切换至 "中华医学电子期刊资源库"
高级检索
中华实验和临床感染病杂志(电子版)

中华实验和临床感染病杂志(电子版) ›› 2026, Vol. 20 ›› Issue (03) : 129 -138. doi: 10.3877/cma.j.issn.1674-1358.2026.03.001

所属专题： 文献；

论著

新型冠状病毒肺炎后肺间质纤维化与口咽部菌群失衡的相关性
陈玉1, 周欣佑2, 蔡昀朴2, 章从恩3, 聂秀红1,†()   
  1. 1　100053　北京，首都医科大学宣武医院呼吸与危重症医学科
    2　100069　北京，首都医科大学
    3　100050　北京，首都医科大学附属北京友谊医院药学部
  • 收稿日期:2026-01-29 出版日期:2026-06-15
  • 通信作者: 聂秀红
  • 基金资助:
    2025年首都医科大学临床本科生科研创新项目(XSKY2025365)

Correlation between pulmonary interstitial fibrosis and oral-pharyngeal microbial dysbiosis in patients with post-coronavirus disease 2019

Yu Chen1, Xinyou Zhou2, Yunpu Cai2, Congen Zhang3, Xiuhong Nie1,†()   

  1. 1 Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China
    2 Capital Medical University, Beijing 100069, China
    3 Department of Pharmacy, Beijing Friendship Hospital of Capital Medical University, Beijing 100050, China
  • Received:2026-01-29 Published:2026-06-15
  • Corresponding author: Xiuhong Nie
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

陈玉, 周欣佑, 蔡昀朴, 章从恩, 聂秀红. 新型冠状病毒肺炎后肺间质纤维化与口咽部菌群失衡的相关性[J/OL]. 中华实验和临床感染病杂志(电子版), 2026, 20(03): 129-138.

Yu Chen, Xinyou Zhou, Yunpu Cai, Congen Zhang, Xiuhong Nie. Correlation between pulmonary interstitial fibrosis and oral-pharyngeal microbial dysbiosis in patients with post-coronavirus disease 2019[J/OL]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2026, 20(03): 129-138.

目的

探索口咽部菌群失衡在新型冠状病毒肺炎（COVID-19）后肺间质纤维化（PCPF）发生与发展中的作用及潜在机制。

方法

采用横断面病例对照研究，选择2022年12月至2023年5月因COVID-19于首都医科大学宣武医院住院治疗并完成出院后2年随访的康复患者为研究对象。根据随访时高分辨率计算机断层扫描影像学表现，将患者分为纤维化组和非纤维化组。Mann-Whitney U检验比较两组患者口咽部微生物菌群α多样性；采用非度量多维尺度分析（NMDS）与主坐标分析（PCoA）评估两组菌群β多样性；以Benjamini-Hochberg法进行FDR校正分析门、属、种的丰度差异，并采用Spearman秩相关分析其与临床症状及运动耐量间的相关性。

结果

共纳入83例患者，其中纤维化组患者43例，非纤维化组患者40例。随访2年时，纤维化组患者出现更多的呼吸道症状，mMRC评分（U=676.0、P=0.008）、BCSS评分（U=625.0、P=0.029）、CAT评分（t=2.127、P=0.036）和CET评分（U=538.5、P=0.002）均显著高于非纤维化组，但6 min步行距离（6MWD）更短（U=598.5、P=0.017），差异均有统计学意义。微生物组分析显示，纤维化组患者口咽微生物α多样性显著升高（Chao1指数：U=580.5、P=0.010；Shannon指数：U=557.0、P=0.005；Simpson指数：U=513.0、P=0.001；Faith系统发育多样性指数：U=579.0、P=0.010；Simpson e指数：U=577.0、P=0.010；Heip e均匀度指数：U=529.0、P=0.035），差异均有统计学意义。β多样性分析显示两组患者菌群结构明显分离。菌群分类学分析显示，纤维化组患者普雷沃菌属（U=358.0、P＜0.001）、韦荣菌属（U=418.0、P＜0.001）及链球菌属（U=538.0、P=0.003）等潜在促炎性菌群相对丰度较非纤维化组患者显著增加，而奈瑟菌属（U=226.0、P＜0.001）显著减少，差异均有统计学意义。部分差异显著菌种如Streptococcus parasanguinis丰度与mMRC评分（r=0.24、P=0.04）和CAT评分（r=0.27、P=0.02）呈正相关；Fusobacterium_C_periodonticum_D的丰度与CAT评分（r=－0.30、P＜0.001）和Warrick评分（r=－0.26、P=0.02）均呈负相关，而与6MWD（r=0.26、P=0.02）呈正相关；Veillonella A rogosae及Streptococcus infantis均与Warrick评分呈负相关（r=－0.30、P＜0.01，r=－0.28、P=0.01），均具有统计学意义。

