Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn
Abstract
Objective: Stroke is a leading cause of death and disability worldwide. Neuroprotective approaches have failed in clinical trials, thus warranting therapeutic innovations with alternative targets. The gut microbiota is an important contributor to many risk factors for stroke. However, the bidirectional interactions between stroke and gut microbiota remain largely unknown. Design: We performed two clinical cohort studies to capture the gut dysbiosis dynamics after stroke and their relationship with stroke prognosis. Then, we used a middle cerebral artery occlusion model to explore gut dysbiosis post-stroke in mice and address the causative relationship between acute ischaemic stroke and gut dysbiosis. Finally, we tested whether aminoguanidine, superoxide dismutase and tungstate can alleviate post-stroke brain infarction by restoring gut dysbiosis. Results: Brain ischaemia rapidly induced intestinal ischaemia and produced excessive nitrate through free radical reactions, resulting in gut dysbiosis with Enterobacteriaceae expansion. Enterobacteriaceae enrichment exacerbated brain infarction by enhancing systemic inflammation and is an independent risk factor for the primary poor outcome of patients with stroke. Administering aminoguanidine or superoxide dismutase to diminish nitrate generation or administering tungstate to inhibit nitrate respiration all resulted in suppressed Enterobacteriaceae overgrowth, reduced systemic inflammation and alleviated brain infarction. These effects were gut microbiome dependent and indicated the translational value of the brain–gut axis in stroke treatment. Conclusions: This study reveals a reciprocal relationship between stroke and gut dysbiosis. Ischaemic stroke rapidly triggers gut microbiome dysbiosis with Enterobacteriaceae overgrowth that in turn exacerbates brain infarction.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Enterobacteriaceae overgrowth in the gut could exacerbate brain infarction and systemic inflammation in stroke patients.
“Enterobacteriaceae overgrowth in the gut could exacerbate brain infarction and systemic inflammation in stroke patients (27).”
From Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice (2022) · cites this paper as [27]
Cites
Search and clustering orders of magnitude faster than BLAST
Edgar, R. C. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq461 · Cited by 20,617 · see citing works
Metagenomic biomarker discovery and explanation
Segata, N., Izard, J., Waldron, L., Gevers, D., Miropolsky, L., Garrett, W. S., & Huttenhower, C. (2011) · Genome Biology · doi:10.1186/gb-2011-12-6-r60 · Cited by 16,192 · see citing works
One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.
Datsenko, K., & Wanner, B. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.120163297 · Cited by 15,902 · see citing works
Human gut microbes associated with obesity
Ley, R. E., Turnbaugh, P. J., Klein, S., & Gordon, J. I. (2006) · Nature · doi:10.1038/4441022a · Cited by 8,785 · see citing works
Powers, W. J., Rabinstein, A. A., Ackerson, T., Adeoye, O. M., Bambakidis, N. C., Becker, K. J., Biller, J., Brown, M., Demaerschalk, B. M., Hoh, B. L., et al. (2019) · Stroke · doi:10.1161/str.0000000000000211 · Cited by 7,673 · see citing works
Guidelines for the Early Management of Patients With Acute Ischemic Stroke
Jauch, E. C., Saver, J. L., Adams, H. P., Bruno, A., Connors, J. J. “., Demaerschalk, B. M., Khatri, P., McMullan, P. W., Qureshi, A. I., Rosenfield, K., et al. (2013) · Stroke · doi:10.1161/str.0b013e318284056a · Cited by 7,648 · see citing works
Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A., & Freeman, B. A. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.4.1620 · Cited by 7,029 · see citing works
A metagenome-wide association study of gut microbiota in type 2 diabetes
Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D., et al. (2012) · Nature · doi:10.1038/nature11450 · Cited by 6,762 · see citing works
Heart Disease and Stroke Statistics—2010 Update: A Report From the American Heart Association
WRITING GROUP MEMBERS, Lloyd-Jones, D., Adams, R. J., Brown, T. M., Carnethon, M., Dai, S., De Simone, G., Ferguson, T. B., Ford, E., Furie, K., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.192667 · Cited by 5,700 · see citing works
FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix
Price, M. N., Dehal, P. S., & Arkin, A. P. (2009) · Molecular Biology and Evolution · doi:10.1093/molbev/msp077 · Cited by 5,602 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Self-citationPowers, W. J., Rabinstein, A. A., Ackerson, T., Adeoye, O. M., Bambakidis, N. C., Becker, K. J., Biller, J., Brown, M., Demaerschalk, B. M., Hoh, B. L., et al. (2018) · Stroke · doi:10.1161/str.0000000000000158 · Cited by 5,505 · see citing works
Zhou, M., Wang, H., Zeng, X., Yin, P., Zhu, J. W., Chen, W., Li, X., Wang, L., Wang, L., Liu, Y., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)30427-1 · Cited by 3,656 · see citing works
Self-citationPyNAST: a flexible tool for aligning sequences to a template alignment
Caporaso, J. G., Bittinger, K. L., Bushman, F. D., DeSantis, T. Z., Andersen, G. L., & Knight, R. D. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp636 · Cited by 3,374 · see citing works
Gut metagenome in European women with normal, impaired and diabetic glucose control
Karlsson, F. H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C. J., Fagerberg, B., Nielsen, J., & Bäckhed, F. (2013) · Nature · doi:10.1038/nature12198 · Cited by 3,115 · see citing works
Peroxynitrite: biochemistry, pathophysiology and development of therapeutics
Szabó, C., Ischiropoulos, H., & Radi, R. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2222 · Cited by 2,134 · see citing works
Gut microbiota dysbiosis contributes to the development of hypertension
Li, J., Zhao, F., Wang, Y., Chen, J., Tao, J., Tian, G., Wu, S., Liu, W., Cui, Q., Geng, B., et al. (2017) · Microbiome · doi:10.1186/s40168-016-0222-x · Cited by 1,685 · see citing works
Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4
Kayagaki, N., Wong, M. T., Stowe, I. B., Ramani, S. R., Gonzalez, L. C., Akashi‐Takamura, S., Miyake, K., Zhang, J., Lee, W. P., Muszyński, A., et al. (2013) · Science · doi:10.1126/science.1240248 · Cited by 1,545 · see citing works
Hayes, J. D., & McLellan, L. I. (1999) · Free Radical Research · doi:10.1080/10715769900300851 · Cited by 1,528 · see citing works
Reperfusion injury and reactive oxygen species: The evolution of a concept
Granger, D. N., & Kvietys, P. R. (2015) · Redox Biology · doi:10.1016/j.redox.2015.08.020 · Cited by 1,510 · see citing works
Salt-responsive gut commensal modulates TH17 axis and disease
Wilck, N., Matus, M. G., Kearney, S. M., Olesen, S. W., Forslund, K., Bartolomaeus, H., Haase, S., Mähler, A., Balogh, A., Markó, L., et al. (2017) · Nature · doi:10.1038/nature24628 · Cited by 1,310 · see citing works
Hankey, G. J. (2016) · The Lancet · doi:10.1016/s0140-6736(16)30962-x · Cited by 1,248 · see citing works
Chamorro, Á., Dirnagl, U., Urra, X., & Planas, A. M. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00114-9 · Cited by 1,198 · see citing works
