{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:07:43Z","timestamp":1779253663825,"version":"3.51.4"},"reference-count":102,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) pathogenesis is driven by complex protein\u2013protein interactions (PPIs) between the host and the gut microbiome, yet these molecular dialogs remain largely unmapped. This study utilizes a Deep Learning framework, enhanced by protein structure embeddings, to predict approximately 8.9 billion interspecies PPIs from clinical metagenomic data. The model achieved high accuracy with an AUROC of 0.9960, identifying a high-confidence interactome representing roughly 16% of evaluated protein pairs. Phenotype-specific analysis revealed that while microbial hubs shift\u2014transitioning from metabolic enzymes in healthy states to transport and regulatory proteins in CRC\u2014the primary human targets remain remarkably consistent across both cohorts. These core human interactors are predominantly metalloproteins and regulators of ubiquitination, apoptosis, and zinc transport, suggesting these pathways are primary focal points for microbial manipulation regardless of disease state. Furthermore, co-occurring bacterial genera exhibit over 99% overlap in host target profiles, indicating significant functional redundancy in microbial engagement with the host. These findings suggest that CRC probably arises from network-level perturbations of stable host signaling hubs, offering a blueprint for identifying novel therapeutic targets and biomarkers.<\/jats:p>","DOI":"10.3390\/ijms27104232","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:49:09Z","timestamp":1778572149000},"page":"4232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping of Phenotype Specific Host\u2013Microbiome Protein\u2013Protein Interaction Networks in Colorectal Cancer Using Deep Learning"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5104-8044","authenticated-orcid":false,"given":"Despoina P.","family":"Kiouri","sequence":"first","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgios C.","family":"Batsis","sequence":"additional","affiliation":[{"name":"AI Lab, Department of Digital Systems, University of Piraeus, Gr. Lampraki 126, 18534 Piraeus, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1877-500X","authenticated-orcid":false,"given":"Ippokratis","family":"Messaritakis","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece"},{"name":"Laboratory of Clinical Microbiology, German Medical Institute, Yiannoukas Labs Ltd., Bioiatriki Group, Limassol 4105, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Souglakos","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece"},{"name":"Laboratory of Pathology, University General Hospital of Heraklion, 70013 Heraklion, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-6245","authenticated-orcid":false,"given":"Christos T.","family":"Chasapis","sequence":"additional","affiliation":[{"name":"Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neuroscience.2024.11.068","article-title":"Beyond digestion: Exploring how the gut microbiota modulates human social behaviors","volume":"565","author":"Abavisani","year":"2025","journal-title":"Neuroscience"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e0033820","DOI":"10.1128\/CMR.00338-20","article-title":"A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders","volume":"35","author":"Sorboni","year":"2022","journal-title":"Clin. 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