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How such balance is impaired in inflammatory bowel diseases (IBDs), including Crohn\u2019s disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of noninflammatory colon-associated macrophages (niColAMs) in IBD recovery. Through trans-scale analyses\u2014integrating computational transcriptomics, proteomics, and in vivo interventional studies\u2014we identified GIV (\n                    <jats:italic>CCDC88A<\/jats:italic>\n                    ) as a key regulator of niColAMs. GIV emerged as the top-ranked gene in niColAMs that physically and functionally interacts with NOD2, an innate immune sensor implicated in CD and UC. Myeloid-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abolishes the protective effects of the NOD2 ligand muramyl dipeptide in colitis and sepsis models. Mechanistically, GIV\u2019s C-terminus binds the terminal leucine-rich repeat 10 (LRR 10) of NOD2 and is required for NOD2 to dampen inflammation and clear microbes. The CD-associated\n                    <jats:italic>1007fs<\/jats:italic>\n                    NOD2 variant, which lacks LRR 10, cannot bind GIV, which provides critical insights into how this clinically relevant variant impairs microbial sensing and clearance. These findings illuminate a critical GIV\u2022NOD2 axis essential for gut homeostasis and highlight its disruption as a driver of dysbiosis and inflammation in IBD.\n                  <\/jats:p>","DOI":"10.1172\/jci190851","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T16:00:15Z","timestamp":1759420815000},"source":"Crossref","is-referenced-by-count":8,"title":["Distinct colitis-associated macrophages drive NOD2-dependent bacterial sensing and gut homeostasis"],"prefix":"10.1172","volume":"135","author":[{"given":"Gajanan D.","family":"Katkar","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahitha Shree","family":"Anandachar","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine,"},{"name":"Biomedical Sciences Graduate Program, School of 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