结论

PCPF患者存在持续的口咽部菌群失衡，其特征与临床症状及功能受损密切相关。口咽微生物可能成为PCPF风险评估的潜在非侵入性生物标志物及新型治疗靶点。

关键词: 肺间质纤维化, 新型冠状病毒, 口咽微生物组, 菌群失衡, 16S rRNA基因测序
Objective

To investigate the role and potential mechanisms of oropharyngeal microbiota dysbiosis in the development and progression of post-coronavirus disease 2019 (COVID-19) pulmonary fibrosis (PCPF).

Methods

A cross-sectional case-control study was conducted, enrolling recovered patients who had been hospitalized for COVID-19 in Xuanwu Hospital Capital Medical University, from December 2022 to May 2023, and had completed a 2-year follow-up after discharge. According to high-resolution computed tomography findings during follow-up, patients were classified into fibrosis group and non-fibrosis group. The α-diversity of the oropharyngeal microbiota between the two groups were compared by Mann-Whitney U test; β-diversity was assessed by non-metric multidimensional scaling (NMDS) and principal coordinates analysis (PCoA). Differences in taxonomic abundance at the phylum, genus and species levels were analyzed by Benjamini-Hochberg method with false discovery rate (FDR) correction. Spearman’s rank correlation was applied to evaluate the associations between microbial taxa and clinical symptoms as well as exercise capacity.

Results

Total of 83 patients were enrolled, 43 cases in fibrosis group and 40 cases in non-fibrosis group. During the 2-year follow-up, patients in fibrosis group had more respiratory symptoms and anxiety. Patients in fibrosis group showed significantly higher scores than non-fibrosis group in mMRC scale (U=676.0, P=0.008), BCSS score (U=625.0, P=0.029), CAT score (t=2.127, P=0.036), CET score (U=538.5, P=0.002) and Hamilton Anxiety Rating Scale score (U=634.0, P=0.039); The 6-minute walking distance of patients in fibrosis group was shorter (U=598.5, P=0.017), all with significant differences. Microbiome analysis revealed significantly elevated α-diversity of oropharyngeal microbiota in fibrosis group (Chao1 index: U=580.5, P=0.010; Shannon index: U=557.0, P=0.005; Simpson index: U=513.0, P=0.001; Faith’s phylogenetic diversity: U=579.0, P=0.010; Simpson’s evenness index: U=577.0, P=0.010; Heip’s evenness index: U=529.0, P=0.035), with significant differences. β-diversity analysis showed distinct separation of microbial community structure between the two groups. Taxonomic analysis demonstrated that the relative abundances of potential pro-inflammatory taxa, including Prevotella (U=358.0, P<0.001), Veillonella (U=418.0, P<0.001) and Streptococcus (U=538.0, P=0.003), were significantly increased in fibrosis group, whereas Neisseria (U=226.0, P<0.001) was significantly decreased. Correlation analysis indicated that the abundance of Streptococcus parasanguinis was positively associated with mMRC (r=0.24, P=0.04) and CAT (r=0.27, P=0.02). In contrast, Fusobacterium periodonticum abundance was negatively correlated with CAT (r=－0.30, P<0.01) and Warrick score (r=－0.26, P=0.02), but positively correlated with 6MWD (r=0.26, P=0.02). Furthermore, Veillonella rogosae and Streptococcus infantis were both significantly and negatively correlated with Warrick score (r=－0.30, P<0.01; r=－0.28, P=0.01).

