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Food availability and usage is a major adaptive force for the successful survival of animals in nature. However, very little is known about the signal from food to activate the hosts digestive system, which facilitates animals to digest more diverse food in nature. Here, by using a food digestion system in C. elegans, we discover that bacterial peptidoglycan (PGN) is a unique food signal that activates animals to digest inedible food. We find that PGN was sensed by a conserved intestinal glycosylated protein (BCF-1) in nematodes via direct interaction, which promoted food digestion through inhibiting the mitochondrial unfolded protein response (UPRmt). Moreover, constitutive activation of UPRmt is sufficient to inhibit food digestion. Thus, our study reveals how bacterial PGN, as a common digestion cue, activates the food digestive system through interacting with a conserved glycosylated protein, which facilitates adaptation of the host animals by increasing ability to consume a wide range of foods in their natural environment.