Gastrointestinal dysbiosis caused by a lack of Paneth cells promotes diet-induced obesity and trafficking of inflammatory immune cells into adipose tissues.

Abstract

Abstract Paneth cells regulate many aspects of gastrointestinal health through the antimicrobial products and cytokines they produce. Loss or defective Paneth cell function leads to dysbiosis and is one of the causes of Inflammatory Bowel Disease (IBD). The prevalence of obesity is growing in the general population and among recently diagnosed IBD patients, leading to the speculation that obesity increases IBD incidence, but the underlying mechanisms remain to be elucidated. We address whether gastrointestinal dysbiosis caused by a lack of Paneth cells influences obesity. Analysis of their fecal bacterial composition showed that Sox9ΔIEC mice, which lack Paneth cells due to a Sox9 gene deletion within the intestinal epithelium, have more Firmicutes bacteria (p<0.001) in their feces. These mice were then fed a high fat diet for 13 weeks. When Sox9ΔIEC mice were fed a high-fat diet, they exhibited increased bacterial dysbiosis. Furthermore, intestinal permeability measured by FITC-dextran absorption in vivo was increased (p<0.05) in Sox9ΔIEC mice. Finally, Sox9ΔIEC mice gained weight faster and ultimately became more obese than the wild-type mice and displayed impaired glucose tolerance (p<0.0001) indicating the presence of a metabolic disorder. The Sox9ΔIEC mice developed larger abdominal fats, which included increased numbers of inflammatory immune cells such as macrophages (p<0.05), neutrophils (p<0.05), and T cells (p<0.05). Interestingly, B cells were the most increased (p<0.0001) immune cell population in abdominal fat tissues. These results suggest a new role for Paneth cells as regulators of diet-induced obesity via their effect on gastrointestinal dysbiosis and immune cell infiltration of omental fat tissues.