Genetic correlations between Alzheimer’s disease and gut microbiome genera

A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer’s disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and...

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Autores principales: Cammann, Davis, Lu, Yimei, Cummings, Melika J., Zhang, Mark L., Cue, Joan Manuel, Do, Jenifer, Ebersole, Jeffrey, Chen, Xiangning, Oh, Edwin C., Cummings, Jeffrey L., Chen, Jingchun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066300/
https://www.ncbi.nlm.nih.gov/pubmed/37002253
http://dx.doi.org/10.1038/s41598-023-31730-5
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author Cammann, Davis
Lu, Yimei
Cummings, Melika J.
Zhang, Mark L.
Cue, Joan Manuel
Do, Jenifer
Ebersole, Jeffrey
Chen, Xiangning
Oh, Edwin C.
Cummings, Jeffrey L.
Chen, Jingchun
author_facet Cammann, Davis
Lu, Yimei
Cummings, Melika J.
Zhang, Mark L.
Cue, Joan Manuel
Do, Jenifer
Ebersole, Jeffrey
Chen, Xiangning
Oh, Edwin C.
Cummings, Jeffrey L.
Chen, Jingchun
author_sort Cammann, Davis
collection PubMed
description A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer’s disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual’s risk for the disease. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the “best-fit” model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.
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spelling pubmed-100663002023-04-02 Genetic correlations between Alzheimer’s disease and gut microbiome genera Cammann, Davis Lu, Yimei Cummings, Melika J. Zhang, Mark L. Cue, Joan Manuel Do, Jenifer Ebersole, Jeffrey Chen, Xiangning Oh, Edwin C. Cummings, Jeffrey L. Chen, Jingchun Sci Rep Article A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer’s disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual’s risk for the disease. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the “best-fit” model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships. Nature Publishing Group UK 2023-03-31 /pmc/articles/PMC10066300/ /pubmed/37002253 http://dx.doi.org/10.1038/s41598-023-31730-5 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Cammann, Davis
Lu, Yimei
Cummings, Melika J.
Zhang, Mark L.
Cue, Joan Manuel
Do, Jenifer
Ebersole, Jeffrey
Chen, Xiangning
Oh, Edwin C.
Cummings, Jeffrey L.
Chen, Jingchun
Genetic correlations between Alzheimer’s disease and gut microbiome genera
title Genetic correlations between Alzheimer’s disease and gut microbiome genera
title_full Genetic correlations between Alzheimer’s disease and gut microbiome genera
title_fullStr Genetic correlations between Alzheimer’s disease and gut microbiome genera
title_full_unstemmed Genetic correlations between Alzheimer’s disease and gut microbiome genera
title_short Genetic correlations between Alzheimer’s disease and gut microbiome genera
title_sort genetic correlations between alzheimer’s disease and gut microbiome genera
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066300/
https://www.ncbi.nlm.nih.gov/pubmed/37002253
http://dx.doi.org/10.1038/s41598-023-31730-5
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