Mechanism of Regulation of NaCl Homeostasis in the Distal Colon During Obesity

Obesity is characterized by low-grade chronic inflammation, similar to the pathophysiology of inflammatory bowel disease (IBD) and colon cancer. IBD, which includes Crohn's disease and ulcerative colitis, is becoming increasingly common in obese individuals. Our previous research documented that both IBD and obesity involve disrupted NaCl homeostasis in the small intestine. The present study investigated how obesity affects NaCl homeostasis in the distal colon, using the Zucker (<i>Lepr^fa</i>) rat as a genetic model of obesity. The functional and molecular alterations in NaCl homeostasis were evaluated through radioactive uptakes, RT-qPCR, and Western blot studies. We found a significant reduction in Cl absorption via Cl^-/HCO₃^- exchanger, Downregulated in Adenoma (DRA) in the distal colon of obese rats compared to lean controls. This reduction was due to a decrease in the maximum transport capacity (V_max) of DRA, with no change in the affinity of the exchanger for chloride. DRA mRNA and protein levels were also downregulated in obese animals. In contrast, Na absorption via Na⁺/H⁺ exchanger and its expression remained unchanged. These findings are the first to demonstrate that DRA is significantly impaired in the distal colon due to obesity. This suggests that net NaCl absorption in the distal colon is compromised in obesity, potentially increasing the risk for IBD and colon cancer.