Source of dietary protein alters the abundance of proteases, intestinal epithelial and immune proteins both directly and via interactions with the gut microbiota

Dietary protein has been shown to impact long-term health outcomes differentially depending on its amount and source. It has been suggested that interactions of the gut microbiota with dietary proteins mediate some of the effects of dietary protein on health outcomes. However, it remains unclear what specific host responses drive the health effects of dietary proteins from different plant and animal sources. Additionally, which specific host responses are mediated by interactions of dietary protein source with the gut microbiota and which host responses are caused by dietary proteins directly is not well understood. We used metaproteomics to quantify dietary, host, and microbial proteins in fecal samples of conventional and germ-free mice fed purified dietary protein from six different plant and animal sources, including casein, egg-white, soy, brown rice, pea, and yeast. We characterized differences in the host fecal proteome across the six dietary protein sources as well as between the conventional and germ-free mice for each source to determine how the host responds to the different dietary protein sources and the role of the gut microbiota in mediating these responses. We found that both the source of dietary protein and the presence or absence of the gut microbiota drive the host response to dietary protein source in the fecal host proteome. Host proteins pertaining to immune response, digestion, and barrier function were differentially abundant in different protein sources with and without the gut microbiota. These changes in the host response correlated with changes in microbial composition and differences in protein digestibility. Our results show how dietary protein sources, through their interactions with the gut microbiota, impact several aspects of host physiology.