Aminoguanidine Prevents Diabetes-Induced Arterial Wall Protein Cross-Linking
Brownlee, M., Vlassara, H., Kooney, A., Ulrich, P. C., & Cerami, A. (1986) · Science · doi:10.1126/science.3487117 · Cited by 1,146 · see citing works
Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells
Benakis, C., Brea, D., Caballero, S., Faraco, G., Moore, J., Murphy, M., Sita, G., Racchumi, G., Ling, L., Pamer, E. G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4068 · Cited by 1,114 · see citing works
Host-Derived Nitrate Boosts Growth of <i>E. coli</i> in the Inflamed Gut
Winter, S. E., Winter, M. G., Xavier, M. N., Thiennimitr, P., Poon, V., Keestra, A. M., Laughlin, R. C., Gomez, G., Wu, J., Lawhon, S. D., et al. (2013) · Science · doi:10.1126/science.1232467 · Cited by 1,019 · see citing works
Regional variation limits applications of healthy gut microbiome reference ranges and disease models
He, Y., Wu, W., Zheng, H.-M., Li, P., McDonald, D., Sheng, H.-F., Chen, M.-X., Chen, Z.-H., Ji, G.-Y., Zheng, Z.-D.-X., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0164-x · Cited by 894 · see citing works
Self-citationRole of the Autonomic Nervous System in Modulating Cardiac Arrhythmias
Shen, M. J., & Zipes, D. P. (2014) · Circulation Research · doi:10.1161/circresaha.113.302549 · Cited by 867 · see citing works
Tumor Necrosis Factor-α: A Mediator of Focal Ischemic Brain Injury
Barone, F. C., Arvin, B., White, R. F., Miller, A., Webb, C. L., Willette, R. N., Lysko, P. G., & Feuerstein, G. Z. (1997) · Stroke · doi:10.1161/01.str.28.6.1233 · Cited by 863 · see citing works
Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., Iwaki, T., Okada, Y., Iida, M., Cua, D. J., et al. (2009) · Nature Medicine · doi:10.1038/nm.1999 · Cited by 842 · see citing works
Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke
Singh, V., Roth, S., Llovera, G., Sadler, R., Garzetti, D., Stecher, B., Dichgans, M., & Liesz, A. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1114-16.2016 · Cited by 800 · see citing works
Selective inhibition of the inducible nitric oxide synthase by aminoguanidine
Misko, T. P., Moore, W. M., Kasten, T. P., Nickols, G. A., Corbett, J. A., Tilton, R. G., McDaniel, M. L., Williamson, J. R., & Currie, M. G. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90357-n · Cited by 722 · see citing works
Yin, J., Liao, S., He, Y., Wang, S., Xia, G., Liu, F., Zhu, J., You, C., Chen, Q., Zhou, L., et al. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002699 · Cited by 669 · see citing works
Self-citationRole of oxygen in the cellular damage induced by re-oxygenation of hypoxic heart
Guarnieri, C. (1980) · Journal of Molecular and Cellular Cardiology · doi:10.1016/0022-2828(80)90081-4 · Cited by 537 · see citing works
Translocation and dissemination of commensal bacteria in post-stroke infection
Stanley, D., Mason, L. J., Mackin, K. E., Srikhanta, Y. N., Lyras, D., Prakash, M. D., Nurgali, K., Venegas, A., Hill, M. D., Moore, R. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4194 · Cited by 464 · see citing works
Early Intrathecal Production of Interleukin-6 Predicts the Size of Brain Lesion in Stroke
Tarkowski, E., Rosengren, L., Blomstrand, C., Wikkelsø, C., Jensen, C., EKHOLM, S. E., & Tarkowski, A. (1995) · Stroke · doi:10.1161/01.str.26.8.1393 · Cited by 384 · see citing works
Houlden, A., Goldrick, M., Brough, D., Vizi, E. S., Lénárt, N., Martinecz, B., Roberts, I. S., & Dénes, Á. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.04.003 · Cited by 369 · see citing works
