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These viruses owe much of their antibacterial potential to phage\u2010encoded endolysins, enzymes capable of rapidly degrading bacterial cell walls with high specificity and low potential for resistance development. Despite their therapeutic promise, the overall composition of the gut phageome and the structural modularity of its endolysins remain poorly understood. In this study, we performed a large\u2010scale analysis of 9141 human gut metagenomic samples from 34 independent studies. Using standardized workflows for assembly, genome clustering, host prediction, and protein domain annotation, we reconstructed 15,267 phage genomes and identified 3794 corresponding endolysins. The recovered genomes showed substantial variation in size and coding density, with an average GC content of 43%. Host prediction indicated that most phages targeted bacterial members of the phyla\n                    <jats:italic>Bacillota<\/jats:italic>\n                    (41%) and\n                    <jats:italic>Bacteroidota<\/jats:italic>\n                    (23%). Endolysin sequences grouped into 296 protein families and displayed striking domain modularity. Catalytic domains such as Amidase_2 and Glyco_hydro_25 frequently co\u2010occurred with cell wall\u2013binding motifs including LysM and CW_7. Remarkably, one endolysin contained 15 distinct domains, the highest natural domain diversity reported to date. Collectively, this study represents the most comprehensive characterization of the human gut phageome and its encoded endolysins to date. The exceptional modular diversity uncovered highlights the gut phageome as a rich reservoir of endolysin variants, providing a strong foundation for developing next\u2010generation therapeutics against multidrug\u2010resistant bacterial pathogens.\n                  <\/jats:p>","DOI":"10.1002\/mbo3.70344","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T05:11:08Z","timestamp":1782105068000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Gut Phageome Analysis Uncovers Thousands of Highly Modular Endolysins"],"prefix":"10.1002","volume":"15","author":[{"given":"Raphael Kabir","family":"Niloy","sequence":"first","affiliation":[{"name":"Department of Genetic Engineering and Biotechnology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurnabi Azad","family":"Jewel","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering and Biotechnology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniyal","family":"Karim","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering and Biotechnology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohimenul Haque","family":"Rolin","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering and Biotechnology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahsin","family":"Khan","sequence":"additional","affiliation":[{"name":"Genome Centre, Infectious Diseases Division, icddr,b Dhaka Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3662-1058","authenticated-orcid":false,"given":"Arzuba","family":"Akter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8366-7745","authenticated-orcid":false,"given":"Shakhinur Islam","family":"Mondal","sequence":"additional","affiliation":[{"name":"Department of Genetic Engineering and Biotechnology Shahjalal University of Science and Technology Sylhet Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/v11020096"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1099\/MGEN.0.000168"},{"key":"e_1_2_11_4_1","unstructured":"Anderson M. 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