微生物相关基因富集分析法鉴定风湿病相关肠道微生物群

何培; 王曼利; 曹蓉蓉; 董晨悦; 邓飞艳; 雷署丰

doi:10.16462/j.cnki.zhjbkz.2021.08.002

微生物相关基因富集分析法鉴定风湿病相关肠道微生物群

doi: 10.16462/j.cnki.zhjbkz.2021.08.002

1.
215123 苏州，苏州大学医学部公共卫生学院遗传流行病与基因组学中心
2.
332000 九江，九江市第一人民医院肾内科

基金项目:

国家自然科学基金 81473046

详细信息

通讯作者:
雷署丰，E-mail：leisf@suda.edu.cn

中图分类号: R593.2
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出版历程
- 收稿日期: 2021-06-29
- 修回日期: 2021-07-16
- 网络出版日期: 2021-08-24
- 刊出日期: 2021-08-10

Identifying rheumatoid diseases-associated gut microbiota using microbiota-related gene set enrichment analysis

1.
Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou 215123, China
2.
Department of Nephrology, Jiujiang No.1 People's Hospital, Jiujiang 332000, China

Funds:

National Natural Science Foundation of China 81473046

More Information

Corresponding author: LEI Shu-feng, E-mail: leisf@suda.edu.cn

摘要

摘要: 目的鉴定与类风湿关节炎(rheumatoid arthritis, RA)、系统性红斑狼疮(systemic lupus erythematosus, SLE)和强直性脊柱炎(ankylosing spondylitis, AS)相关的肠道微生物群。方法利用已发表的全基因组关联研究(genome-wide association study, GWAS)和肠道微生物群GWAS的总结数据，运用肠道微生物群相关基因富集分析(gene set enrichment analysis, GSEA)方法检测肠道微生物群和风湿病之间的关联。结果通过鉴定发现多个肠道微生物群均与三种风湿病相关(均有P＜0.05)。其中，瘤胃球菌属(Ruminococcaceae_UCG-009)与RA、SLE和AS均相关(均有P＜0.05)；Intestinibacter属和发酵性厌氧梭菌潜在新物种(Candidatus_Soleaferrea)则与RA和SLE相关(均有P＜0.05)。结论部分肠道微生物群可能通过其代谢物的作用成为新的风湿病调节因子，这为揭示肠道微生物群在风湿病中的作用提供了新的线索。
- 风湿病 /
- 肠道微生物 /
- 全基因组关联研究 /
- 肠道微生物群相关基因富集分析
Abstract: Objective This study aims to detect the association between gut microbiota and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS). Methods The microbiota-related gene set enrichment analysis (GSEA) was applied to identify rheumatoid diseases-related gut microbiota using published genome-wide association study (GWAS) and GWAS of gut microbiota summary statistic data. Results Several associations between three rheumatoid diseases and gut microbiota were identified (all P < 0.05). Thereinto, Ruminococcaceae_UCG-009 was significantly associated with RA, SLE and AS (all P < 0.05). For RA and SLE, association signals were observed for Intestinibacter and Candidatus_Soleaferrea (all P < 0.05). Conclusion This study found that part of the gut microbiota could be novel regulators of rheumatoid diseases via the effects of its metabolites, and may provide novel clues for revealing the roles of gut microbiota in rheumatology.
- Rheumatoid diseases /
- Gut microbiota /
- GWAS /
- Microbiota-related GSEA

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表 1 全基因组关联研究数据集基本信息

Table 1. Basic information of Genome-wide association study datasets

PMID号	疾病	病例(例)	对照(例)	人群来源	SNP关联数^a(万)
20453842^[8]	RA	5 539	129 273	欧洲人	< 13
26502338^[9]	SLE	7 219	15 991	欧洲人	< 790
23749187^[10]	AS	10 619	15 145	欧洲人	< 12
注：^a单核苷酸多态性(single nucleotide polymorphism, SNP)关联数。

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表 2 类风湿关节炎、系统性红斑狼疮和强直性脊柱炎相关肠道微生物群

Table 2. Gut microbiota associated with rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis

