目的 分析婴幼儿川崎病（Kawasaki disease, KD）急性期肠道菌群的构成、丰度及功能差异，探索肠道菌群在KD发病机制中的作用。 方法 前瞻性选择2021年7—10月在首都儿科研究所附属儿童医院心血管内科住院的6例0~3岁KD急性期婴幼儿为KD组，选取同期体检的年龄、性别匹配的6例健康婴幼儿为健康对照组。采用宏基因组测序检测并比较两组婴幼儿粪便样本的菌群结构及功能差异。 结果 两组样本肠道菌群在结构组成、多样性分析方面差异有统计学意义（P<0.05）。KD组婴幼儿肠道菌群中单核细胞增生李斯特菌（李斯特菌科、李斯特氏菌属）、鲁塞蒂双歧杆菌、海氏肠球菌、鸟肠球菌丰度高于健康对照组（|LDA|>2，P<0.05）。KD组中类固醇降解和细胞凋亡通路较健康对照组显著升高，而细菌分泌系统、硫代谢、丁酸甲酯代谢、苯甲酸降解、β丙氨酸代谢、α亚麻酸代谢等通路显著减低（|LDA|>2，P<0.05）。 结论 0~3岁KD急性期婴幼儿肠道菌群在结构及多样性方面与健康婴幼儿相比均有显著差异，提示KD急性期存在肠道菌群紊乱，尤其是单核细胞增生李斯特菌、海氏肠球菌、鸟肠球菌可能通过类固醇降解及细胞凋亡参与KD的发病机制。
Abstract
Objective To study the composition, abundance, and functional profiles of the intestinal microbiota in infants and young children with Kawasaki disease (KD) during the acute phase, and to explore the potential role of intestinal microbiota in the pathogenesis of KD. Methods Six children aged 0-3 years with acute KD admitted to the Department of Cardiology, Children's Hospital Affiliated to Capital Institute of Pediatrics from July to October 2021 were prospectively included as the KD group. Six age- and sex-matched healthy children who underwent physical examinations at the hospital during the same period were selected as the healthy control group. Metagenomics sequencing was used to detect and compare the differences in the microflora structure and functional profiles of fecal samples between the two groups. Results There were significant differences in the structural composition and diversity of intestinal microbiota between the two groups (P<0.05). Compared with the healthy control group, the abundance of Listeria_monocytogenes (family Listeriaceae and genus Listeria), Bifidobacterium_rousetti, Enterococcus_avium, and Enterococcus_hirae was significantly higher in the intestinal microbiota in the KD group (|LDA|>2.0, P<0.05). The steroid degradation and apoptosis pathways were significantly upregulated in the KD group compared with the healthy control group, while the Bacterial_secretion_system, Sulfur_metabolism, Butanoate_metabolism, Benzoate_degradation, β-alanine metabolism, and α-linolenic acid pathways were significantly downregulated (|LDA|>2, P<0.05). Conclusions There are significant differences in the structure and diversity of intestinal microbiota between children aged 0-3 years with acute KD and healthy children, suggesting that disturbances in intestinal microbiota occur during the acute phase of KD. In particular, Listeria_monocytogenes, Enterococcus_avium, and Enterococcus_hirae may be involved in the pathogenesis of KD through steroid degradation and apoptosis pathways.
关键词
川崎病 /
肠道菌群 /
宏基因组学 /
婴幼儿
Key words
Kawasaki disease /
Intestinal microbiota /
Metagenomics /
Infant and young child
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参考文献
1 McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association[J]. Circulation, 2017, 135(17): e927-e999. PMID: 28356445. DOI: 10.1161/CIR.0000000000000484.
2 Lei WT, Chang LS, Zeng BY, et al. Pharmacologic interventions for Kawasaki disease in children: a network meta-analysis of 56 randomized controlled trials[J]. EBioMedicine, 2022, 78: 103946. PMID: 35306339. PMCID: PMC8933672. DOI: 10.1016/j.ebiom.2022.103946.
3 Gomaa EZ. Human gut microbiota/microbiome in health and diseases: a review[J]. Antonie Van Leeuwenhoek, 2020, 113(12): 2019-2040. PMID: 33136284. DOI: 10.1007/s10482-020-01474-7.
4 Dai Y, Shen Z, Khachatryan LG, et al. Unraveling mechanistic insights into the role of microbiome in neurogenic hypertension: a comprehensive review[J]. Pathol Res Pract, 2023, 249: 154740. PMID: 37567034. DOI: 10.1016/j.prp.2023.154740.
5 Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure[J]. Nat Rev Cardiol, 2019, 16(3): 137-154. PMID: 30410105. PMCID: PMC6377322. DOI: 10.1038/s41569-018-0108-7.
6 Felizardo RJF, Watanabe IKM, Dardi P, et al. The interplay among gut microbiota, hypertension and kidney diseases: the role of short-chain fatty acids[J]. Pharmacol Res, 2019, 141: 366-377. PMID: 30639376. DOI: 10.1016/j.phrs.2019.01.019.
7 Gorelik M, Chung SA, Ardalan K, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of Kawasaki disease[J]. Arthritis Care Res (Hoboken), 2022, 74(4): 538-548. PMID: 35257507. DOI: 10.1002/acr.24838.
8 Chen J, Yue Y, Wang L, et al. Altered gut microbiota correlated with systemic inflammation in children with Kawasaki disease[J]. Sci Rep, 2020, 10(1): 14525. PMID: 32884012. PMCID: PMC7471315. DOI: 10.1038/s41598-020-71371-6.
