Proc. Natl Acad. Sci USA https://doi.org/10.1073/pnas.1817376116 (2019)

Immunohomeostasis in the gut relies on the maintenance of a diversified microbiota. In the Proceedings of the National Academy of Sciences USA, Wehkamp and colleagues investigate how the environment of the small intestine can alter the activity of the Paneth cell–produced antimicrobial peptides HD-5 and HD-6. The duodenum is mainly a reducing environment and is flooded with duodenal proteases. Reduced HD-6 is resistant to these proteases, but reduced HD-5 is cleaved into a large number (hundreds) of different fragments. These HD-5 fragments retain variable degrees of antimicrobial activity depending on the microbial species to which they are exposed. Cleavage of HD-5 by the duodenal environment thereby, in a combinatorial way, increases the range of antimicrobial activity and can help enforce a diverse microbiome.