Yamashiro, K., Tanaka, R., Urabe, T., Ueno, Y., Yamashiro, Y., Nomoto, K., Takahashi, T., Tsuji, H., Asahara, T., & Hattori, N. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171521 · Cited by 318 · see citing works
Freedman, B. I., Wuerth, J.-P., Cartwright, K. J., Bain, R. P., Dippe, S. E., Hershon, K. S., Mooradian, A. D., & Spinowitz, B. (1999) · Controlled Clinical Trials · doi:10.1016/s0197-2456(99)00024-0 · Cited by 257 · see citing works
Xia, G., You, C., Gao, X., Zeng, X., Zhu, J., Xu, K., Tan, C., Xu, R., Wu, Q., Zhou, H., et al. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00397 · Cited by 220 · see citing works
Self-citationVagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease
Bonaz, B., Sinniger, V., & Pellissier, S. (2017) · Journal of Internal Medicine · doi:10.1111/joim.12611 · Cited by 213 · see citing works
Increased Cytokine Release from Peripheral Blood Cells after Acute Stroke
Ferrarese, C., Mascarucci, P., Zoia, C., Cavarretta, R., Frigo, M., Begni, B., Sarinella, F., Frattola, L., & Simoni, M. G. D. (1999) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199909000-00008 · Cited by 209 · see citing works
Linking gut microbiota, metabolic syndrome and economic status based on a population-level analysis
He, Y., Wu, W. H., Wu, S., Zheng, H., Li, P., Sheng, H.-F., Chen, M.-X., Chen, Z., Ji, G., Zheng, Z., et al. (2018) · Microbiome · doi:10.1186/s40168-018-0557-6 · Cited by 187 · see citing works
Self-citationOxidative Stress Developed During the Reperfusion of Ischemic Myocardium Induces Apoptosis
Maulik, N., Yoshida, T., & Das, D. K. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(97)00388-2 · Cited by 181 · see citing works
BIPES, a cost-effective high-throughput method for assessing microbial diversity
Zhou, H., Li, D., Tam, N. F. Y., Jiang, X., Zhang, H., Sheng, H.-F., Qin, J., Liu, X., & Zou, F. (2010) · The ISME Journal · doi:10.1038/ismej.2010.160 · Cited by 173 · see citing works
Self-citationDénes, Á., Ferenczi, S., & Kovács, K. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-164 · Cited by 162 · see citing works
Manwani, B., Bentivegna, K., Benashski, S. E., Venna, V. R., Xu, Y., Arnold, A. P., & McCullough, L. D. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.186 · Cited by 138 · see citing works
Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality
Shi, Z., Guan, Y., Huo, Y. R., et al. (2015) · Stroke · doi:10.1161/strokeaha.115.009136 · Cited by 124 · see citing works
Wissenbach, U., Kr�ger, A., & Unden, G. (1990) · Archives of Microbiology · doi:10.1007/bf00249179 · Cited by 113 · see citing works
The sympathetic nervous system and ischaemic heart disease.
Wj, R. (1998) · PubMed · Cited by 113 · see citing works
Heinrichs, D. E., Monteiro, M. A., Perry, M. B., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.15.8849 · Cited by 106 · see citing works
Benakis, C., Poon, C., Lane, D., Brea, D., Sita, G., Moore, J. M. R., Murphy, M., Racchumi, G., Iadecola, C., & Anrather, J. (2020) · Stroke · doi:10.1161/strokeaha.120.029262 · Cited by 99 · see citing works
Gates, A. J., Hughes, R. O., Sharp, S. R., Millington, P. D., Nilavongse, A., Cole, J. A., Leach, E.-R., Jepson, B., Richardson, D. J., & Butler, C. S. (2003) · FEMS Microbiology Letters · doi:10.1016/s0378-1097(03)00122-8 · Cited by 53 · see citing works
Klimiec, E., Pera, J., Chrzanowska-Waśko, J., Golenia, A., Słowik, A., & Dziedzic, T. (2016) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2016.05.006 · Cited by 44 · see citing works
Lee, M. W., & Choy, J. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.475319 · Cited by 32 · see citing works
