Paneth cell-derived intestinal luminal lysozyme shapes mucolytic microbiota and controls mucosal inflammatory tone
Paneth cells are the primary, and possibly the sole, source of lysozyme in the intestinal lumen. Mice lacking the Paneth cell lysozyme gene, Lyz1, had diminished NLR signaling and basal inflammation, and were further protected from experimental colitis. Protection depended on an enhanced goblet and tuft cell program that was driven by IL13-IL4Ra-Stat6 signaling and required an expansion of lysozyme-sensitive mucolytic bacteria. Forced ectopic lysozyme production in colonic epithelium suppressed these bacteria and exacerbated colitis. Single cell RNA-seq of Lyz1 KO lamina propria revealed an activated ILC2 profile towards cytokine production. One lysozymesensitive species, Ruminococcus gnavus , when processed by lysozyme, induced a pro-inflammatory response, while non-processed R. gnavus stimulated IL13 production in lymphocytes. Consistent with a role of lysozyme for cell-wall processing in the inflammatory response, Lyz1 KO microbiota was anti-colitogenic in lysozymedeficient hosts but colitogenic in lysozyme-sufficient hosts. Thus, Paneth cell lysozyme regulates inflammatory tone by modulating mucosal response to specific bacterial groups. Overall design: Mouse Ileum fragments (3-4 mice/genotype/treatment) were collected and subjected to RNA extraction. RNA samples were submitted for sequencing using BGISEQ500 (BGI-US). Sequenced files were aligned to mm9 genome index using Kallisto (v0.45.0) (Bray et al., 2016) with default settings and 1000 bootstraps. Reads were normalized in DESeq2 (Build 3.9) using default settings in R.