Paneth Cell-Derived Lysozyme Defines the Composition of Mucolytic Microbiota and the Inflammatory Tone of the Intestine

Shiyan Yu, Iyshwarya Balasubramanian, Daniel Laubitz, Kevin Tong, Sheila Bandyopadhyay, Xiang Lin, Juan Flores, Rajbir Singh, Yue Liu, Carlos Macazana, Yanlin Zhao, Fabienne Béguet-Crespel, Karuna Patil, Monica T. Midura-Kiela, Daniel Wang, George S. Yap, Ronaldo P. Ferraris, Zhi Wei, Edward M. Bonder, Max M. HäggblomLanjing Zhang, Veronique Douard, Michael P. Verzi, Ken Cadwell, Pawel R. Kiela, Nan Gao

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1−/− hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.

Original languageEnglish (US)
Pages (from-to)398-416.e8
JournalImmunity
Volume53
Issue number2
DOIs
StatePublished - Aug 18 2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Keywords

  • IL-13
  • Lyz1
  • Paneth cell
  • Ruminococcus gnavus
  • colitis
  • inflammation
  • lysozyme
  • mucolytic bacteria
  • type 2 immunity

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