Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells
Abstract
BACKGROUND: Myocardial infarction (MI) is a high-prevalence disease that threatens human survival and quality of life worldwide. Considerable evidence has suggested that periodontitis (PD) is detrimental to MI. However, the direct impact of PD on MI is unclear; which oral pathobionts contribute to and how microbial signals regulate the pathogenesis of MI remain obscure. METHODS: The effect of PD on MI was assessed in a mouse model that combined ligature-induced PD with MI. Ectopic accumulation of oral pathobionts in infarcted hearts was identified by bacterial sequencing and fluorescence in situ hybridization. Oral pathobionts–reactive B2 cells detrimental for MI were determined by flow cytometry and verified in gnotobiotic mice. Several mouse strains, including CD45.1, Kaede, and knockout strains for Ighm, Rag1, C-X-C motif chemokine ligand 13, S1pr, interleukin-6, and tumor necrosis factor-α, were used for mechanistical exploration. Mutant strains of Fusobacterium nucleatum and Porphyromonas gingivalis deficient in adhesion proteins were generated to investigate bacterial mechanism involved in MI exacerbation. Patients with MI with or without PD were recruited to test the deteriorating impact of PD on MI and the association between oral pathobionts and cardiac function. RESULTS: Ligature-induced PD and subgingival plaques of patients with PD exacerbated MI in mice by oral pathobionts. Prevotella intermedia , Fusobacterium nucleatum , Selenomonas sputigena , Porphyromonas gingivalis , and Bacteroides plebeius expanded in the oral cavity and ectopically accumulated in the infarcted hearts through impairment of epithelial and endothelial cell barriers. These oral pathobionts mobilized B cells, particularly B2 cells that produced interleukin-6 and tumor necrosis factor-α, to aggravate MI. Mechanistically, oral pathobiont–promoted B cells egress from cervical lymph nodes by a sphingosine-1-phosphate–sphingosine-1-phosphate receptor axis and infiltrate infarcted hearts by a C-X-C motif chemokine ligand 13–C-X-C motif chemokine receptor 5 axis. CONCLUSIONS: Oral pathobionts and proinflammatory B2 cells significantly exacerbate MI, supporting the oral-heart axis as a novel pathogenic pathway. Interventions targeting PD, oral pathobionts, or related immunological mechanisms may improve the therapy of MI.
Article Details
Authors (27)
Bo-Yan Chen
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China (B.-Y.C., S.-Z.D.).
Hong Zhu
School of Life and Health Technology
Yu-Lin Li
Jun Zhang
Shuo Xu
Frontiers Science Center for New Organic Matter, Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), State Key Laboratory of Advanced Chemical Power Sources, College of Chemistry
Lu-Jun Zhou
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Lin-Juan Du
National Center for Stomatology, National Clinical Research Center for Oral Diseases, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Ting Liu
Xue-Nan Sun
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas (X.-N.S.).
Guo-Cai Tian
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Jie Li
Xiao-Qian Meng
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Hui-Lin Ye
Xue-Bing Bai
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Wen-Zhen Lin
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Hu-Xiao Li
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Jian-Xuan Li
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, China (J.-X.L., Y.D.).
Jian-Yong Sun
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Yan Liu
Wu-Chang Zhang
Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Key Laboratory of Stomatology, College of Stomatology, China (B.-Y.C., H.Z., Y.-L.L., J.Z., S.X., L.-J.Z., L.-J.D., T.L., G.-C.T., J.L., X.-Q.M., H.-L.Y., X.-B.B., W.-Z.L., H.-X.L., J.-Y.S., Y.L., W.-C.Z.).
Lu Zhang
Jing-Yuan Fang
Daqian Xu
Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine
Mengfei Yu
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China (B.-Y.C., H.Z., M.Y., Q.C., S.-Z.D.).
Yuxiang Dai
Department of Materials Physics and Chemistry, School of Materials Science and Engineering
Qianming Chen
Sheng-Zhong Duan