Lytic phages lead to targeted and sustained depletion of Akkermansia muciniphila in the gut microbiome
Abstract
Natural bacteriophages are major regulators of gut bacterial populations, but their capacity to impose sustained, taxon-selective control over individual commensals in the gut remains unclear. Here, we establish a collection of isolated lytic phages targeting Akkermansia muciniphila, a mucosa-associated and context-dependent gut commensal, and demonstrate their utility as precision perturbation tools. We isolated 27 phages representing two distinct vOTUs within the class Caudoviricetes, neither of which had close cultured representatives in public databases. The phages lysed susceptible A. muciniphila strains at low multiplicities of infection and showed no detectable activity against other tested gut bacteria. Selected phages reproducibly depleted A. muciniphila across distinct stool-derived in vitro communities, demonstrating that the magnitude of structural disruption scales with the target's baseline abundance. Oral gavage of the optimized cocktail PC6 achieved targeted and sustained suppression in A. muciniphila-colonized and human microbiota-associated mouse models, with infective phages recoverable from feces. Shotgun metagenomics revealed changes in a limited subset of taxa and functional pathways, comprising both shared and donor-specific responses, without broad loss of pathway-level diversity. These findings expand the collection of cultured phages that infect A. muciniphila and provide a tractable strategy for causally probing the ecological roles of defined gut commensals.
References
[1] Reyes, A. et al. (2013). Gnotobiotic mouse model of phage–bacterial host dynamics in the human gut. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1319470110.
[2] Hsu, B.B. et al. (2019). Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2019.05.001.
[3] Venturelli, O.S. et al. (2018). Deciphering microbial interactions in synthetic human gut microbiome communities. Molecular Systems Biology. https://doi.org/10.15252/msb.20178157.
[4] Grant, E.T. et al. (2026). Navigating the duality of Akkermansia muciniphila. Nature Microbiology. https://doi.org/10.1038/s41564-025-02222-1.
[5] Ioannou, A. et al. (2024). Akkermansia muciniphila: biology, microbial ecology, host interactions and therapeutic potential. Nature Reviews Microbiology. https://doi.org/10.1038/s41579-024-01106-1.
[6] Mo, C. et al. (2024). The influence of Akkermansia muciniphila on intestinal barrier function. Gut Pathogens. https://doi.org/10.1186/s13099-024-00635-7.
[7] Cani, P.D. et al. (2022). Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nature Reviews Gastroenterology & Hepatology. https://doi.org/10.1038/s41575-022-00631-9.
[8] Miyauchi, E. et al. (2023). The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nature Reviews Immunology. https://doi.org/10.1038/s41577-022-00727-y.
[9] Wang, W. et al. (2025). ILC3s regulate the gut microbiota via host intestinal galactosylation to limit pathogen infection in mice. Nature Microbiology. https://doi.org/10.1038/s41564-025-01933-9.
[10] Qu, S. et al. (2023). Excessive consumption of mucin by over-colonized Akkermansia muciniphila promotes intestinal barrier damage during malignant intestinal environment. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2023.1111911.
[11] Seregin, S.S. et al. (2017). NLRP6 Protects Il10 Mice from Colitis by Limiting Colonization of Akkermansia muciniphila. Cell Reports. https://doi.org/10.1016/j.celrep.2017.03.080.
[12] Wang, Y. et al. (2025). Akkermansia muciniphila exacerbates acute radiation–induced intestinal injury by depleting mucin and enhancing inflammation. The ISME Journal. https://doi.org/10.1093/ismejo/wraf084.
[13] Dohlman, A.B. et al. (2026). Biodiversity and biogeography of the multi-kingdom cancer microbiome. Cell. https://doi.org/10.1016/j.cell.2026.04.015.
[14] Kuang, X. et al. (2025). Applications of bacteriophages in precision engineering of the human gut microbiome. Engineering Microbiology. https://doi.org/10.1016/j.engmic.2025.100189.
[15] Su, R. et al. (2025). Dietary whey protein protects against Crohn’s disease by orchestrating cross-kingdom interaction between the gut phageome and bacteriome. Gut. https://doi.org/10.1136/gutjnl-2024-334516.
[16] Zünd, M. et al. (2021). High throughput sequencing provides exact genomic locations of inducible prophages and accurate phage-to-host ratios in gut microbial strains. Microbiome. https://doi.org/10.1186/s40168-021-01033-w.
[17] Tisza, M.J. and Buck, C.B. (2021). A catalog of tens of thousands of viruses from human metagenomes reveals hidden associations with chronic diseases. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2023202118.
[18] Du, Z. et al. (2026). High-resolution phage-host assignment through key proteins using large language models. Nature Communications. https://doi.org/10.1038/s41467-026-70613-x.
