Microbiota modulation by a human Paneth cell α-defensin fragment protects against DSS-induced colitis

Erica Bonazzi; Fuhua Hao; Andrew D Patterson; Laurent Peyrin-Biroulet; Benjamin A H Jensen; Benoit Chassaing

doi:10.1016/j.isci.2025.114310

Microbiota modulation by a human Paneth cell α-defensin fragment protects against DSS-induced colitis

iScience. 2025 Dec 2;29(1):114310. doi: 10.1016/j.isci.2025.114310. eCollection 2026 Jan 16.

Authors

Erica Bonazzi^{1

2}, Fuhua Hao³, Andrew D Patterson³, Laurent Peyrin-Biroulet^{4

5

6

7}, Benjamin A H Jensen⁸, Benoit Chassaing^{1

2

6}

Affiliations

¹ Institut Pasteur, Université Paris Cité, INSERM U1306, Microbiome-Host Interactions, Paris, France.
² INSERM U1016, Team "Mucosal Microbiota in Chronic Inflammatory Diseases", CNRS UMR 8104, Université Paris Cité, Paris, France.
³ Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, State College, PA, USA.
⁴ INSERM, NGERE, University of Lorraine, Nancy, France.
⁵ FHU-CURE, Nancy University Hospital, Vandoeuvre-lès-Nancy, Nancy, France.
⁶ CHRU Nancy, IHU Infiny, 54000 Nancy, France.
⁷ Department of Gastroenterology, Nancy University Hospital, Vandoeuvre-lès-Nancy, Nancy, France.
⁸ Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Abstract

The gastrointestinal tract hosts a diverse microbial community, named the intestinal microbiota, which plays a vital role in gut health. Host defense peptides (HDPs), such as defensins, help regulate interactions between the host and its microbiota. Dysfunction in HDPs expression has been associated with a greater risk of inflammatory bowel diseases (IBDs), while some HDPs may positively shape the gut environment. Human alpha defensin 5 (HD5) can be cleaved by intestinal enzymes into bioactive fragments such as HD5_1-9. In this study, we screened various HDPs (LL-37, hBD2, HD5, and HD5_1-9) for their modulatory effects on healthy human microbiotas in vitro and found distinct, donor-specific effects, with HD5_1-9 showing the strongest functional impact. Testing HD5_1-9 in a mouse colitis model revealed potent and microbiota-dependent protection against DSS-induced inflammation, partly through the beneficial of mucus-microbiota interactions. These findings highlight the potential of HDPs, especially HD5_1-9, in modulating gut microbiota and treating intestinal inflammation.

Keywords: Gastroenterology; Immunology; Microbiology.