Conclusions

Patients with post-COVID-19 pulmonary fibrosis exhibited persistent oropharyngeal microbial dysbiosis, which is closely associated with clinical symptoms and functional impairment. The oropharyngeal microbiome might serve as a potential non-invasive biomarker for risk assessment and a novel therapeutic target for post-COVID-19 pulmonary fibrosis.

Key words: Pulmonary fibrosis, Coronavirus disease 2019, Oropharyngeal microbiome, Microbial dysbiosis, 16S rRNA gene sequencing
表1 纤维化组和非纤维化组COVID-19患者基线资料
基线资料 纤维化组（43例） 非纤维化组（40例） 统计量 P值
年龄 [M（P25，P75），岁] 67.00（62.00，69.00） 62.50（49.50，69.75） U=676.0a 0.093
男性 [例（%）] 30（69.77） 21（52.50） χ2=2.608b 0.106
BMI [M（P25，P75），kg/m2] 26.44（24.56，29.06） 25.95（22.96，27.76） U=662.0a 0.071
吸烟 [例（%）] 12（27.91） 8（20.00） χ2=0.708b 0.400
高血压 [例（%）] 32（74.41） 22（55.00） χ2=3.438b 0.064
糖尿病 [例（%）] 21（48.84） 12（30.00） χ2=3.070b 0.080
冠心病 [例（%）] 20（46.51） 11（27.50） χ2=3.201b 0.074
入院前发热 [例（%）] 35（81.40） 34（85.00） χ2=1.424b 0.233
入院前症状天数 [M（P25，P75），d] 5.00（3.00，6.00） 5.00（4.00，6.00） U=829.5a 0.778
入院时Warrick评分 [M（P25，P75）] 3.00（2.00，3.00） 3.00（2.00，4.00） U=676.5a 0.078
激素治疗 [例（%）] 36（83.72） 32（80.00） χ2=0.194b 0.660
抗病毒治疗 [例（%）] 24（55.81） 23（57.50） χ2=0.024b 0.877
重-危重度病例 [例（%）] 25（58.14） 16（40.00） χ2=2.728b 0.099
高浓度氧疗（FiO2≥50）[例（%）] 10（23.26） 5（12.50） χ2=1.619b 0.203
住院时长 [M（P25，P75），d]​ 15.00（11.00，21.00） 12.00（8.00，18.00） U=650.0a 0.055
表2 纤维化组和非纤维化组COVID-19患者随访指标
临床参数 纤维化组（43例） 非纤维化组（40例） 统计量 P值
mMRC评分 [M（P25，P75）] 1（1，2） 1（0，2） U=676.000a 0.008
BCSS评分 [M（P25，P75）] 3（1，4） 2（1，2） U=625.000a 0.029
CAT评分（
±s）		 11.14±5.48 8.55±5.60 t=2.127 0.036
CET评分 [M（P25，P75）] 7（5，8） 5（5，6） U=538.500a 0.002
6MWD [M（P25，P75），min] 410（365，465） 450（187，540） U=598.500a 0.017
Warrick评分 [M（P25，P75）] 9（7，14） 0（0，3） U=0.055a ＜0.001
图1 纤维化组和非纤维化组COVID-19患者口咽微生物菌群分析 注：图A～F为COVID-19康复患者有/无肺间质纤维化者口咽部微生物群的 α多样性指标，A为Chao1指数、B为Simpson均匀度、C为Heip均匀度、D为Simpson指数、E为Shannon entropy指数、F为Faith系统发育多样性指数。图G～I为基于β多样性排序的样本间群落结构比较，G为基于Bray-Curtis不相似性的NMDS、H为基于加权UniFrac距离的 NMDS、I为主坐标分析（PCoA）。*P＜0.05、**P＜0.01
图2 PCPF患者门水平微生物群组成及差异 注：A为门水平相对丰度的堆叠条形图，显示样本中整体群落组成模式；B为基于微生物谱相似性对样本进行层次聚类的门水平相对丰度热图；C为DESeq2火山图显示纤维化组与非纤维化组患者间差异丰度的门类；D为柱状图比较各组间选定菌门的绝对数量分析。*P＜0.05、**P＜0.01、***P＜0.001
图3 PCPF患者属水平微生物群组成及差异 注：A为属水平相对丰度的堆叠条形图，显示样本中整体群落组成模式；B为基于微生物谱相似性对样本进行层次聚类的属水平相对丰度热图；C为柱状图比较各组间选定菌属的绝对数量分析。*P＜0.05、**P＜0.01、***P＜0.001
