Gut microbiome and atrial fibrillation-results from a large population-based study

Joonatan Palmu¹, Christin S Börschel², Alfredo Ortega-Alonso³, Lajos Markó⁴, Michael Inouye⁵, Pekka Jousilahti⁶, Rodolfo A Salido⁷, Karenina Sanders⁷, Caitriona Brennan⁷, Gregory C Humphrey⁷, Jon G Sanders⁸, Friederike Gutmann⁴, Dominik Linz⁹, Veikko Salomaa⁶, Aki S Havulinna¹⁰, Sofia K Forslund¹¹, Rob Knight¹², Leo Lahti¹³, Teemu Niiranen¹, Renate B Schnabel¹⁴

Affiliations

¹ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Department of Internal Medicine, Turku University Hospital and University of Turku, Finland.
² Department of Cardiology, University Heart and Vascular Centre Hamburg-Eppendorf, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
³ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁴ Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin and the Max-Delbrück Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany.
⁵ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland.
⁷ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Cornell Institute for Host-Microbe Interaction and Disease, Cornell University, Ithaca, NY, USA.
⁹ Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Centre for Heart Rhythm Disorders, Royal Adelaide Hospital, and University of Adelaide, Adelaide, Australia; Department of Cardiology, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁰ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Institute for Molecular Medicine Finland, FIMM - HiLIFE, Helsinki, Finland.
¹¹ Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin and the Max-Delbrück Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany; Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany.
¹² Center for Microbiome Innovation, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Computer Science & Engineering, University of California San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, USA.
¹³ Department of Computing, University of Turku, Turku, Finland.
¹⁴ Department of Cardiology, University Heart and Vascular Centre Hamburg-Eppendorf, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: r.schnabel@uke.de.

PMID: 37119735
PMCID: PMC10165189
DOI: 10.1016/j.ebiom.2023.104583

Gut microbiome and atrial fibrillation-results from a large population-based study

Joonatan Palmu et al. EBioMedicine. 2023 May.

. 2023 May:91:104583.

doi: 10.1016/j.ebiom.2023.104583. Epub 2023 Apr 27.

Authors

Affiliations

¹ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Department of Internal Medicine, Turku University Hospital and University of Turku, Finland.
² Department of Cardiology, University Heart and Vascular Centre Hamburg-Eppendorf, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
³ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Neuroscience Center, University of Helsinki, Helsinki, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁴ Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin and the Max-Delbrück Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany.
⁵ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland.
⁷ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Cornell Institute for Host-Microbe Interaction and Disease, Cornell University, Ithaca, NY, USA.
⁹ Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Centre for Heart Rhythm Disorders, Royal Adelaide Hospital, and University of Adelaide, Adelaide, Australia; Department of Cardiology, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁰ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Turku, Finland; Institute for Molecular Medicine Finland, FIMM - HiLIFE, Helsinki, Finland.
¹¹ Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin and the Max-Delbrück Center, Berlin, Germany; Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany; Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany.
¹² Center for Microbiome Innovation, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Computer Science & Engineering, University of California San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, USA.
¹³ Department of Computing, University of Turku, Turku, Finland.
¹⁴ Department of Cardiology, University Heart and Vascular Centre Hamburg-Eppendorf, Hamburg, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. Electronic address: r.schnabel@uke.de.

PMID: 37119735
PMCID: PMC10165189
DOI: 10.1016/j.ebiom.2023.104583

Abstract

Background: Atrial fibrillation (AF) is an important heart rhythm disorder in aging populations. The gut microbiome composition has been previously related to cardiovascular disease risk factors. Whether the gut microbial profile is also associated with the risk of AF remains unknown.

Methods: We examined the associations of prevalent and incident AF with gut microbiota in the FINRISK 2002 study, a random population sample of 6763 individuals. We replicated our findings in an independent case-control cohort of 138 individuals in Hamburg, Germany.

Findings: Multivariable-adjusted regression models revealed that prevalent AF (N = 116) was associated with nine microbial genera. Incident AF (N = 539) over a median follow-up of 15 years was associated with eight microbial genera with false discovery rate (FDR)-corrected P < 0.05. Both prevalent and incident AF were associated with the genera Enorma and Bifidobacterium (FDR-corrected P < 0.001). AF was not significantly associated with bacterial diversity measures. Seventy-five percent of top genera (Enorma, Paraprevotella, Odoribacter, Collinsella, Barnesiella, Alistipes) in Cox regression analyses showed a consistent direction of shifted abundance in an independent AF case-control cohort that was used for replication.

Interpretation: Our findings establish the basis for the use of microbiome profiles in AF risk prediction. However, extensive research is still warranted before microbiome sequencing can be used for prevention and targeted treatment of AF.

Funding: This study was funded by European Research Council, German Ministry of Research and Education, Academy of Finland, Finnish Medical Foundation, and the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, and the Paavo Nurmi Foundation.

Keywords: Atrial fibrillation; Epidemiology; Gut microbiome; Metagenomics.

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Conflict of interest statement

Declaration of interests RK has received consulting fees from GenCirq Inc, DayTwo Ltd and JGilbert Consulting LLC, payment for lectures from BP Technology Ventures Inc and Hamilton College, support for attending meetings and/or travel from the Chilean Senate, the University of Melbourne, the Shenzhen Society of Science and Technology, the Norwegian Institute of Public Health and participated on a data safety monitoring board for Diversigen, GenCirq Inc, DayTwo Ltd, Cybele Microbiome Inc, BiomeSense Inc, Micronoma Inc. He owns stocks or stock options from Biota Technology Inc, Diversigen, GenCirq Inc Cybele Microbiome Inc and Micronoma Inc. RBS has received lecture fees and advisory board fees from BMS/Pfizer outside this work. TN received payment for lectures or presentations from Servier. JGS occasionally perform bioinformatics consulting for research group in the field of microbiome science via the Center for Microbiome Innovation and Clarity Genomics. VS has ongoing research collaboration with Bayer Ltd., unrelated to the present study.

Figures

**Fig. 1**
Microbial diversity (Bray–Curtis dissimilarity) shown using principal coordinate analysis of species-level microbial abundances with prevalent atrial fibrillation cases denoted using red.

**Fig. 2**
Heatmap showing log-fold change associated with atrial fibrillation in common microbial genera for nominally significant associations after FDR-corrected P value. Asterisk denotes association with bacterial plasmid. DEseq2 models were adjusted for age, sex, body mass index, systolic blood pressure, smoking, alcohol consumption, diabetes mellitus, heart failure, antihypertensive medication use, and total cholesterol.

**Fig. 3**
The trends in top bacterial genera with atrial fibrillation in derivation and validation cohorts. High agreement between bacterial genera scoring highest versus incident atrial fibrillation under a Cox regression model (see Table 4) with the direction (upwards-facing blue: positive association; downwards-facing red: negative association) in FINRISK (Cox estimate) and the validation cohort (Cliff's Delta nonparametric effect size parameter).

**Fig. 4**
The circle illustrates the interaction between cardiovascular risk factors, gut 2 microbiome, and atrial fibrillation (AF) initiation/perpetuation. The upper dark green box shows 3 the observed associations of prevalent AF with microbial genera, the lower box the top 4 associations of incident AF with genera in DESeq2 analyses. The light green box comprises 5 the top associated genera in both analyses. ∗Associations have been reported in prior studies.

See this image and copyright information in PMC

References

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Gut microbiome and atrial fibrillation-results from a large population-based study

Affiliations

Gut microbiome and atrial fibrillation-results from a large population-based study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

LinkOut - more resources

Full Text Sources

Medical