疾病	菌群	NES ^a	P值
RA
	genus.Allisonella.id.2174 ^b	7.925	＜0.001
	genus.Candidatus_Soleaferrea.id.11350 ^c	5.913	＜0.001
	genus.Intestinibacter.id.11345 ^d	6.215	＜0.001
	genus.Oxalobacter.id.2978 ^e	5.349	＜0.001
	genus.Ruminococcaceae_UCG-009.id.11366 ^f	8.641	＜0.001
SLE
	genus.Eubacterium coprostanoligenes group.id.11375 ^g	5.303	＜0.001
	genus.Candidatus_Soleaferrea.id.11350	5.956	＜0.001
	genus.Intestinibacter.id.11345	5.463	＜0.001
	genus.Ruminococcaceae_UCG-009.id.11366	4.418	＜0.001
	genus.Enterorhabdus.id.820 ^h	3.234	0.001
AS
	order.Gastranaerophilales.id.1591 ⁱ	3.475	＜0.001
	genus.Ruminococcaceae_UCG-009.id.11366	3.449	＜0.001
	genus.Romboutsia.id.11347 ^j	2.690	0.003
	family.Peptostreptococcaceae.id.2042 ^k	2.732	0.003
注：^a校正后的富集分数(normalized enrichment score, NES)；^b阿里松菌属(Allisonella)；^c发酵性厌氧梭菌潜在新物种(Candidatus_Soleaferrea)；^d Intestinibacter属；^e草酸杆菌属(Oxalobacter)；^f瘤胃球菌属(Ruminococcaceae_UCG-009)；^g产粪甾醇真细菌属(Eubacterium coprostanoligenes group)；^h肠杆菌属(Enterorhabdus)；ⁱ胃厌氧菌目(Gastranaerophilales)；^j罗姆布茨菌属(Romboutsia)；^k消化链球菌科(Peptostreptococcaceae)。

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表 3 风湿病相关肠道微生物群相关宿主基因

Table 3. Host genes associated with rheumatoid diseases-associated gut microbiota

疾病	菌群	基因
RA ^a	genus.Allisonella.id.2174 ^b	AL353637.1，AL353637.2，DNAJB5P1，GCNT1，H3P32，LYPLA2P3，PCA3，PCSK5，PPIAP87，PRUNE2，RBM22P5，RFK，RPSAP9
RA、SLE ^c	genus.Candidatus_Soleaferrea.id.11350 ^d	AC008532.1，AC008745.1，AC008985.1，AC010331.1，AC010519.1，AC073548.1，AC073548.2，ARHGAP35，BBC3，BICRA，BICRA-AS1，BSPH1，C5AR1，C5AR2，CCDC9，CRX，DHX34，EHD2，INAFM1，KPTN，LINC01595，MEIS3，NAPA，NAPA-AS1，NOP53，NOP53-AS1，NPAS1，RPL23AP80，SAE1，SELENOW，SLC8A2，SULT2A1，TMEM160，TPRX1，TPRX2P，ZC3H4，ZNF541
RA、SLE	genus.Intestinibacter.id.11345 ^e	AC006296.1，AC006296.2，AC006296.3，AC073848.1，AC092546.1，AC095052.1，LINC00504，LINC01085，LINC01182，MTND2P31
RA、SLE	genus.Oxalobacter.id.2978 ^f	AL157886.1，AL354692.1，AL354897.1，AL354897.2，AL583827.1，NTRK2，UBE2V1P10
RA、SLE及AS ^g	genus.Ruminococcaceae_UCG-009.id.11366 ^h	AL109628.1，AL109628.2，AL132639.1，AL132639.2，AL132639.3，AL132994.2，AL132994.3，AL355835.1，AL357094.1，GEMIN2，KRT8P1，LINC00639，MIA2，PNN，PPIAP4，RPL7AP2，SEC23A，SEC23A-AS1，TRAPPC6B，YTHDF2P1
SLE	genus.Eubacterium coprostanoligenesgroup.id.11375 ⁱ	AC004691.1，AC004691.2，AC005090.1，AC005154.3，AC005154.5，AC006022.1，AC006380.1，AC006398.1，AC006466.1，ADCYAP1R1，AQP1，CRHR2，GARS1，GARS1-DT，GHRHR，INMT，INMT-MINDY4，ITPRID1，MINDY4，NEUROD6
SLE	genus.Enterorhabdus.id.820 ^j	AC097528.1，AC104664.1，H3P15，LINC02379，RBM48P1
AS	genus.Romboutsia.id.11347 ^k	AC067747.1，AC073367.1，AL133415.1，AL353576.1，AL365215.2，C1QL3，CUBN，PTER，RSU1，ST8SIA6，ST8SIA6-AS1，TRDMT1，VIM，VIM-AS1
AS	family.Peptostreptococcaceae.id.2042 ^l	AC067747.1，AC073367.1，AL133415.1，AL353576.1，AL365215.2，C1QL3，CUBN，PTER，RSU1，ST8SIA6，ST8SIA6-AS1，TRDMT1，VIM，VIM-AS1
注：^a类风湿关节炎(rheumatoid arthritis, RA)；^b阿里松菌属(Allisonella)；^c系统性红斑狼疮(systemic lupus erythematosus, SLE)；^d发酵性厌氧梭菌潜在新物种(Candidatus Soleaferrea)；^e Intestinibacter属；^f草酸杆菌属(Oxalobacter); ^g强直性脊柱炎(ankylosing spondylitis, AS); ^h瘤胃球菌属(Ruminococcaceae_UCG-009)；ⁱ产粪甾醇真细菌属(Eubacterium coprostanoligenes group)；^j肠杆菌属(Enterorhabdus)；^k罗姆布茨菌属(Romboutsia)；^l消化链球菌科(Peptostreptococcaceae)。

