Although the beneficial capacities of probiotics are more and more substantiated, their effects clearly depend on the strains used and their mechanisms of action remain poorly understood. Recent evidences have highlighted the potential role of cell-wall components in the anti-inflammatory capacity of selected lactobacilli. In this addendum, we summarize our recent results concerning the role of peptidoglycan (PGN) and NOD2 signaling in the regulation of intestinal inflammation. We showed that the protective effect of Lactobacillus PGN is strain-specific and linked to the induction of diverse immune regulatory pathways. Moreover the beneficial effect of Lactobacillus PGN correlated with the release of a specific muropeptide sensed by NOD2. These findings allow for a better understanding of how probiotic lactobacilli exert their beneficial effect and will help guide for more successful strain selection.