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Mammalian chitinases include the catalytically active chitotriosidase (CHIT1) and acidic mammalian chitinase (CHIA\/AMCase), alongside nonenzymatic chitinase-like proteins such as chitinase-3-like protein 1 (CHI3L1\/YKL-40), which exert distinct but interconnected functions. Host chitinases and microbial chitinolytic systems may converge in environmental chitin processing, whereas CHI3L1 can influence epithelial\u2013microbial interactions and mucus-associated microbial organization through nonenzymatic mechanisms. Environmental exposure and host genetic variability add further complexity: changes in exposure to microorganisms and chitin-containing organisms may modify chitinase-related pathways, while functional variants in CHIT1 and CHIA alter host chitinolytic capacity. However, their consequences for human microbial ecology remain incompletely defined. CHI3L1 also has established functions in neuroinflammatory and astroglial responses, raising the possibility of convergence with microbiota-dependent gut\u2013brain communication, although a direct chitinase\u2013microbiota\u2013brain pathway has not been demonstrated. Here, we propose a multidimensional chitinase\u2013microbiota axis integrating environmental chitin exposure, host and microbial chitinolytic activity, innate immune signaling, epithelial\u2013microbial interactions, and tissue remodeling. We distinguish experimentally established mechanisms from emerging or hypothetical connections and identify critical gaps for testing causal relationships across mucosal, metabolic, and neuroimmune compartments. Reframing chitinases and chitinase-like proteins as context-dependent components of host\u2013microbial ecosystems may provide a mechanistic framework for investigating inflammatory, metabolic, and neuroimmune diseases and defining future biomarker and therapeutic opportunities.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag130","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:34:36Z","timestamp":1791286476000},"source":"Crossref","is-referenced-by-count":0,"title":["The chitinase\u2013microbiota axis: connecting innate immunity, microbial ecology, and mucosal homeostasis"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5171-7963","authenticated-orcid":false,"given":"Lucia","family":"Malaguarnera","sequence":"first","affiliation":[{"name":"Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania , Via Santa Sofia 94, 95123 Catania 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