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Here we develop a CAZyme profiler called Cayman (Carbohydrate Active Enzymes Profiling of Metagenomes) and a hierarchical substrate annotation scheme for use with genomic or shotgun metagenomic datasets. Using these tools, we systematically surveyed CAZymes in human gut microorganisms (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009107,683 genomes) and identified several putative mucin-foraging bacteria, including\n                    <jats:italic>Hungatella<\/jats:italic>\n                    and\n                    <jats:italic>Eisenbergiella<\/jats:italic>\n                    species, which were confirmed experimentally. We compared CAZymes in gut metagenomes (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093,960) from high-income settings versus low- and middle-income settings and found that low- and middle-income setting metagenomes are enriched in fibre-degrading CAZymes, while CAZyme richness is generally higher in high-income setting metagenomes. Additional analysis (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20091,998) indicated that metagenomes of individuals with colorectal cancer are depleted in fibre-targeting and enriched in glycosaminoglycan-targeting CAZymes. Finally, we inferred CAZyme substrates from genomic co-localization of CAZyme domains. Cayman is broadly applicable and freely available from\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/github.com\/zellerlab\/cayman\" ext-link-type=\"uri\">https:\/\/github.com\/zellerlab\/cayman<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41564-026-02318-2","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T09:02:16Z","timestamp":1777021336000},"page":"1739-1753","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cayman enables large-scale analysis of gut microbiome carbohydrate-active enzyme repertoires"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7077-2127","authenticated-orcid":false,"given":"Quinten R.","family":"Ducarmon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Karcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1771-3288","authenticated-orcid":false,"given":"Samir","family":"Giri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6270-2110","authenticated-orcid":false,"given":"Hanne L. 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