图4 PCPF患者种水平微生物群组成及差异 注：A为种水平相对丰度的堆叠条形图，显示各样本中最常见的物种；B为物种丰度的层次聚类热图，基于群落组成展示样本聚类情况；C为DESeq2火山图，识别纤维化组和非纤维化组患者间丰度存在显著差异的物种；D为选定差异丰度物种的绝对定量分析。*P＜0.05、**P＜0.01、***P＜0.001
图5 PCPF患者差异物种与症状负担/运动耐受性/HRCT Warrick评分的相关性 注：细胞颜色编码相关系数（红色为正相关、蓝色为负相关），颜色越深表示绝对值越大。椭圆表示相关强度，形状越窄表示相关性越强。*P＜0.05、**P＜0.01
[1]
Duong-Quy S, Vo-Pham-Minh T, Tran-Xuan Q, et al. Post-COVID-19 pulmonary fibrosis: facts--challenges and futures: a narrative review[J]. Pulm Ther,2023,9(3):295-307.
[2]
Han X, Chen L, Fan Y, et al. Longitudinal assessment of chest CT findings and pulmonary function after COVID-19 infection[J]. Radiology,2023,307(2):e222888.
[3]
Hama Amin BJ, Kakamad FH, Ahmed GS, et al. Post COVID-19 pulmonary fibrosis; a meta-analysis study[J]. Ann Med Surg (Lond),2022,77:103590.
[4]
中国研究型医院学会呼吸病学专业委员会, 北京中西医结合学会呼吸病分会. 新型冠状病毒感染引起的肺间质病变诊断和治疗专家建议[J]. 中华结核和呼吸杂志,2020,43(10):827-833.
[5]
Lazar M, Sandulescu M, Barbu E C, et al. The role of cytokines and molecular pathways in lung fibrosis following SARS-CoV-2 infection: a physiopathologic (re)view[J]. Biomedicines,2024,12(3):639.
[6]
Niayesh-Mehr R, Kalantar M, Bontempi G, et al. The role of epithelial-mesenchymal transition in pulmonary fibrosis: lessons from idiopathic pulmonary fibrosis and COVID-19[J]. Cell Commun Signal,2024,22(1):542.
[7]
Sardarni U K, Byrareddy S N. Post‐COVID‐19 pulmonary fibrosis: Mechanisms, biomarkers, and therapeutic perspectives[J]. Clin Transl Discov,2025,5(1):e70034.
[8]
Wilde J, Slack E, Foster K R. Host control of the microbiome: mechanisms, evolution, and disease[J]. Science,2024,385(6706):eadi3338.
[9]
Yeoh Y K, Zuo T, Lui G C Y, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19[J]. Gut,2021,70(4):698-706.
[10]
Senel S. An overview of physical, microbiological and immune barriers of oral mucosa[J]. Int J Mol Sci,2021,22(15):7821.
[11]
Gao M, Wang H, Luo H, et al. Characterization of the human oropharyngeal microbiomes in SARS-CoV-2 infection and recovery patients[J]. Adv Sci (Weinh),2021,8(20):e2102785.
[12]
国家卫生健康委员会. 新型冠状病毒感染诊疗方案(试行第十版)[EB/OL]. (2023-01-06)[2026-01-28].
[13]
Tardella M, Di Carlo M, Carotti M, et al. Ultrasound B-lines in the evaluation of interstitial lung disease in patients with systemic sclerosis: Cut-off point definition for the presence of significant pulmonary fibrosis[J]. Medicine (Baltimore),2018,97(18):e0566.
