Disruptions of Anaerobic Gut Bacteria Are Associated with Stroke and Post-stroke Infection: a Prospective Case–Control Study
Tóm tắt
In recent years, preclinical studies have illustrated the potential role of intestinal bacterial composition in the risk of stroke and post-stroke infections. The results of these studies suggest that bacteria capable of producing volatile metabolites, including trimethylamine-N-oxide (TMAO) and butyrate, play opposing, yet important roles in the cascade of events leading to stroke. However, no large-scale studies have been undertaken to determine the abundance of these bacterial communities in stroke patients and to assess the impact of disrupted compositions of the intestinal microbiota on patient outcomes. In this prospective case–control study, rectal swabs from 349 ischemic and hemorrhagic stroke patients (median age, 71 years; IQR: 67–75) were collected within 24 h of hospital admission. Samples were subjected to 16S rRNA amplicon sequencing and subsequently compared with samples obtained from 51 outpatient age- and sex-matched controls (median age, 72 years; IQR, 62–80) with similar cardiovascular risk profiles but without active signs of stroke. Plasma protein biomarkers were analyzed using a combination of nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography–mass spectrometry (LC-MS). Alpha and beta diversity analyses revealed higher disruption of intestinal communities during ischemic and hemorrhagic stroke compared with non-stroke matched control subjects. Additionally, we observed an enrichment of bacteria implicated in TMAO production and a loss of butyrate-producing bacteria. Stroke patients displayed two-fold lower plasma levels of TMAO than controls (median 1.97 vs 4.03 μM, Wilcoxon p < 0.0001). Finally, lower abundance of butyrate-producing bacteria within 24 h of hospital admission was an independent predictor of enhanced risk of post-stroke infection (odds ratio 0.77, p = 0.005), but not of mortality or functional patient outcome. In conclusion, aberrations in trimethylamine- and butyrate-producing gut bacteria are associated with stroke and stroke-associated infections.
Tài liệu tham khảo
citation_journal_title=BMC Neurol; citation_title=Post-stroke infection: A systematic review and meta-analysis; citation_author=WF Westendorp, PJ Nederkoorn, J-D Vermeij, MG Dijkgraaf, D Beek; citation_volume=11; citation_publication_date=2011; citation_pages=110; citation_doi=10.1186/1471-2377-11-110; citation_id=CR1
citation_journal_title=Nat Rev Neurol; citation_title=The immunology of acute stroke; citation_author=Á Chamorro, A Meisel, AM Planas, X Urra, D Beek, R Veltkamp; citation_volume=8; citation_publication_date=2012; citation_pages=401-410; citation_doi=10.1038/nrneurol.2012.98; citation_id=CR2
citation_journal_title=Nat Med Nature Publishing Group; citation_title=Translocation and dissemination of commensal bacteria in post-stroke infection; citation_author=D Stanley, LJ Mason, KE MacKin, YN Srikhanta, D Lyras, MD Prakash; citation_volume=22; citation_publication_date=2016; citation_pages=1277-1284; citation_doi=10.1038/nm.4194; citation_id=CR3
