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

SUMMARYPerturbed 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 gutGraphical AbstractModel 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 PYY1-36 release from PCs. (B) Increased virulent hyphae (purple hyphae) results in PYY1-36 release from crypt PCs into the mucus. Hyphae are targeted by PYY1-36 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 PYY1-36 release or mucus depletion and PC dysfunction.

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P109 SMOKING NEGATIVELY AFFECTS DISEASE COURSE REGARDLESS OF SMOKING AMOUNT AND MAY BE ASSOCIATED WITH PANETH CELL PHENOTYPE IN JAPANESE CROHN’S DISEASE PATIENTS

Gastroenterology ◽

10.1053/j.gastro.2017.11.155 ◽

2018 ◽

Vol 154 (1) ◽

pp. S56

Author(s):

Takeo Naito ◽

Ta-Chiang Liu ◽

Yoichi Kakuta ◽

Rintaro Moroi ◽

Masatake Kuroha ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Paneth Cell ◽

Cell Phenotype ◽

Disease Course

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Faculty Opinions recommendation of Reduced Paneth cell alpha-defensins in ileal Crohn's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13822.471323 ◽

2006 ◽

Author(s):

Nur Alam

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Paneth Cell

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Faculty Opinions recommendation of Reduced Paneth cell alpha-defensins in ileal Crohn's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13822.358636 ◽

2006 ◽

Author(s):

Lora Hooper

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Paneth Cell

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Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease

Cells ◽

10.3390/cells10061349 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1349

Author(s):

Kibrom M. Alula ◽

Dakota N. Jackson ◽

Andrew D. Smith ◽

Daniel S. Kim ◽

Kevin Turner ◽

...

Keyword(s):

Crohn’S Disease ◽

Lipid Metabolism ◽

Crohn's Disease ◽

Paneth Cell ◽

Mitochondrial Damage ◽

Paneth Cells ◽

Cell Phenotype ◽

Type I ◽

Targeted Therapeutics ◽

Gene Signatures

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

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