Loss of Paneth cells dysregulates gut ILC subsets and enhances weight gain response to high fat diet in a mouse model

Abstract

AbstractObesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9ΔIECmice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9ΔIECmice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9ΔIECmice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9ΔIEC. Transplantation of fecal materials from Sox9ΔIECmice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.