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参考文献(29)

[1]	马凤云. 硫酸羟氯喹治疗风湿病的临床效果分析[J]. 中国继续医学教育, 2020, 12(14): 163-164. DOI: 10.3969/j.issn.1674-9308.2020.14.066. Ma FY. Clinical effect of hydroxychloroquine sulfate in the treatment of rheumatism[J]. China Continuing Med Educ, 2020, 12(14): 163-164. DOI: 10.3969/j.issn.1674-9308.2020.14.066.
[2]	Tong YL, Marion T, Schett G, et al. Microbiota and Metabolites in rheumatic diseases[J]. Autoimmun Rev, 2020, 19(8): 102530. DOI: 10.1016/j.autrev.2020.102530.
[3]	Consortium THMP. Structure, function and diversity of the healthy human microbiome[J]. Nature, 2012, 486(7402): 207-214. DOI: 10.1038/nature11234.
[4]	Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome[J]. Cell, 2014, 159(4): 789-799. DOI: 10.1016/j.cell.2014.09.053.
[5]	Khachatryan ZA, Ktsoyan ZA, Manukyan GP, et al. Predominant role of host genetics in controlling the composition of gut microbiota[J]. PLoS One, 2008, 3(8): e3064. DOI: 10.1371/journal.pone.0003064.
[6]	Visscher PM, Brown MA, McCarthy MI, et al. Five years of GWAS discovery[J]. Am J Hum Genet, 2012, 90(1): 7-24. DOI: 10.1016/j.ajhg.2011.11.029.
[7]	Cheng SQ, Han B, Ding M, et al. Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis[J]. Brief Bioinform, 2020, 21(3): 1016-1022. DOI: 10.1093/bib/bbz034.
[8]	Stahl EA, Raychaudhuri S, Remmers EF, et al. Genome-wide association study Meta-analysis identifies seven new rheumatoid arthritis risk loci[J]. Nat Genet, 2010, 42(6): 508-514. DOI: 10.1038/ng.582.
[9]	Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus[J]. Nat Genet, 2015, 47(12): 1457-1464. DOI: 10.1038/ng.3434.
[10]	International Genetics of Ankylosing Spondylitis Consortium (IGAS), Cortes A, Hadler J, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci[J]. Nat Genet, 2013, 45(7): 730-738. DOI: 10.1038/ng.2667.
[11]	Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al. Large-scale association analyses identify host factors influencing human gut microbiome composition[J]. Nat Genet, 2021, 53(2): 156-165. DOI: 10.1038/s41588-020-00763-1.
[12]	Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles[J]. Proc Natl Acad Sci USA, 2005, 102(43): 15545-15550. DOI: 10.1073/pnas.0506580102.
[13]	Wu GD, Zhi DG. Pathway-based approaches for sequencing-based genome-wide association studies[J]. Genet Epidemiol, 2013, 37(5): 478-494. DOI: 10.1002/gepi.21728.
[14]	Levy M, Kolodziejczyk AA, Thaiss CA, et al. Dysbiosis and the immune system[J]. Nat Rev Immunol, 2017, 17(4): 219-232. DOI: 10.1038/nri.2017.7.
[15]	Zhang X, Zhang DY, Jia HJ, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment[J]. Nat Med, 2015, 21(8): 895-905. DOI: 10.1038/nm.3914.
[16]	Scher JU, Joshua V, Artacho A, et al. The lung microbiota in early rheumatoid arthritis and autoimmunity[J]. Microbiome, 2016, 4(1): 60. DOI: 10.1186/s40168-016-0206-x.