[14]
Guo L, Wang X, Lin Y, et al. Microorganisms that are critical for the fermentation quality of paper mulberry silage[J]. Food Energy Secur,2021,10(4):e304.
[15]
O’Dwyer DN, Kim JS, Ma SF, et al. Commensal oral microbiota, disease severity, and mortality in fibrotic lung disease[J]. Am J Respir Crit Care Med,2024,209(9):1101-1110.
[16]
Hou S, Wang X, Guo J, et al. Triangle correlations of lung microbiome, host physiology and gut microbiome in a rat model of idiopathicpulmonary fibrosis[J]. Sci Rep,2024,14(1):28743.
[17]
Xu J, Wu D, Yang J, et al. Adult outpatients with long COVID infected with SARS-CoV-2 Omicron variant. Part 1: oral microbiota alterations[J]. Am J Med,2025,138(4):732-741.
[18]
Dickson RP, Erb-Downward JR, Martinez FJ, et al. The microbiome and the respiratory tract[J]. Annu Rev Physiol,2016,78(1):481-504.
[19]
Salisbury ML, Han MK, Dickson RP, et al. Microbiome in interstitial lung disease: from pathogenesis to treatment target[J]. Curr Opin Pulm Med,2017,23(5):404-410.
[20]
Gaeckle NT, Pragman AA, Pendleton KM, et al. The oral-lung axis: the impact of oral health on lung health[J]. Respir Care,2020,65(8):1211-1220.
[21]
Huang Y, Tang J, Cai Z, et al. Prevotella induces the production of Th17 cells in the colon of mice[J]. J Immunol Res,2020,2020:9607328.
[22]
Larsen JM. The immune response to Prevotella bacteria in chronic inflammatory disease[J]. Immunology,2017,151(4):363-374.
[23]
Crowley LE, Stockley RA, Thickett DR, et al. Neutrophil dynamics in pulmonary fibrosis: pathophysiological and therapeutic perspectives[J]. Eur Respir Rev,2024,33:240139.
[24]
Senoo S, Higo H, Taniguchi A, et al. Pulmonary fibrosis and type-17 immunity[J]. Respir Investig,2023,61(5):553-562.
[25]
Shengli M, Fan Z, Fengxia Z, et al. Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19[J]. Signal Transduct Target Ther,2021(6):191.
[26]
Huang P, Yang Z, Zhan C, et al. Alteration of the airway microbiota is associated with the progression of post-COVID-19 chronic cough in adults: a prospective study[J]. J Genet Genomics,2024,51(10):1111-1120.
[27]
Zhou P, Manoil D, Belibasakis GN, et al. Veillonellae: beyond bridging species in oral biofilm ecology[J]. Front Oral Health,2021,2:774115.