Klimiec, E., Pasińska, P., Kowalska, K., Pera, J., Słowik, A., & Dziedzic, T. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.12.034 · Cited by 30 · see citing works
Sheng, Y., Li, H., Liu, M., Xie, B., Wei, W. Z., Wu, J., Meng, F., Wang, H. Y., & Chen, D. (2019) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izz097 · Cited by 24 · see citing works
Self-citationImbalance in the force: the dark side of the microbiota on stroke risk and progression
Kumar, K. P., & Wong, C. H. Y. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.10.002 · Cited by 18 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Xiao, W., Su, J., Gao, X., Yang, H., Weng, R., Ni, W., & Gu, Y. (2022) · Microbiome · doi:10.1186/s40168-022-01255-6 · Cited by 252 · see citing works
Self-citationZhao, N., Chen, Q.-G., Chen, X., Liu, X.-T., Geng, F., Zhu, M.-M., Yan, F.-L., Zhang, Z.-J., & Ren, Q.-G. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.11.013 · Cited by 105 · see citing works
Lou, X., Xue, J., Shao, R., Yang, Y., Ning, D., Mo, C., Wang, F., & Chen, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1063543 · Cited by 87 · see citing works
Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice
Fang, H., Wang, Y., Deng, J., Zhang, H., Wu, Q., He, L., Xu, J., Shao, X., Ouyang, X., He, Z., et al. (2022) · mSystems · doi:10.1128/msystems.01399-21 · Cited by 87 · see citing works
“Enterobacteriaceae overgrowth in the gut could exacerbate brain infarction and systemic inflammation in stroke patients (27).”
BackgroundSelf-citationXie, Y., Zou, X., Han, J., Zhang, Z., Feng, Z., Ouyang, Q., Hua, S., Liu, Z., Li, C., Cai, Y., et al. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114081 · Cited by 80 · see citing works
Targeting the human gut microbiome with small-molecule inhibitors
Woo, A. Y. M., Aguilar Ramos, M. A., Narayan, R., Richards-Corke, K. C., Wang, M. L., Sandoval-Espinola, W. J., & Balskus, E. P. (2023) · Nature Reviews Chemistry · doi:10.1038/s41570-023-00471-4 · Cited by 42 · see citing works
- Authors
- Xu, K., Gao, X., Xia, G., Chen, M., Zeng, N., Wang, S., You, C., Tian, X., Di, H., Tang, W., Li, P., Wang, H., Zeng, X., Tan, C., Meng, F., Li, H., He, Y., Zhou, H., & Yin, J.
- Affiliations
- Zhujiang Hospital (CN)
- Nanfang Hospital (CN)
- Soochow University (CN)
- Corresponding author
- He, Yan
- Zhou, Hongwei
- Yin, Jia
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2021-02-08
- Volume
- 70
- Issue
- 8
- Pages
- 1486-1494
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W3126277686
- Cited by
- 308
- References
- 58
- Citations by year
- 2026: 53 · 2025: 69 · 2024: 56 · 2023: 52 · 2022: 58 · 2021: 20
- FWCI
- 14.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Postdoctoral Science Foundation (2018M630967 (K.X.))
- Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY025 (J.Y.))
- Science and Technology Program of Guangzhou, China (201904010091 (Y.H.))
- National Key R&D Program of China (2019YFA0802300 (Y.H.))
- National Natural Science Foundation of China (NSFC31800415 (K.X.), NSFC81671171 (J.Y.), NSFC81800746 (Y.H.), NSFC81870936 (J.Y.), NSFC81925026 (H.Z.), NSFC82022044 (Y.H.))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Surgery › Abdominal vascular conditions and treatments
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- stroke, gut dysbiosis, gut microbiota, cerebral infarction, ischemic stroke, Enterobacteriaceae, gut-brain axis, intestinal ischemia, nitrate, systemic inflammation, aminoguanidine, superoxide dismutase, tungstate, middle cerebral artery occlusion, stroke prognosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