[19] Shen, J. et al. (2023). Large-scale phage cultivation for commensal human gut bacteria. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2023.03.013.
[20] Xing, B. et al. (2025). Gut Phage Biobank: a collection of bacteriophages targeting human commensal bacteria. Nature Communications. https://doi.org/10.1038/s41467-025-61946-0.
[21] Federici, S. et al. (2022). Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell. https://doi.org/10.1016/j.cell.2022.07.003.
[22] Koo, H. et al. (2025). A synthetic gut microbiota provides an understanding of the maintenance and functional impact of phage. mBio. https://doi.org/10.1128/mbio.02341-25.
[23] Shkoporov, A.N. et al. (2018). ΦCrAss001 represents the most abundant bacteriophage family in the human gut and infects Bacteroides intestinalis. Nature Communications. https://doi.org/10.1038/s41467-018-07225-7.
[24] Guerin, E. et al. (2021). Isolation and characterisation of ΦcrAss002, a crAss-like phage from the human gut that infects Bacteroides xylanisolvens. Microbiome. https://doi.org/10.1186/s40168-021-01036-7.
[25] Knowles, B. et al. (2016). Lytic to temperate switching of viral communities. Nature. https://doi.org/10.1038/nature17193.
[26] Silveira, C.B. and Rohwer, F.L. (2016). Piggyback-the-Winner in host-associated microbial communities. npj Biofilms and Microbiomes. https://doi.org/10.1038/npjbiofilms.2016.10.
[27] Wu, L. et al. (2024). Data-driven prediction of colonization outcomes for complex microbial communities. Nature Communications. https://doi.org/10.1038/s41467-024-46766-y.
[28] Wrzosek, L. (2018). Transplantation of human microbiota into conventional mice durably reshapes the gut microbiota. Scientific REPORTS.
[29] Bin Jang, H. et al. (2019). Taxonomic assignment of uncultivated prokaryotic virus genomes is enabled by gene-sharing networks. Nature Biotechnology. https://doi.org/10.1038/s41587-019-0100-8.
[30] Karcher, N. et al. (2021). Genomic diversity and ecology of human-associated Akkermansia species in the gut microbiome revealed by extensive metagenomic assembly. Genome Biology. https://doi.org/10.1186/s13059-021-02427-7.
[31] Derrien, M. et al. (2008). The Mucin Degrader Akkermansia muciniphila Is an Abundant Resident of the Human Intestinal Tract. Applied and Environmental Microbiology. https://doi.org/10.1128/AEM.01226-07.
[32] Porter, N.T. et al. (2020). Phase-variable capsular polysaccharides and lipoproteins modify bacteriophage susceptibility in Bacteroides thetaiotaomicron. Nature Microbiology. https://doi.org/10.1038/s41564-020-0746-5.
[33] Hryckowian, A.J. et al. (2020). Bacteroides thetaiotaomicron-Infecting Bacteriophage Isolates Inform Sequence-Based Host Range Predictions. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2020.06.011.
[34] Sørensen, M.C.H. et al. (2015). Primary Isolation Strain Determines Both Phage Type and Receptors Recognised by Campylobacter jejuni Bacteriophages. PLOS ONE. https://doi.org/10.1371/journal.pone.0116287.
[35] Van Cauwenberghe, J. et al. (2021). Spatial patterns in phage- Rhizobium coevolutionary interactions across regions of common bean domestication. The ISME Journal. https://doi.org/10.1038/s41396-021-00907-z.
[36] Labrie, S.J. et al. (2010). Bacteriophage resistance mechanisms. Nature Reviews Microbiology. https://doi.org/10.1038/nrmicro2315.
[37] Mangalea, M.R. and Duerkop, B.A. (2020). Fitness Trade-Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies. Infection and Immunity. https://doi.org/10.1128/IAI.00926-19.
[38] Tisza, M.J. et al. (2025). Longitudinal phage–bacteria dynamics in the early life gut microbiome. Nature Microbiology. https://doi.org/10.1038/s41564-024-01906-4.
[39] Langenfeld, K. et al. (2025). Development of a quantitative metagenomic approach to establish quantitative limits and its application to viruses. Nucleic Acids Research. https://doi.org/10.1093/nar/gkaf118.
[40] Needham, D.M. et al. (2013). Short-term observations of marine bacterial and viral communities: patterns, connections and resilience. The ISME Journal. https://doi.org/10.1038/ismej.2013.19.
[41] Gutiérrez, N. and Garrido, D. (2019). Species Deletions from Microbiome Consortia Reveal Key Metabolic Interactions between Gut Microbes. mSystems. https://doi.org/10.1128/mSystems.00185-19.
