The chitinase-microbiota axis: connecting innate immunity, microbial ecology, and mucosal homeostasis.

Chitinases and chitinase-like proteins are evolutionarily conserved molecules increasingly recognized as components of biological networks linking environmental exposure, innate immunity, tissue organization, and host-microbial interactions. 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-microbial 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-brain communication, although a direct chitinase-microbiota-brain pathway has not been demonstrated. Here, we propose a multidimensional chitinase-microbiota axis integrating environmental chitin exposure, host and microbial chitinolytic activity, innate immune signaling, epithelial-microbial 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-microbial ecosystems may provide a mechanistic framework for investigating inflammatory, metabolic, and neuroimmune diseases and defining future biomarker and therapeutic opportunities.