu YG, Lu YQ, 2020. Use of Tripterygium wilfordii Hook F for immune-mediated inflammatory diseases: progress and future prospects. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(4):280-290.

[94]Su GJ, Guo YY, 2014. Expression of Foxp3, TGF-β1 and IL-10 in the gastric mucosa of patients with Helicobacter pylori infection. World Chin J Digestol, 22(32):‍4964-4968 (in Chinese).http://dx.doi.org/10.11569/wcjd.v22.i32.4964

[95]Su JY, Su L, Li D, et al., 2018. Antitumor activity of extract from the sporoderm-breaking spore of Ganoderma lucidum: restoration on exhausted cytotoxic T cell with gut microbiota remodeling. Front Immunol, 9:1765.

[96]Sultana Z, Bankura B, Pattanayak AK, et al., 2018. Association of interleukin-1 beta and tumor necrosis factor-alpha genetic polymorphisms with gastric cancer in India. Environ Mol Mutagen, 59(7):653-667.

[97]Sung J, Kim N, Kim J, et al., 2016. Comparison of gastric microbiota between gastric juice and mucosa by next generation sequencing method. J Cancer Prev, 21(1):60-65.

[98]Tsilimigras MCB, Fodor A, Jobin C, 2017. Carcinogenesis and therapeutics: the microbiota perspective. Nat Microbiol, 2(3):17008.

[99]Tsuda A, Suda W, Morita H, et al., 2015. Influence of proton-pump inhibitors on the luminal microbiota in the gastrointestinal tract. Clin Transl Gastroenterol, 6(6):e89.

[100]Venerito M, Vasapolli R, Malfertheiner P, 2016. Helicobacter pylori and gastric cancer: timing and impact of preventive measures. Adv Exp Med Biol, 908:409-418.

[101]von Rosenvinge EC, Song Y, White JR, et al., 2013. Immune status, antibiotic medication and pH are associated with changes in the stomach fluid microbiota. ISME J, 7(7):1354-1366.

[102]Wan Y, Yuan JH, Li J, et al., 2020. Unconjugated and secondary bile acid profiles in response to higher-fat, lower-carbohydrate diet and associated with related gut microbiota: a 6-month randomized controlled-feeding trial. Clin Nutr, 39(2):395-404.

[103]Wang CZ, Zhang CF, Chen L, et al., 2015. Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin. Int J Oncol, 47(5):1749-1758.http://doi.org/10.3892/ijo.2015.3173

[104]Wang CZ, Yu CH, Wen XD, et al., 2016a. American ginseng attenuates colitis associated colon carcinogenesis in mice: impact on gut microbiota and metabolomics. Cancer Prev Res, 9(10):803-811.

[105]Wang CZ, Anderson S, Yuan CS, 2016b. Phytochemistry and anticancer potential of notoginseng. Am J Chin Med, 44(1):23-34.

[106]Wang J, Wang P, Li DT, et al., 2020. Beneficial effects of ginger on prevention of obesity through modulation of gut microbiota in mice. Eur J Nutr, 59(2):699-718.

[107]Wang LL, Liu Y, Zai K, 2020. Research on Evodia alkaloids combined with omeprazole in the treatment of Helicobacter pylori infection. Cardiovasc Dis Electron J Integrated Tradit Chin Western Med, 8(14):90-91 (in Chinese).

[108]Watanabe M, Ito H, Hosono S, et al., 2015. Declining trends in prevalence of Helicobacter pylori infection by birth-year in a Japanese population. Cancer Sci, 106(12):1738-1743.

[109]Wei X, 1989. My humble opinion about the microecology. Chin J Microecol, 1(1):4-5 (in Chinese).

[110]Wong BCY, Lam SK, Wong WM, et al., 2004. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA, 291(2):187-194.

[111]Wong JMW, de Souza R, Kendall CWC, et al., 2006. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol, 40(3):235-243.

[112]Wong SH, Kwong TNY, Wu CY, et al., 2019. Clinical applications of gut microbiota in cancer biology. Semin Cancer Biol, 55:28-36.

[113]Wu SS, 2002. Effect of Salvia miltiorrhiza on atrophic gastritis with dysplasia. Lishizhen Med Mater Med Res, 13(12):751-752 (in Chinese).

[114]Wu WM, Yang YS, Peng LH, 2014. Microbiota in the stomach: new insights. J Dig Dis, 15(2):54-61.

[115]Xu J, Chen HB, Li SL, 2017. Understanding the molecular mechanisms of the interplay between herbal medicines and gut microbiota. Med Res Rev, 37(5):1140-1185.

[116]Yang K, Lui HY, Wang XJ, et al., 2016. Pepsinogen effect of Weizhuan’an treatment of patients with PLGC. Chin Arch Trad Chin Med, 34(10):2464-2467 (in Chinese).

[117]Yang XN, 2020. Modified Huangqi Jianzhong Decoction in the treatment of gastric ulcer of spleen stomach deficiency cold type and the clinical observation of the influence on Helicobacter pylori. Smart Healthc, 6(13):52-54 (in Chinese).

[118]Yap TW, Gan HM, Lee YP, et al., 2016. Helicobacter pylori eradication causes perturbation of the human gut microbiome in young adults. PLoS ONE, 11(3):e151893.

[119]Yu GQ, Torres J, Hu N, et al., 2017. Molecular characterization of the human stomach microbiota in gastric cancer patients. Front Cell Infect Microbiol, 7:302.

[120]Yu XQ, Baade P, 2017. RE: cancer incidence and mortality in China, 2013 by Chen et al. Cancer Lett, 401:72-73.

[121]Yue SJ, Liu J, Wang AT, et al., 2019. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. Am J Physiol Endocrinol Metab, 316(1):E73-E85.

[122]Zam W, 2018. Gut microbiota as a prospective therapeutic target for curcumin: a review of mutual influence. J Nutr Metab, 2018:1367984.

[123]Zeng HW, Umar S, Rust B, et al., 2019. Secondary bile acids and short chain fatty acids in the colon: a focus on colonic microbiome, cell proliferation, inflammation, and cancer. Int J Mol Sci, 20(5):1214.

[124]Zhan Y, Chen PJ, Sadler WD, et al., 2013. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res, 73(24):7199-7210.https://dio.org/10.1158/0008-5472.CAN-13-0827

[125]Zhang J, Li HH, Chen YF, et al., 2020. Microencapsulation of immunoglobulin Y: optimization with response surface morphology and controlled release during simulated gastrointestinal digestion. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(8):611-627.

[126]Zhao YQ, Guo T, Qian JM, 2013. Effects of broth culture filtrate protein of VacA⁺ Helicobacter pylori on the proliferation and apoptosis of gastric epithelial cells. Chin Med J, 126(11):2168-2173.

[127]Zheng W, 2019. The Effects of Helicobacter pylori Infection on Microbiota Associated with Gastroduodenal Mucosa in Children and its Pathogenesis. PhD Thesis, Zhejiang Univeristy, Hangzhou, China (in Chinese).

[128]Zhu YY, Wen JX, Ren XM, et al., 2017. The distribution characteristics of intestinal flora in patients with gastric cancer. Chin J Microecol, 29(6):655-658 (in Chinese).

[129]Zitvogel L, Daillère R, Roberti MP, et al., 2017. Anticancer effects of the microbiome and its products. Nat Rev Microbiol, 15(8):465-478.