citation_journal_title=Lancet Elsevier Ltd; citation_title=The preventive antibiotics in stroke study (PASS): a pragmatic randomised open-label masked endpoint clinical trial; citation_author=WF Westendorp, JD Vermeij, E Zock, IJ Hooijenga, ND Kruyt, HJLW Bosboom, VIH Kwa, M Weisfelt, MJM Remmers, R ten Houten, AHCM(T) Schreuder, SE Vermeer, EJ van Dijk, DWJ Dippel, MGW Dijkgraaf, L Spanjaard, M Vermeulen, T van der Poll, JM Prins, FH Vermeij, YBWEM Roos, RP Kleyweg, H Kerkhoff, MC Brouwer, AH Zwinderman, D van de Beek, PJ Nederkoorn; citation_volume=385; citation_publication_date=2015; citation_pages=1519-1526; citation_doi=10.1016/S0140-6736(14)62456-9; citation_id=CR4
citation_journal_title=Nat Med. Nature Publishing Group; citation_title=Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells; citation_author=C Benakis, D Brea, S Caballero, G Faraco, J Moore, M Murphy, G Sita, G Racchumi, L Ling, EG Pamer, C Iadecola, J Anrather; citation_volume=22; citation_publication_date=2016; citation_pages=516-523; citation_doi=10.1038/nm.4068; citation_id=CR5
citation_journal_title=J Cereb Blood Flow Metab; citation_title=Gut microbiota impact on stroke outcome: fad or fact?; citation_author=K Winek, A Meisel, U Dirnagl; citation_volume=36; citation_publication_date=2015; citation_pages=891-898; citation_doi=10.1177/0271678X16636890; citation_id=CR6
citation_journal_title=Cell. Elsevier Inc; citation_title=Role of the microbiota in immunity and inflammation; citation_author=Y Belkaid, TW Hand; citation_volume=157; citation_publication_date=2014; citation_pages=121-141; citation_id=CR7
citation_journal_title=Nat Med; citation_title=Signals from the gut microbiota to distant organs in physiology and disease; citation_author=BO Schroeder, F Bäckhed; citation_volume=22; citation_publication_date=2016; citation_pages=1079-1089; citation_doi=10.1038/nm.4185; citation_id=CR8
Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol. 2017:135–43.
citation_journal_title=N Engl J Med; citation_title=Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk; citation_author=WHW Tang, Z Wang, BS Levison, RA Koeth, EB Britt, X Fu, Y Wu, SL Hazen; citation_volume=368; citation_publication_date=2013; citation_pages=1575-1584; citation_doi=10.1056/NEJMoa1109400; citation_id=CR10
citation_journal_title=Nat Med; citation_title=Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis; citation_author=RA Koeth, Z Wang, BS Levison, JA Buffa, E Org, BT Sheehy, EB Britt, X Fu, Y Wu, L Li, JD Smith, JA DiDonato, J Chen, H Li, GD Wu, JD Lewis, M Warrier, JM Brown, RM Krauss, WHW Tang, FD Bushman, AJ Lusis, SL Hazen; citation_volume=19; citation_publication_date=2013; citation_pages=576-585; citation_doi=10.1038/nm.3145; citation_id=CR11
citation_journal_title=Cell. Elsevier Inc.; citation_title=Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk; citation_author=W Zhu, JC Gregory, E Org, JA Buffa, N Gupta, Z Wang; citation_volume=165; citation_publication_date=2016; citation_pages=111-124; citation_id=CR12
citation_journal_title=Eur Heart J; citation_title=Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis; citation_author=GG Schiattarella, A Sannino, E Toscano, G Giugliano, G Gargiulo, A Franzone, B Trimarco, G Esposito, C Perrino; citation_volume=38; citation_publication_date=2017; citation_pages=2948-2956; citation_doi=10.1093/eurheartj/ehx342; citation_id=CR13
