Fecal microbial load is a major determinant of gut microbiome variation and a confounder for disease associations

Suguru Nishijima, Evelina Stankevic, Oliver Aasmets, Thomas S.B. Schmidt, Naoyoshi Nagata, Marisa Isabell Keller, Pamela Ferretti, Helene Bæk Juel, Anthony Fullam, Shahriyar Mahdi Robbani, Christian Schudoma, Johanne Kragh Hansen, Louise Aas Holm, Mads Israelsen, Robert Schierwagen, Nikolaj Torp, Anja Telzerow, Rajna Hercog, Stefanie Kandels, Diënty H.M. HazenbrinkManimozhiyan Arumugam, Flemming Bendtsen, Charlotte Brøns, Cilius Esmann Fonvig, Jens Christian Holm, Trine Nielsen, Julie Steen Pedersen, Maja Sofie Thiele, Jonel Trebicka, Elin Org, Aleksander Krag, Torben Hansen, Michael Kuhn*, Peer Bork, GALAXY and MicrobLiver consortia

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

2 Citationer (Scopus)

Abstract

The microbiota in individual habitats differ in both relative composition and absolute abundance. While sequencing approaches determine the relative abundances of taxa and genes, they do not provide information on their absolute abundances. Here, we developed a machine-learning approach to predict fecal microbial loads (microbial cells per gram) solely from relative abundance data. Applying our prediction model to a large-scale metagenomic dataset (n = 34,539), we demonstrated that microbial load is the major determinant of gut microbiome variation and is associated with numerous host factors, including age, diet, and medication. We further found that for several diseases, changes in microbial load, rather than the disease condition itself, more strongly explained alterations in patients’ gut microbiome. Adjusting for this effect substantially reduced the statistical significance of the majority of disease-associated species. Our analysis reveals that the fecal microbial load is a major confounder in microbiome studies, highlighting its importance for understanding microbiome variation in health and disease.
OriginalsprogEngelsk
TidsskriftCell
Vol/bind188
Udgave nummer1
Sider (fra-til)222-236
Antal sider15
ISSN0092-8674
DOI
StatusUdgivet - 2025

Bibliografisk note

Funding Information:
We thank members of the Bork group at EMBL for their support and constructive discussions. We also thank Anna G\u0142azek, Anna Schwarz, Roman Thielemann, Leonie Thomas, Ela Cetin, Moritz von Stetten, Mariam Hassen, and Kasimir Noack for their help with the metadata curation. This work was supported by funding from the European Union's Horizon 2020 research and innovation program under grant agreement numbers 668031 (GALAXY) and 825694 (MICROB-PREDICT). This reflects only the authors\u2019 view, and the European Commission is not responsible for any use that may be made of the information it contains. The study was also supported by the Novo Nordisk Foundation through a Challenge Grant \u201CMicrobLiver\u201D (grant number NNF15OC0016692) and through a core grant (grant number NNF18CC0034900), the Innovation Fund Denmark (grant number: 0603-00484B), the EMBO Installation Grant (no. 3573), an Estonian Research Council grant (PRG1414), and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under project numbers 460129525 and 403224013 (project A09). S.N. was partially supported by the Overseas Postdoctoral Fellowships of the Uehara Memorial Foundation. C.E.F. was supported by the BRIDGE \u2013 Translational Excellence Programme (grant number: NNF18SA0034956), Steno Diabetes Center Sjaelland, and The Region Zealand Health Scientific Research Foundation. N.N. was partially supported by the Japan Agency for Medical Research and Development (AMED) (Research Program on HIV/AIDS: JP22fk0410051 and Research Program on Emerging and Re-emerging Infectious Diseases: JP22fk0108538) and the Ministry of Health, Labour, and Welfare, Japan (grant number: 22HB1003). L.A.H. was supported by the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation (grant no. NNF20SA0067242) and the Danish Heart Foundation (grant no. PhD2023009-HF).

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