Gastrokine 1 (GKN1) is an 18kDa protein made in the stomach antrum, where it is secreted lumenally. Its expression is downregulated in H. pylori infection, non-steroidal anti-inflammatory drug (NSAID) use and gastric cancer. The secreted protein contains a BRICHOS domain, and is highly stable and protease resistant. Although it is highly conserved, its biological function is unknown. A role for GKN1 in maintaining GI mucosal integrity has been suggested. We have generated a GKN1-/- mouse to elucidate the function(s) of this protein. GKN1-/- and GKN1+/+ littermates were challenged with the NSAID piroxicam incorporated into chow at 200ppm. By day 7, all GKN1-/- had succumbed while all GKN1+/+ controls survived. By day 3, GKN1-/- develop more severe GI ulcers and inflammation, marked by neutrophil infiltration of the mucosa. To asses colonic protection, GKN1-/- mice were administered 2% DSS in drinking water. After DSS, GKN1-/- lose more weight and exhibit higher mortality. By day 3, GKN1-/- have increased colonic epithelial cell death. After recovering to day 13, GKN1-/- still show disrupted crypt formation. Administration of a 21 amino acid bioactive peptide of GKN1 acts therapeutically and prophylactically against mouse models of colitis. GKN1-/- are smaller and leaner than GKN1+/+ and resist weight gain on high fat diet. GKN1-/- have beige adipocytes in white adipose depots. Phyla-level microbiome sequencing shows that the microbiota remains stable when GKN1-/- are switched to HFD. GKN1 binds bacteria in the GI lumen. Overall our studies identify two novel functions for the stomach: protecting GI epithelial cell health and promoting weight gain and adiposity. Both roles are mediated by GKN1, likely via direct interaction of GKN1 with intestinal epithelial cells and/or gut bacteria.