citation_journal_title=Nature.; citation_title=Richness of human gut microbiome correlates with metabolic markers; citation_author=E Chatelier, T Nielsen, J Qin, E Prifti, F Hildebrand, G Falony; citation_volume=500; citation_publication_date=2013; citation_pages=541-546; citation_doi=10.1038/nature12506; citation_id=CR14
citation_journal_title=Nat Neurosci; citation_title=Host microbiota constantly control maturation and function of microglia in the CNS; citation_author=D Erny, AL Hrabě de Angelis, D Jaitin, P Wieghofer, O Staszewski, E David; citation_volume=18; citation_publication_date=2015; citation_pages=965-977; citation_doi=10.1038/nn.4030; citation_id=CR15
citation_journal_title=J Neurosci; citation_title=Short-chain fatty acids improve poststroke recovery via immunological mechanisms; citation_author=R Sadler, JV Cramer, S Heindl, S Kostidis, D Betz, KR Zuurbier, BH Northoff, M Heijink, MP Goldberg, EJ Plautz, S Roth, R Malik, M Dichgans, LM Holdt, C Benakis, M Giera, AM Stowe, A Liesz; citation_volume=40; citation_publication_date=2020; citation_pages=1162-1173; citation_doi=10.1523/JNEUROSCI.1359-19.2019; citation_id=CR16
citation_journal_title=J Neurochem; citation_title=The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain; citation_author=HJ Kim, P Leeds, D-M Chuang; citation_volume=110; citation_publication_date=2009; citation_pages=1226-1240; citation_doi=10.1111/j.1471-4159.2009.06212.x; citation_id=CR17
citation_journal_title=PLoS One; citation_title=Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke; citation_author=K Yamashiro, R Tanaka, T Urabe, Y Ueno, Y Yamashiro, K Nomoto; citation_volume=12; citation_publication_date=2017; citation_pages=1-15; citation_id=CR18
citation_journal_title=J Am Heart Assoc; citation_title=Dysbiosis of gut microbiota with reduced trimethylamine-n-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack; citation_author=J Yin, SX Liao, Y He, S Wang, GH Xia, FT Liu; citation_volume=4; citation_publication_date=2015; citation_pages=1-12; citation_doi=10.1161/JAHA.115.002699; citation_id=CR19
citation_journal_title=Front Neurol; citation_title=Stroke dysbiosis index (SDI) in gut microbiome are associated with brain injury and prognosis of stroke; citation_author=GH Xia, C You, XX Gao, XL Zeng, JJ Zhu, KY Xu; citation_volume=10; citation_publication_date=2019; citation_pages=1-13; citation_doi=10.3389/fneur.2019.00001; citation_id=CR20
citation_journal_title=BMC Microbiol; citation_title=Change of intestinal microbiota in cerebral ischemic stroke patients; citation_author=N Li, X Weng, C Sun, X Wu, M Lu, Y Si; citation_volume=19; citation_publication_date=2019; citation_pages=1-8; citation_doi=10.1186/s12866-018-1372-8; citation_id=CR21
citation_journal_title=Nat Commun Nature Publishing Group; citation_title=The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia; citation_author=K Chakraborty, M Raundhal, BB Chen, C Morse, YY Tyurina, A Khare; citation_volume=8; citation_publication_date=2017; citation_pages=1-15; citation_id=CR22
citation_journal_title=Immunity. Cell Press; citation_title=The short chain fatty acid butyrate imprints an antimicrobial program in macrophages; citation_author=J Schulthess, S Pandey, M Capitani, KC Rue-Albrecht, I Arnold, F Franchini; citation_volume=50; citation_publication_date=2019; citation_pages=432–445.e7; citation_id=CR23
Haak BW, Littmann ER, Chaubard J-L, Pickard AJ, Fontana E, Adhi F, et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood. 2018;131.