[42] Belzer, C. et al. (2017). Microbial Metabolic Networks at the Mucus Layer Lead to Diet-Independent Butyrate and Vitamin B12 Production by Intestinal Symbionts. mBio. https://doi.org/10.1128/mBio.00770-17.
[43] Gracia, L. et al. (2026). A phase-variable capsule facilitates Akkermansia muciniphila colonization of the intestinal mucus layer. mBio. https://doi.org/10.1128/mbio.01048-26.
[44] Lourenço, M. et al. (2020). The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2020.06.002.
[45] Shkoporov, A.N. et al. (2021). Long-term persistence of crAss-like phage crAss001 is associated with phase variation in Bacteroides intestinalis. BMC Biology. https://doi.org/10.1186/s12915-021-01084-3.
[46] Shuoker, B. et al. (2023). Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria. Nature Communications. https://doi.org/10.1038/s41467-023-37533-6.
[47] Derrien, M. et al. (2004). Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. International Journal of Systematic and Evolutionary Microbiology. https://doi.org/10.1099/ijs.0.02873-0.
[48] Chia, L.W. et al. (2018). Deciphering the trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach. Antonie van Leeuwenhoek. https://doi.org/10.1007/s10482-018-1040-x.
[49] Davey, L.E. et al. (2023). A genetic system for Akkermansia muciniphila reveals a role for mucin foraging in gut colonization and host sterol biosynthesis gene expression. Nature Microbiology. https://doi.org/10.1038/s41564-023-01407-w.
[50] Tian, L. et al. (2020). Deciphering functional redundancy in the human microbiome. Nature Communications. https://doi.org/10.1038/s41467-020-19940-1.
[51] Lozupone, C.A. et al. (2012). Diversity, stability and resilience of the human gut microbiota. Nature. https://doi.org/10.1038/nature11550.
[52] Zuo, W.Understanding ripple effects in the gut microbiome.
[53] Davey, L.E. et al. (2023). A genetic system for Akkermansia muciniphila reveals a role for mucin foraging in gut colonization and host sterol biosynthesis gene expression. Nature Microbiology. https://doi.org/10.1038/s41564-023-01407-w.
[54] Gelsinger, D.R. and Wang, H.H. (2026). Toward precision microbiome therapeutics: From black box to blueprint. Cell Host & Microbe. https://doi.org/10.1016/j.chom.2026.06.014.
[55] Chen, S. et al. (2018). fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. https://doi.org/10.1093/bioinformatics/bty560.
[56] Wick, R.R. et al. (2017). Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads. PLOS Computational Biology. https://doi.org/10.1371/journal.pcbi.1005595.
[57] Langmead, B. and Salzberg, S.L. (2012). Fast gapped-read alignment with Bowtie 2. Nature Methods. https://doi.org/10.1038/nmeth.1923.
[58] Nayfach, S. et al. (2021). CheckV assesses the quality and completeness of metagenome-assembled viral genomes. Nature Biotechnology. https://doi.org/10.1038/s41587-020-00774-7.
[59] Bouras, G. et al. (2023). Pharokka: a fast scalable bacteriophage annotation tool. Bioinformatics. https://doi.org/10.1093/bioinformatics/btac776.
[60] Bouras, G. et al. (2026). Protein structure-informed bacteriophage genome annotation with Phold. Nucleic Acids Research. https://doi.org/10.1093/nar/gkaf1448.
[61] Camarillo-Guerrero, L.F. et al. (2021). Massive expansion of human gut bacteriophage diversity. Cell. https://doi.org/10.1016/j.cell.2021.01.029.
[62] Shannon, P. et al. (2003). Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Research. https://doi.org/10.1101/gr.1239303.
[63] Zielezinski, A. et al. (2025). Ultrafast and accurate sequence alignment and clustering of viral genomes. Nature Methods. https://doi.org/10.1038/s41592-025-02701-7.
[64] Sullivan, M.J. et al. (2011). Easyfig: a genome comparison visualizer. Bioinformatics. https://doi.org/10.1093/bioinformatics/btr039.
[65] Wood, D.E. et al. (2019). Improved metagenomic analysis with Kraken 2. Genome Biology. https://doi.org/10.1186/s13059-019-1891-0.
[66] Lu, J. et al. (2017). Bracken: estimating species abundance in metagenomics data. PeerJ Computer Science. https://doi.org/10.7717/peerj-cs.104.
[67] Beghini, F. et al. (2021). Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3. eLife. https://doi.org/10.7554/eLife.65088.
[68] Jiang, S. et al. (2025). Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Research. https://doi.org/10.1093/nar/gkae973.
Metrics
DOI:
Submission ID:
Downloads
Posted
How to Cite
Download Citation
Declaration of Competing Interests
The authors declare no competing interests to disclose.
Copyright
The copyright holder for this preprint is the author/funder.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.