系统性红斑狼疮患者肠道菌群与外周血淋巴细胞亚群的相关性研究

doi:10.16138/j.1673-6087.2025.02.07

摘要/Abstract

摘要：

目的：通过检测系统性红斑狼疮（systemic lupus erythematosus，SLE）患者肠道菌群丰度变化及外周血淋巴细胞亚群数量，分析关键差异菌群分布与淋巴细胞亚群之间的相关性。方法：共纳入SLE患者23例和相匹配的健康对照（healthy control，HC）16名，流式细胞术检测外周血淋巴细胞亚群数量，16S rRNA技术检测肠道菌群多样性及丰度，分析外周血淋巴细胞亚群数量与肠道菌群的相关性，通过SPSS 26.0进行统计学分析。结果：与HC组相比，SLE组调节性T（regulatory T，Treg）细胞（t=-2.284，P=0.022）、初始CD4⁺T细胞（t=-2.084，P=0.037）、分泌干扰素（interferon，IFN）γ的γδT细胞（t=-2.370，P=0.017）明显减少；SLE组厚壁菌门相对丰度下降（t=-2.323，P=0.020），与Tfr细胞（r=0.544，P=0.029）、生发中心（germinal center，GC）-B细胞（r=0.518，P=0.040）呈正相关；拟杆菌门丰度与Tfr细胞呈负相关（r=-0.521，P=0.039）。结论：SLE患者外周血多种淋巴细胞亚型、肠道菌群结构与HC相比存在显著差异；肠道菌群与淋巴细胞亚群间存在相关性，尤其厚壁菌门、拟杆菌门与Tfr、Tfh、GC-B细胞存在相关性。

关键词: 系统性红斑狼疮, 肠道菌群, 滤泡调节性T细胞, 滤泡辅助性T细胞

Abstract:

Objective To investigate the correlation between the distribution of critical differential bacterial populations and lymphocyte subsets in systemic lupus erythematosus （SLE） patients by detecting the abundance changes of intestinal microbiota and lymphocyte subsets. Methods Twenty-three SLE patients and 16 healthy controls (HC) were included. Flow cytometry was used to detect the number of peripheral blood lymphocyte subsets, and 16S rRNA technology was used to detect the diversity and abundance of intestinal microbiota. The correlation between peripheral blood lymphocyte subsets and intestinal microbiota was investigated, and the experimental data were analyzed using SPSS 26.0. Results Compared with HC, the numbers of regulatory T（Treg） cells, initial CD4⁺T cells, and interferon（IFN）γ-secreting γδT cells in SLE patients were significantly reduced (t=-2.284, P=0.022; t=-2.084, P=0.037; t=-2.370, P=0.017), and follicular regulatory T （Tfr）, follicular helper T （Tfh）, germinal center B （GC-B）and B lymphocytes showed a downward trend. The relative abundance of Firmicutes in SLE patients was significantly decreased (t=-2.323, P=0.020) and was positively correlated with Tfr (r=0.544, P=0.029) and GC-B cells (r=0.518, P=0.040). The abundance of Bacteroidetes was positively correlated with Tfr cells (r=0.521, P=0.039). Conclusions The peripheral blood lymphocyte subsets and intestinal microbiota levels of SLE patients are significantly different from those of HC, there was a correlation between the intestinal flora and lymphocyte subpopulations in the intestinal tract of SLE patients, especially the Firmicutes and Bacteroidetes are positively correlated with Tfr, Tfh and GC-B cells, suggesting that the structural changes of intestinal microbiota may affect lymphocyte subsets and mediate the progression of the disease.

Key words: Systemic lupus erythematosus, Gut microbiota, T follicular regulatory cell, T follicular helper cell

中图分类号:

R593.24

岑星, 赵春苗, 卜玉洁, 赵桂芳, 杨金华, 陈俊伟. 系统性红斑狼疮患者肠道菌群与外周血淋巴细胞亚群的相关性研究[J]. 内科理论与实践, 2025, 20(02): 140-145.

CEN Xing, ZHAO Chunmiao, BU Yujie, ZHAO Guifang, YANG Jinhua, CHEN Junwei. Investigating correlation between gut microbiota and peripheral lymphocyte subsets in patients with systemic lupus erythematosus[J]. Journal of Internal Medicine Concepts & Practice, 2025, 20(02): 140-145.

