Adipocyte-Epithelial Interactions and Crohn's Disease - An Emerging Drug Target

Visceral fat accumulation as observed in Crohn's disease and obesity is linked to chronic gut inflammation, suggesting that accumulation of gut adipocytes can trigger local inflammatory signaling. However, direct interactions between intestinal epithelial cells (IECs) and adipocytes have not been investigated, in part because IEC physiology is difficult to replicate in culture. In this study, we originally prepared intact, polarized, and cytokine responsive IEC monolayers from primary or induced pluripotent stem cell-derived intestinal organoids by simple and repeatable methods. When these physiological IECs were co-cultured with differentiated adipocytes in Transwell, pro-inflammatory genes were induced in both cell types, suggesting reciprocal inflammatory activation in the absence of immunocompetent cells. These inflammatory responses were blocked by nuclear factor-κB or signal transducer and activator of transcription 3 inhibition and by anti-tumor necrosis factor- or anti-interleukin-6-neutralizing antibodies. Our results highlight the utility of these monolayers for investigating IEC biology. Furthermore, this system recapitulates the intestinal epithelium–mesenteric fat signals that potentially trigger or worsen inflammatory disorders such as Crohn's disease and obesity-related enterocolitis.
Highlights • Intact intestinal epithelial monolayers are developed from primary or induced pluripotent stem cell-derived organoids. • Intestinal epithelial cells and adipocytes mutually enhance inflammatory responses in the absence of immune cells. • The inflammatory responses are mediated by nuclear factor-κB and signal transducer and activator of transcription 3. One of the inflammatory bowel diseases, Crohn's disease (CD), frequently accompanies mesenteric fat accumulation and inflammation; however, the biological significance has not been elucidated so far. Here, we co-cultured intact intestinal epithelial cells developed from mouse and human intestinal organoids with mature adipocytes, and found that inflammation responses were reciprocally induced. The responses were blocked by small molecule compounds and neutralizing antibodies. Our results indicate mesenteric fat abnormalities may lead to the initiation and/or progression of CD, and provide the possibility that disconnecting the inflammatory signaling would be a promising approach to treat CD.