Peptide YY: a novel Paneth cell antimicrobial peptide that maintains fungal commensalism

SUMMARY Perturbed interactions between the intestinal microbes and host correlate with emergence of fungal virulence. Here we report a previously unknown role for peptide YY (PYY), a described endocrine molecule, as an antimicrobial peptide (AMP) expressed by gut immune epithelial Paneth Cells (PC). PC-PYY differs from other AMPs, including lysozyme, because of limited antibacterial activity, packaging in discrete secretory granules, and selective antifungal activity to virulent hyphae, but not yeast forms of Candida albicans . The latter action is through binding of cationic PC-PYY to the anionic hyphal surface, resulting in membrane disruption and killing. PC-PYY is compartmentalized to surface mucus, which optimizes activity and prevents conversion to endocrine PYY by dipeptidyl peptidase-IV (DPP-IV). We conclude PC-PYY is a unique AMP with selective antifungal activity that maintains gut fungal commensalism. Compromised PC-PYY action from PC dysfunction and/or mucus depletion in ileal Crohn’s disease may initiate or contribute to disease via fungal pathogenesis. Highlights ⍰ Paneth Cell PYY (PC-PYY) is an antimicrobial peptide that differs from endocrine-PYY ⍰ PC-PYY is a selective anti-fungal peptide, targeting the virulent form of C. albicans ⍰ PC-PYY is separately packaged, retained by mucus, and released by C. albicans hyphae ⍰ PC-PYY is proposed as essential for maintenance of fungal commensalism in the gut Graphical Abstract Model for Paneth cell (PC) PYY action and regulation of fungal commensalisms and potential role in the pathogenesis of ileal Crohn’s Disease (iCD) (A) In a healthy ileum, commensal yeast reside and do not stimulate PYY 1-36 release from PCs. (B) Increased virulent hyphae (purple hyphae) results in PYY 1-36 release from crypt PCs into the mucus. Hyphae are targeted by PYY 1-36 and killed (red hyphae) to manage the increased fungi community in gut. (C) In a diseased ileum such as iCD, hyphal load induces immune activation and increased inflammation through PC dysfunction (gray PCs) and decreased PYY 1-36 release or mucus depletion and PC dysfunction.