citation_journal_title=Appl Environ Microbiol; citation_title=Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy; citation_author=Q Wang, GM Garrity, JM Tiedje, JR Cole; citation_volume=73; citation_publication_date=2007; citation_pages=5261-5267; citation_doi=10.1128/AEM.00062-07; citation_id=CR25
citation_journal_title=Nucleic Acids Res; citation_title=The SILVA ribosomal RNA gene database project: improved data processing and web-based tools; citation_author=C Quast, E Pruesse, P Yilmaz, J Gerken, T Schweer, P Yarza; citation_volume=41; citation_publication_date=2013; citation_pages=590-596; citation_doi=10.1093/nar/gks1219; citation_id=CR26
citation_journal_title=mSystems; citation_title=Colonic butyrate-producing communities in humans: an overview using omics data. Shade A, editor; citation_author=M Vital, A Karch, DH Pieper; citation_volume=2; citation_publication_date=2017; citation_pages=43-51; citation_doi=10.1128/mSystems.00130-17; citation_id=CR27
citation_journal_title=Microbiome Microbiome; citation_title=Uncovering the trimethylamine-producing bacteria of the human gut microbiota; citation_author=S Rath, B Heidrich, DH Pieper, M Vital; citation_volume=5; citation_publication_date=2017; citation_pages=1-14; citation_doi=10.1186/s40168-016-0209-7; citation_id=CR28
citation_journal_title=Circ Res; citation_title=Gut microbiota in cardiovascular health and disease; citation_author=WHW Tang, T Kitai, SL Hazen; citation_volume=120; citation_publication_date=2017; citation_pages=1183-1196; citation_doi=10.1161/CIRCRESAHA.117.309715; citation_id=CR29
citation_journal_title=Lancet Neurol; citation_title=Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes; citation_author=MJ Reeves, CD Bushnell, G Howard, JW Gargano, PW Duncan, G Lynch, A Khatiwoda, L Lisabeth; citation_volume=7; citation_publication_date=2008; citation_pages=915-926; citation_doi=10.1016/S1474-4422(08)70193-5; citation_id=CR30
citation_journal_title=PLoS One; citation_title=phyloseq: An R package for reproducible interactive analysis and graphics of microbiome census data. Watson M, editor; citation_author=PJ McMurdie, S Holmes; citation_volume=8; citation_publication_date=2013; citation_pages=e61217; citation_doi=10.1371/journal.pone.0061217; citation_id=CR31
citation_journal_title=Stroke.; citation_title=A predictive risk model for outcomes of ischemic stroke; citation_author=KC Johnston, AF Connors, DP Wagner, WA Knaus, XQ Wang, EC Haley; citation_volume=31; citation_publication_date=2000; citation_pages=448-455; citation_doi=10.1161/01.STR.31.2.448; citation_id=CR32
citation_journal_title=Stroke.; citation_title=Diagnosis of stroke-associated pneumonia: recommendations from the pneumonia in stroke consensus group; citation_author=CJ Smith, AK Kishore, A Vail, A Chamorro, J Garau, SJ Hopkins, M di Napoli, L Kalra, P Langhorne, J Montaner, C Roffe, AG Rudd, PJ Tyrrell, D van de Beek, M Woodhead, A Meisel; citation_volume=46; citation_publication_date=2015; citation_pages=2335-2340; citation_doi=10.1161/STROKEAHA.115.009617; citation_id=CR33
citation_journal_title=J Stroke; citation_title=Biomarker for ischemic stroke using metabolome: a clinician perspective; citation_author=E Sidorov, DK Sanghera, JKP Vanamala; citation_volume=21; citation_publication_date=2019; citation_pages=31-41; citation_doi=10.5853/jos.2018.03454; citation_id=CR34
citation_journal_title=Eur Heart J.; citation_title=The gut microbiome as novel cardio-metabolic target: The time has come!; citation_author=S Vinjé, E Stroes, M Nieuwdorp, SL Hazen; citation_volume=35; citation_publication_date=2014; citation_pages=883-887; citation_doi=10.1093/eurheartj/eht467; citation_id=CR35
citation_journal_title=Front Cell Infect Microbiol; citation_title=Higher risk of stroke is correlated with increased opportunistic pathogen load and reduced levels of butyrate-producing bacteria in the gut; citation_author=X Zeng, X Gao, Y Peng, Q Wu, J Zhu, C Tan, G Xia, C You, R Xu, S Pan, H Zhou, Y He, J Yin; citation_volume=9; citation_publication_date=2019; citation_pages=4; citation_doi=10.3389/fcimb.2019.00004; citation_id=CR36
citation_journal_title=Chest.; citation_title=Bleeding and stroke risk in a real-world prospective primary prevention cohort of patients with atrial fibrillation; citation_author=D Poli, S Testa, E Antonucci, E Grifoni, O Paoletti, GYH Lip; citation_volume=140; citation_publication_date=2011; citation_pages=918-924; citation_doi=10.1378/chest.10-3024; citation_id=CR37
citation_journal_title=J Stroke.; citation_title=Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update; citation_author=SJ An, TJ Kim, B-W Yoon; citation_volume=19; citation_publication_date=2017; citation_pages=3-10; citation_doi=10.5853/jos.2016.00864; citation_id=CR38
citation_journal_title=Lancet Neurol; citation_title=Intracerebral haemorrhage: mechanisms of injury and therapeutic targets; citation_author=RF Keep, Y Hua, G Xi; citation_volume=11; citation_publication_date=2012; citation_pages=720-731; citation_doi=10.1016/S1474-4422(12)70104-7; citation_id=CR39
Tan C, Wang H, Gao X, Xu R, Zeng X, Cui Z, et al. Dynamic changes and prognostic value of gut microbiota-dependent trimethylamine-N-oxide in acute ischemic stroke. Front Neurol. 2020;11.