[17]	Kamada N, Seo SU, Chen GY, et al. Role of the gut microbiota in immunity and inflammatory disease[J]. Nat Rev Immunol, 2013, 13(5): 321-335. DOI: 10.1038/nri3430.
[18]	Koboziev I, Reinoso Webb C, Furr KL, et al. Role of the enteric microbiota in intestinal homeostasis and inflammation[J]. Free Radic Biol Med, 2014, 68: 122-133. DOI: 10.1016/j.freeradbiomed.2013.11.008.
[19]	Cai J, Zhou L, Song XD, et al. Alteration of intestinal microbiota in 3-deoxyglucosone-induced prediabetic rats[J]. Biomed Res Int, 2020, 2020: 8406846. DOI: 10.1155/2020/8406846.
[20]	Donaldson GP, Lee SM, Mazmanian SK. Gut biogeography of the bacterial microbiota[J]. Nat Rev Microbiol, 2016, 14(1): 20-32. DOI: 10.1038/nrmicro3552.
[21]	Hooda S, Boler BM, Serao MC, et al. 454 pyrosequencing reveals a shift in fecal microbiota of healthy adult men consuming polydextrose or soluble corn fiber[J]. J Nutr, 2012, 142(7): 1259-1265. DOI: 10.3945/jn.112.158766.
[22]	Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study[J]. Eur J Neurol, 2016, 23(8): 1308-1321. DOI: 10.1111/ene.13026.
[23]	Zha Z, Lyu Y, Tang H, et al. An orally administered butyrate-releasing xylan derivative reduces inflammation in dextran sulphate sodium-induced murine colitis[J]. Int J Biol Macromol, 2020, 156: 1217-1233. DOI: 10.1016/j.ijbiomac.2019.11.159.
[24]	Hov JR, Zhong HZ, Qin BC, et al. The influence of the autoimmunity-associated ancestral HLA haplotype AH8.1 on the human gut microbiota: a cross-sectional study[J]. PLoS One, 2015, 10(7): e0133804. DOI: 10.1371/journal.pone.0133804.
[25]	Clavel T, Duck W, Charrier C, et al. Enterorhabdus caecimuris sp. nov., a member of the family Coriobacteriaceae isolated from a mouse model of spontaneous colitis, and emended description of the genus Enterorhabdus Clavel et al. 2009[J]. Int J Syst Evol Microbiol, 2010, 60(Pt 7): 1527-1531. DOI: 10.1099/ijs.0.015016-0.
[26]	Vernocchi P, Gili T, Conte F, et al. Network analysis of gut microbiome and Metabolome to discover microbiota-linked biomarkers in patients affected by non-small cell lung cancer[J]. Int J Mol Sci, 2020, 21(22): 8730. DOI: 10.3390/ijms21228730.
[27]	Johanson DM, Goertz JE, Marin IA, et al. Experimental autoimmune encephalomyelitis is associated with changes of the microbiota composition in the gastrointestinal tract[J]. Sci Rep, 2020, 10(1): 15183. DOI: 10.1038/s41598-020-72197-y.
[28]	Jalanka J, Cheng J, Hiippala K, et al. Colonic mucosal microbiota and association of bacterial taxa with the expression of host antimicrobial peptides in pediatric ulcerative colitis[J]. Int J Mol Sci, 2020, 21(17): 6044. DOI: 10.3390/ijms21176044.
[29]	Yan N, Wang L, Li Y, et al. Metformin intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation[J]. PloS one, 2021, 16(7): e254321. DOI: 10.1371/journal.pone.0254321.