9 Tamburini S, Shen N, Wu HC, et al. The microbiome in early life: implications for health outcomes[J]. Nat Med, 2016, 22(7): 713-722. PMID: 27387886. DOI: 10.1038/nm.4142.
10 林瑶, 李晓惠, 石琳, 等. 2017年版《川崎病的诊断、治疗及远期管理——美国心脏协会对医疗专业人员的科学声明》解读[J]. 中国实用儿科杂志, 2017, 32(9): 641-648. DOI: 10.19538/j.ek2017090601.
11 Zeng Q, Zeng R, Ye J. Alteration of the oral and gut microbiota in patients with Kawasaki disease[J]. PeerJ, 2023, 11: e15662. PMID: 37456866. PMCID: PMC10340105. DOI: 10.7717/peerj.15662.
12 Ahearn-Ford S, Berrington JE, Stewart CJ. Development of the gut microbiome in early life[J]. Exp Physiol, 2022, 107(5): 415-421. PMID: 35041771. PMCID: PMC9305283. DOI: 10.1113/EP089919.
13 Milani C, Duranti S, Bottacini F, et al. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota[J]. Microbiol Mol Biol Rev, 2017, 81(4): e00036-17. PMID: 29118049. PMCID: PMC5706746. DOI: 10.1128/MMBR.00036-17.
14 Kaneko K, Akagawa S, Akagawa Y, et al. Our evolving understanding of Kawasaki disease pathogenesis: role of the gut microbiota[J]. Front Immunol, 2020, 11: 1616. PMID: 32793240. PMCID: PMC7393004. DOI: 10.3389/fimmu.2020.01616.
15 Rowley AH. Is Kawasaki disease an infectious disorder?[J]. Int J Rheum Dis, 2018, 21(1): 20-25. PMID: 29105346. PMCID: PMC5777874. DOI: 10.1111/1756-185X.13213.
16 Tsoukas P, Yeung RSM. Kawasaki disease-associated cytokine storm syndrome[J]. Adv Exp Med Biol, 2024, 1448: 365-383. PMID: 39117827.DOI: 10.1007/978-3-031-59815-9_25.
17 Esposito S, Polinori I, Rigante D. The gut microbiota-host partnership as a potential driver of Kawasaki syndrome[J]. Front Pediatr, 2019, 7: 124. PMID: 31024869. PMCID: PMC6460951. DOI: 10.3389/fped.2019.00124.
18 沈男, 王莹, 王兴翠, 等. 川崎病对儿童肠道菌群的影响[J]. 基础医学与临床, 2019, 39(5): 636-640. DOI: 10.3969/j.issn.1001-6325.2019.05.005.
19 Fiore E, Van Tyne D, Gilmore MS. Pathogenicity of Enterococci[J]. Microbiol Spectr, 2019, 7(4): 10.1128/microbiolspec.gpp3-0053-2018. PMID: 31298205. PMCID: PMC6629438. DOI: 10.1128/microbiolspec.GPP3-0053-2018.
20 Wu WL, Adame MD, Liou CW, et al. Microbiota regulate social behaviour via stress response neurons in the brain[J]. Nature, 2021, 595(7867): 409-414. PMID: 34194038. PMCID: PMC8346519. DOI: 10.1038/s41586-021-03669-y.
21 Agbavor C, Zimnicka A, Kumar A, et al. The chaperone PrsA2 regulates the secretion, stability, and folding of listeriolysin O during Listeria monocytogenes infection[J]. mBio, 2024, 15(7): e0074324. PMID: 38809022. PMCID: PMC11253611. DOI: 10.1128/mbio.00743-24.
22 Skrobas U, Zie WS, Bielewicz J, et al. The rapidly progressing and fatal outcome of rhombencephalitis by listeriosis in a 61-year-old male[J]. Ann Agric Environ Med, 2024, 31(2): 311-314. PMID: 38940119. DOI: 10.26444/aaem/178178.
23 Wing EJ, Gregory SH. Listeria monocytogenes: clinical and experimental update[J]. J Infect Dis, 2002, 185 Suppl 1: S18-S24. PMID: 11865436. DOI: 10.1086/338465.
24 Ling Z, Zhao D, Xie X, et al. inlF enhances Listeria monocytogenes early-stage infection by inhibiting the inflammatory response[J]. Front Cell Infect Microbiol, 2022, 11: 748461. PMID: 35223532. PMCID: PMC8866704. DOI: 10.3389/fcimb.2021.748461.
25 Shen J, Ding Y, Yang Z, et al. Effects of changes on gut microbiota in children with acute Kawasaki disease[J]. PeerJ, 2020, 8: e9698. PMID: 33005487. PMCID: PMC7512135. DOI: 10.7717/peerj.9698.
26 Teramoto Y, Akagawa S, Hori SI, et al. Dysbiosis of the gut microbiota as a susceptibility factor for Kawasaki disease[J]. Front Immunol, 2023, 14: 1268453. PMID: 38022552. PMCID: PMC10644744. DOI: 10.3389/fimmu.2023.1268453.
27 Khan I, Li XA, Law B, et al. Correlation of gut microbial compositions to the development of Kawasaki disease vasculitis in children[J]. Future Microbiol, 2020, 15: 591-600. PMID: 32490694. DOI: 10.2217/fmb-2019-0301.
基金
首都儿科研究所临床培育项目（LCPY-2021-10）。
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