citation_journal_title=Eur J Neurol; citation_title=Trimethylamine-N-oxide is elevated in the acute phase after ischaemic stroke and decreases within the first days; citation_author=C Schneider, JG Okun, KV Schwarz, J Hauke, M Zorn, C Nürnberg, M Ungerer, PA Ringleb, S Mundiyanapurath; citation_volume=27; citation_publication_date=2020; citation_pages=1596-1603; citation_doi=10.1111/ene.14253; citation_id=CR41
citation_journal_title=Transpl Infect Dis; citation_title=Butyrate-producing gut bacteria and viral infections in kidney transplant recipients: a pilot study; citation_author=JR Lee, J Huang, M Magruder; citation_volume=21; citation_publication_date=2019; citation_pages=e13180; citation_id=CR42
citation_journal_title=Proc Natl Acad Sci U S A; citation_title=The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition; citation_author=PV Chang, L Hao, S Offermanns, R Medzhitov; citation_volume=111; citation_publication_date=2014; citation_pages=2247-2252; citation_doi=10.1073/pnas.1322269111; citation_id=CR43
citation_journal_title=Science (80- ); citation_title=The microbial metabolite desaminotyrosine protects from influenza through type I interferon; citation_author=AL Steed, GP Christophi, GE Kaiko, L Sun, VM Goodwin, U Jain; citation_volume=357; citation_publication_date=2017; citation_pages=498-502; citation_doi=10.1126/science.aam5336; citation_id=CR44
citation_journal_title=Nature Nature Publishing Group; citation_title=Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation; citation_author=N Arpaia, C Campbell, X Fan, S Dikiy, J Veeken, P Deroos; citation_volume=504; citation_publication_date=2013; citation_pages=451-455; citation_id=CR45
citation_journal_title=Nat Med; citation_title=Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke; citation_author=A Liesz, E Suri-Payer, C Veltkamp, H Doerr, C Sommer, S Rivest, T Giese, R Veltkamp; citation_volume=15; citation_publication_date=2009; citation_pages=192-199; citation_doi=10.1038/nm.1927; citation_id=CR46
Haak BW, de Jong HK, Kostidis S, Giera M, Maude RR, Samad R, et al. Altered patterns of compositional and functional disruption of the gut microbiota in typhoid fever and nontyphoidal febrile illness. Open Forum Infect Dis. 2020;7.
citation_journal_title=Eur Stroke J; citation_title=Development and internal validation of a prediction rule for post-stroke infection and post-stroke pneumonia in acute stroke patients; citation_author=WF Westendorp, JD Vermeij, NA Hilkens, MC Brouwer, A Algra, HB Worp, DWJ Dippel, D van de Beek, PJ Nederkoorn; citation_volume=3; citation_publication_date=2018; citation_pages=136-144; citation_doi=10.1177/2396987318764519; citation_id=CR48