Encrypted peptides identified in the human gut metaproteome interact specifically with the innate immune system favouring regulatory responses

The human gastrointestinal tract (GIT) is a very complex ecosystem involving a continuous interaction between nutrients, host cells and microorganisms. Recently, we have discovered a new family of immunomodulatory peptides that are encrypted within the sequence of a precise extracellular protein, which is secreted by the lactic acid bacterium Lactobacillus plantarum (Patent WO 2013034795 A1) (1). The genetic information about commensal/probiotic bacteria and gut microbiomes that is present in public repositories is huge, with only a list of 10 million unique bacterial proteins available mainly from the METAHIT and HMP projects (http://gigadb.org/dataset/100064). Our aim is to explore these 10 million unique proteins to obtain information on encrypted peptides which might have immunomodulatory bioactivity on host cells. With this in mind we have developed the MAHMI (Mechanism of Action of the Human Microbiome) database, a unique resource that provides comprehensive information about the sequence of potential immunomodulatory and antiproliferative peptides encrypted in the proteins produced by the human gut microbiota. Fifteen peptides were chosen by its potential immunomodulatory bioactivity. Selected peptides were assayed in vitro at a final concentration of 10 µg/mL using monocyte derived cells (Mo-DCs). Our bioinformatics/in vitro methodology allowed selection of new inmunomodulatory peptides encrypted in the human intestinal bacteria metaproteome. HM14 signaled through an unknown receptor, and imprinted anti-inflammatory traits in immune cells as evidenced by RNASeq and flow cytometry. The mechanisms used by this kind of peptides may be useful for the treatment of inflammatory diseases