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

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 <i>in vitro</i> 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.