[28]
Ge Y, Tang G, Fu Y, et al. The impact of environmental factors on respiratory tract microbiome and respiratory system diseases[J]. Eur J Med Res,2025,30(1):236.
[29]
Gupta A, Bhanushali S, Sanap A, et al. Oral dysbiosis and its linkage with SARS-CoV-2 infection[J]. Microbiol Res,2022,261:127055.
[30]
Smith DJF, Teng NMY, Denneny E K, et al. The respiratory microbiome in patients with post-COVID-19 residual lung abnormalities resembles that of healthy individuals and is distinct from idiopathic pulmonary fibrosis[J]. ERJ Open Res,2025,11(3):00826-2024.
[1] 张可妍, 白萌, 邓慧玲. 脂质组学在病毒性传染病研究中的应用进展[J/OL]. 中华实验和临床感染病杂志(电子版), 2026, 20(01): 4-9.
[2] 董凯华, 姚艳青, 苗敏. Omicron变异株流行期间不同年龄段儿童感染新型冠状病毒的临床特征及核酸转阴时间影响因素[J/OL]. 中华实验和临床感染病杂志(电子版), 2025, 19(06): 353-361.
[3] 董凯华, 姚艳青, 苗敏. Omicron变异株流行期间妊娠晚期孕产妇感染新型冠状病毒对母婴临床结局的影响[J/OL]. 中华实验和临床感染病杂志(电子版), 2025, 19(05): 298-306.
[4] 石宛鑫, 商子梦, 吴桐, 卢帅, 邱倩, 徐艳利, 张强, 江宇泳, 刘秀颖, 蒋协远, 杨志云. 新型冠状病毒感染后中老年人维生素D缺乏对骨质疏松患病风险的影响[J/OL]. 中华实验和临床感染病杂志(电子版), 2025, 19(03): 136-145.
[5] 徐保平, 彭怀文, 喻怀斌, 王晓涛. 新型冠状病毒肺炎继发糖尿病酮症酸中毒合并肝门静脉积气一例[J/OL]. 中华实验和临床感染病杂志(电子版), 2024, 18(04): 250-255.
[6] 岳雅丽, 史学军, 田瑶. 血清LMR、DCN 在肺间质纤维化患者抗纤维化治疗中的变化及临床意义[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(01): 140-144.
[7] 朱万涌, 王乐, 徐越, 王新军, 叶晨, 李宁, 陈启仪, 李龙. 肠道菌群失衡与功能性肠病：从机制探讨到肠菌移植疗法[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(02): 142-147.
[8] 张今宜, 李月红. 慢性肾脏病患者接种新型冠状病毒疫苗有效力及接种策略的研究进展[J/OL]. 中华肾病研究电子杂志, 2024, 13(02): 97-100.
[9] 田学, 谢晖, 王瑞兰. 急性呼吸窘迫综合征相关肺纤维化的研究进展[J/OL]. 中华重症医学电子杂志, 2024, 10(03): 258-264.
[10] 王晶晶, 谢晖, 邓璞钰, 张晨晨, 田学, 谢云, 王瑞兰. 新型冠状病毒感染ARDS患者EIT监测下俯卧位通气成像的改变[J/OL]. 中华重症医学电子杂志, 2024, 10(01): 31-37.
[11] 刘付蓉, 翁利, 杜斌. 2020年至2022年中国重症医学临床研究进展[J/OL]. 中华重症医学电子杂志, 2024, 10(01): 48-53.
[12] 葛静萍, 尹媛媛, 李燕. 梯度压力袜联合间歇充气加压在老年新型冠状病毒肺炎患者预防下肢深静脉血栓形成中的应用[J/OL]. 中华介入放射学电子杂志, 2024, 12(01): 70-74.
[13] 张浩名, 曾志奇, 刘勇. 基于荧光免疫层析技术建立SARS-CoV-2中和抗体检测方法及其性能评价[J/OL]. 中华临床实验室管理电子杂志, 2025, 13(04): 206-212.
[14] 麦芷桐, 李倩颖, 曾志奇, 陈瑞晗, 梁靖怡, 陈瑞凤, 关文达, 杨子峰. 两种新型冠状病毒抗体快速检测方法的评价与应用[J/OL]. 中华临床实验室管理电子杂志, 2025, 13(03): 135-142.
[15] 张宇, 王林. 急诊内科老年新型冠状病毒感染患者低钠血症发生情况调查分析[J/OL]. 中华老年病研究电子杂志, 2024, 11(02): 10-14.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号

AI
小
编
AI小编
你好！我是《中华医学电子期刊资源库》AI小编，有什么可以帮您的吗？