Background and Aims: Phosphate homeostasis is critical for many physiological functions. Up to 85% of phosphate is stored in bone and teeth. The remaining 15% is distributed in cells. Phosphate absorption across the brush-border membrane (BBM) of enterocytes occurs mainly via a sodium-dependent pathway, which is mediated by type IIb sodium-phosphate cotransporters (NaPi-IIb). Patients of inflammatory bowel diseases (IBDs) suffer not only from diarrhea and nutrient malabsorption but also from bone loss. About 31-59% of IBD patients develop bone disorders. Since the intestine is a primary location for dietary phosphate absorption, it is logical to postulate that there is an inverse relationship between gastrointestinal disorders and phosphate transport, which in turn contributes to bone disorders observed in IBD patients. Methods: Phosphate absorption, NaPi-IIb expression was studied with BBMVs isolated from TNBS animals as well as in Caco-2 cells. The mechanism of TNF- downregulation of NaPi-IIb expression was investigated by luciferase assay, gel mobility shift assay, coimmunoprecipitation. Results: Intestinal phosphate absorption mediated by sodium-phosphate cotransporter (NaPi-IIb) was reduced both in TNBS colitis and in TNF- treated cells. Transient transfection indicated that TNF- inhibits NaPi-IIb expression by reducing NaPi-IIb basal promoter activity. GMSAs identified NF1 protein as an important factor in TNF- mediated NaPi-IIb downregulation. Signaling transduction study and coimmunopreciptation suggested that TNF- interacts with EGFR to activate ERK1/2 pathway. Conclusions: Intestinal phosphate absorption mediated by NaPi-IIb protein is reduced in colitis. This inhibition is mediated by proinflammatory cytokine, TNF-, through a novel molecular mechanism involving TNF-/EGFR interaction.