Molecular Mechanisms Driving Peinosis of the Colon in Obesity

Obesity, driven largely by the overconsumption of foods high in fats and sugars, is now more prevalent than at any other time in human history and is a major risk factor for numerous chronic diseases that impair quality of life and shorten lifespan. While a high-fat, high-protein (HFHP) diet contributes to obesity, our findings reveal that it also causes shortening of the colon, a condition we term peinosis, whose underlying mechanisms and clinical significance have not been previously defined. In this study, we show that HFHP feeding induces a dysbiotic gut microbiome, elevates colonic inflammatory cytokines, suppresses stem cell–mediated epithelial regeneration, promotes apoptosis, and upregulates survivin—an anti-apoptotic protein implicated in tumorigenesis. Together, these alterations generate a microenvironment that may predispose to inflammatory bowel disease and colorectal cancer. Conversely, shifting from an HFHP to a fiber-rich diet reduces weight, increases colon and cecum length, promotes the restoration of a beneficial microbiome and metabolome, stimulates intestinal stem cell renewal, reduces apoptosis and inflammation, and decreases survivin expression. Remarkably, this shift leads to stabilization of the microbiome and reversal of tissue damage within approximately 30 days. These findings underscore the powerful regenerative potential of dietary fiber and its role in protecting intestinal health. They also highlight the gut as a dynamic, diet-responsive organ system and position dietary fiber as a critical modulator in preventing diet-induced intestinal diseases, including IBD and colorectal cancer.