Epigenetic phase variation in the gut microbiome enhances bacterial adaptation
Open accessPublished version of a preprint
Abstract
The human microbiome continuously adapts to variations in diet and host physiology. Epigenetic phase variation (ePV) mediated by bacterial DNA methylation can generate phenotypic heterogeneity within clonal populations. ePVs have been characterized in human pathogens, but their roles in commensals remain unclear. Here, we cataloged ePVs in infant and adult gut microbiomes, revealing genome-wide and site-specific ePV in response to antibiotics and fecal microbiota transplantation. Long-read metagenomics revealed genome-wide ePV mediated by structural variations of DNA methyltransferases. Analysis of public short-read metagenomic datasets further revealed a high prevalence of genome-wide ePVs in the human microbiome. Site-specific ePVs were identified and associated with antibiotics or probiotic engraftment. Focusing on an Akkermansia muciniphila isolate, we find a specific ePV regulating mucC, a gene of unknown function but whose heterologous expression enhances bacterial tolerance to antibiotics via a bet-hedging strategy. Thus, epigenetic modifications are used by gut bacteria to adapt to fluctuating environments.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Wirbel, J., Pyl, P. T., Kartal, E., Zych, K., Kashani, A., Milanese, A., Fleck, J. S., Voigt, A. Y., Palleja, A., Ponnudurai, R., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0406-6 · Cited by 1,373 · see citing works
Yassour, M., Vatanen, T., Siljander, H., Hämäläinen, A.-M., Härkönen, T., Ryhänen, S. J., Franzosa, E. A., Vlamakis, H., Huttenhower, C., Gevers, D., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad0917 · Cited by 1,043 · see citing works
Derosa, L., Routy, B., Thomas, A. M., Iebba, V., Zalcman, G., Friard, S., Mazieres, J., Audigier-Valette, C., Moro-Sibilot, D., Goldwasser, F., et al. (2022) · Nature Medicine · doi:10.1038/s41591-021-01655-5 · Cited by 685 · see citing works
Akkermansia muciniphila phospholipid induces homeostatic immune responses
Bae, M., Cassilly, C. D., Liu, X., Park, S.-M., Tusi, B. K., Chen, X., Kwon, J., Filipčík, P., Bolze, A. S., Liu, Z., et al. (2022) · Nature · doi:10.1038/s41586-022-04985-7 · Cited by 413 · see citing works
Structural variation in the gut microbiome associates with host health
Zeevi, D., Korem, T., Godneva, A., Bar, N., Kurilshikov, A., Lotan-Pompan, M., Weinberger, A., Fu, J., Wijmenga, C., Zhernakova, A., et al. (2019) · Nature · doi:10.1038/s41586-019-1065-y · Cited by 351 · see citing works
Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy
Smith, M., Dai, A., Ghilardi, G., Amelsberg, K. V., Devlin, S. M., Pajarillo, R., Slingerland, J. B., Beghi, S., Herrera, P. S., Giardina, P., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01702-9 · Cited by 349 · see citing works
Bacterial SNPs in the human gut microbiome associate with host BMI
Zahavi, L., Lavon, A., Reicher, L., Shoer, S., Godneva, A., Leviatan, S., Rein, M., Weissbrod, O., Weinberger, A., & Segal, E. (2023) · Nature Medicine · doi:10.1038/s41591-023-02599-8 · Cited by 58 · see citing works
Flagged first, then by citations
- Authors
- Ni, M., Junker, K., Liu, Y., Fan, Y., Li, Y., Qiao, W., Zhang, X.-S., Ksiezarek, M., Mead, E. A., Tourancheau, A., Jiang, W., Blaser, M. J., Valdivia, R. H., Davey, L. E., & Fang, G.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Victoria (CA)
- Rutgers, The State University of New Jersey (US)
- Duke University (US)
- Corresponding author
- Fang, Gang
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2026-06
- Volume
- 34
- Issue
- 6
- Pages
- 1033-1049.e8
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC13196444
- OpenAlex
- W4406289903
- Cited by
- 13
- References
- 9
- Citations by year
- 2026: 11 · 2025: 2
- FWCI
- 22.73
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Host & Microbe (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of General Medical Sciences
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- DNA methylation, gut microbiota, bacterial adaptation, DNA methyltransferases, structural variants, bet-hedging, Akkermansia muciniphila, antibiotic tolerance, fecal microbiota transplantation, probiotics, infant gut microbiota, clonal heterogeneity, gene expression regulation
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