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参考文献 28

[1]	Tian J, Zhang D, Yao X, et al. Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study[J]. Ann Rheum Dis, 2023, 82(3): 351-356.
[2]	Chen S, Hu D, Shi X, et al. The relationship between Th1/Th2-type cells and disease activity in patients with systemic lupus erythematosus[J]. Chin Med J (Engl), 2000, 113(10):877-880.
[3]	Yang J, Chu Y, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus[J]. Arthritis Rheum, 2009, 60(5): 1472-1483.
[4]	Deng J, Wei Y, Fonseca VR, et al. T follicular helper cells and T follicular regulatory cells in rheumatic diseases[J]. Nat Rev Rheumatol, 2019, 15(8): 475-490. doi: 10.1038/s41584-019-0254-2 pmid: 31289377
[5]	Song W, Craft J. T follicular helper cell heterogeneity: time, space, and function[J]. Immunol Rev, 2019, 288(1):85-96. doi: 10.1111/imr.12740 pmid: 30874350
[6]	Hao H, Nakayamada S, Yamagata K, et al. Conversion of T follicular helper cells to T follicular regulatory cells by interleukin-2 through transcriptional regulation in systemic lupus erythematosus[J]. Arthritis Rheumatol, 2021, 73(1): 132-142.
[7]	Fan H, Liu F, Dong G, et al. Activation-induced necroptosis contributes to B-cell lymphopenia in active systemic lupus erythematosus[J]. Cell Death Dis, 2014, 5(9): e1416.
[8]	Krustev E, Clarke AE, Barber MRW. B cell depletion and inhibition in systemic lupus erythematosus[J]. Expert Rev Clin Immunol, 2023, 19(1): 55-70.
[9]	Choi VM, Herrou J, Hecht AL, et al. Activation of bacteroides fragilis toxin by a novel bacterial protease contributes to anaerobic sepsis in mice[J]. Nat Med, 2016, 22(5): 563-567. doi: 10.1038/nm.4077 pmid: 27089515
[10]	Zaiss MM, Joyce Wu HJ, Mauro D, et al. The gut-joint axis in rheumatoid arthritis[J]. Nat Rev Rheumatol, 2021, 17(4): 224-237. doi: 10.1038/s41584-021-00585-3 pmid: 33674813
[11]	Gao B, Wang Z, Wang K, et al. Relationships among gut microbiota, plasma metabolites, and juvenile idiopathic arthritis: a mediation Mendelian randomization study[J]. Front Microbiol, 2024, 15: 1363776.
[12]	Bianchimano P, Britton GJ, Wallach DS, et al. Mining the microbiota to identify gut commensals modulating neuroinflammation in a mouse model of multiple sclerosis[J]. Microbiome, 2022, 10(1): 174. doi: 10.1186/s40168-022-01364-2 pmid: 36253847
[13]	Wang Y, Wei J, Zhang W, et al. Gut dysbiosis in rheumatic diseases: a systematic review and meta-analysis of 92 observational studies[J]. EBioMedicine, 2022, 80:104055.
[14]	Xiang K, Wang P, Xu Z, et al. Causal effects of gut microbiome on systemic lupus erythematosus: a two-sample Mendelian randomization study[J]. Front Immunol, 2021,12: 667097.
[15]	Azzouz D, Omarbekova A, Heguy A, et al. Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal[J]. Ann Rheum Dis, 2019, 78(7): 947-956. doi: 10.1136/annrheumdis-2018-214856 pmid: 30782585
[16]	Wang T, Sternes PR, Guo XK, et al. Autoimmune diseases exhibit shared alterations in the gut microbiota[J]. Rheumatology (Oxford), 2024, 63(3): 856-865.
[17]	Hevia A, Milani C, López P, et al. Intestinal dysbiosis associated with systemic lupus erythematosus[J]. mBio, 2014, 5(5): e01548-14.
[18]	Bates NA, Li A, Fan T, et al. Gut commensal segmented filamentous bacteria fine-tune T follicular regulatory cells to modify the severity of systemic autoimmune arthritis[J]. J Immunol, 2021, 206(5): 941-952. doi: 10.4049/jimmunol.2000663 pmid: 33462137
[19]	Liang M, Liwen Z, Jianguo S, et al. Fecal microbiota transplantation controls progression of experimental autoimmune hepatitis in mice by modulating the TFR/TFH immune imbalance and intestinal microbiota composition[J]. Front Immunol, 2021, 12: 728723.
[20]	Zhang H, Liao X, Sparks JB, et al. Dynamics of gut microbiota in autoimmune lupus[J]. Appl Environ Microbiol, 2014, 80(24): 7551-7560.
[21]	Van de Wiele T, Van Praet JT, Marzorati M, et al. How the microbiota shapes rheumatic diseases[J]. Nat Rev Rheumatol, 2016, 12(7): 398-411. doi: 10.1038/nrrheum.2016.85 pmid: 27305853
[22]	Tyagi AM, Yu M, Darby TM, et al. The microbial metabolite butyrate stimulates bone formation via T regulatory cell-mediated regulation of WNT10B expression[J]. Immunity, 2018, 49(6): 1116-1131. doi: S1074-7613(18)30478-3 pmid: 30446387
[23]	Faliti CE, Mesina M, Choi J, et al. Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis[J]. Immunity, 2024, 57(12): 2772-2789. doi: 10.1016/j.immuni.2024.11.006 pmid: 39612915
[24]	Zhang SX, Wang J, Chen JW, et al. The level of peripheral regulatory T cells is linked to changes in gut commensal microflora in patients with systemic lupus erythematosus[J]. Ann Rheum Dis, 2021, 80(11): e177.
[25]	Wu R, Wang D, Cheng L, et al. Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites[J]. Arthritis Res Ther, 2024, 26(1): 21. doi: 10.1186/s13075-023-03260-y pmid: 38218985
[26]	Wu JL, Zou JY, Hu ED, et al. Sodium butyrate ameliorates S100/FCA-induced autoimmune hepatitis through regulation of intestinal tight junction and toll-like receptor 4 signaling pathway[J]. Immunol Lett, 2017, 190:169-176.
[27]	Xu MQ, Cao HL, Wang WQ, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders[J]. World J Gastroenterol, 2015, 21(1):102-111.
[28]	Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease[J]. Nat Rev Microbiol, 2023, 21(11): 719-733. doi: 10.1038/s41579-023-00904-3 pmid: 37316582

