Gastric Control of the Intestinal Microbiome and IBD

Gastrokine-1 (Gkn1) is a small, protease resistant protein that is expressed exclusively and abundantly in the stomach.  It is secreted into the stomach mucus and is not found in the circulation.  We have found that Gkn1 travels the length of the gastrointestinal tract intact, and binds to a subset of microbes within the gut lumen. Gkn1-/- mice display subtle changes in gene expression in colonic tissue, suggesting that Gkn1 impacts colonic physiology. Gkn1-/- mice have markedly reduced body fat and do not gain weight on a high fat diet, compared to Gkn1+/- littermates.  The microbiome of Gkn1-/- mice is resistant to high fat diet-induced changes in the microbiome and maintains the typical ratio of Bacteroidetes:Firmicutes seen in Gkn1+/- or Gkn1-/- mice on a regular chow diet.  Gkn1-/- mice are exquisitely sensitive to DSS-induced colitis.  Gkn1 is anti-amyloidogenic and, consistent with this, we find that Gkn1 prevents bacterial biofilm formation in vitro.  We hypothesize that the Gkn1-/- microbiome is resistant to diet induced modification due to the community stability provided by biofilm formation in the gut.  Thus, a highly stable protein made in the stomach impacts the colonic microbiome and intestinal health.  This suggests that eating Gkn1 could provide a benefit for patients with intestinal mucosal injury, or that eating anti-Gkn1 antibody could promote weight loss or prevent weight gain. These findings have implications for patients with iatrogenic lumenal discontinuity between the intestine and stomach.