淋巴细胞亚群	ds-DNA		ESR		C3		C4		SLEDAI
淋巴细胞亚群	r	P	r	P	r	P	r	P	r	P
Treg细胞	-0.13	0.57	-0.31	0.15	0.01	0.96	-0.26	0.24	-0.24	0.28
初始CD4细胞	-0.20	0.36	-0.20	0.35	0.001	0.99	-0.22	0.32	-0.24	0.27
IFN-γ⁺γδT细胞	-0.12	0.59	-0.18	0.40	0.14	0.54	-0.14	0.53	-028	0.20
Th17细胞	-0.16	0.49	-0.09	0.67	0.05	0.83	-0.23	0.29	-0.27	0.22
Tfr细胞	-0.20	0.36	-0.13	0.54	-0.03	0.89	-0.29	0.19	-0.24	0.28
Tfh细胞	-0.19	0.40	-0.16	0.46	-0.01	0.98	-0.24	0.27	-0.23	0.28
GC-B细胞	-0.25	0.25	-0.17	0.44	0.07	0.74	-0.10	0.67	-0.19	0.39
B细胞	-0.37	0.09	0.06	0.79	-0.003	0.99	-0.13	0.58	0.04	0.87

淋巴细胞亚群	HC组（n=16）	SLE组（n=23）	t	P
Treg细胞	1.59±1.30	0.80±1.20	-2.284	0.022
初始CD4⁺T细胞	48.61±58.56	46.31±110.32	-2.084	0.037
IFN-γ⁺γδT细胞	4.49±6.16	1.93±3.18	-2.370	0.017
Th17细胞	1.23±1.41	2.14±4.94	-0.542	0.601
Tfr细胞	0.31±0.55	0.20±0.20	0.228	0.832
Tfh细胞	3.90±7.38	2.96±6.68	-0.685	0.507
GC-B细胞	3.12±3.36	2.48±4.29	-1.114	0.275
B细胞	19.22±3.36	16.69±23.80	-1.599	0.114

菌群	HC组（n=16）	SLE组（n=23）	t	P
厚壁菌门	0.62±0.13	0.48±0.19	-2.323	0.020
拟杆菌门	0.29±0.97	0.40±0.21	1.747	0.081
变形菌门	0.04±0.05	0.09±0.13	1.259	0.214
放线菌门	0.02±0.01	0.02±0.03	-0.339	0.745

指数	HC组（n=16）	SLE组（n=23）	Z	P
丰度指数	289.00(213.25,356.50)	235.00(137.00，302.00)	-2.128	0.032
Chao1指数	333.10(284.83,363.18)	228.20(168.40,336.70)	-2.342	0.019
Shannon指数	3.76(3.52,4.07)	3.33(2.86,3.65)	2.202	0.034

指标	厚壁菌门		拟杆菌门
指标	r	P	r	P
ds-DNA	-0.061	0.821	0.139	0.608
ESR	-0.359	0.172	0.237	0.378
C3	0.265	0.340	-0.154	0.584
C4	0.431	0.109	-0.256	0.357
SLEDAI	-0.192	0.477	0.123	0.649