Absence of conventional dendritic cells type 1 (cDC1) impairs intestinal homeostasis and permeability and leads to the development of obesity

Abstract

Abstract The maintenance of intestinal homeostasis depends on a complex interaction between microbiota, intestinal epithelial barrier and immune system. Alteration in of one of these components could lead to the development of chronic inflammatory diseases such as inflammatory bowel diseases (IBD). Recent studies have associated obesity with more severe IBD. In obesity, pro-inflammatory macrophages accumulate in adipose tissue and their numbers correlate with inflammation and insulin resistance. BATF3 is a transcription factor implicated in the development of conventional dendritic cells type 1 (cDC1). Here, we show that aged Batf3−/− mice developed obesity as characterized by increased body weight, fasting glucose levels (Batf3−/−: 213, WT: 115 mg/dl, p < 0.005), size of abdominal white adipocyte, and development of hepatosteatosis. We also observed increased intestinal permeability in Batf3−/− mice (FITC-dextran gavage; p < 0.01) suggesting impaired epithelial barrier function. Feeding high-fat diet for 2 months further enhanced the metabolic phenotype in Batf3−/− mice, leading to increased fasting glucose levels (300 vs. 246 mg/dl, p < 0.05), and increased adipocyte size. Moreover, during high-fat diet Batf3−/− mice were more susceptible to dextran sulfate sodium (DSS) colitis with more severe cecal inflammation, increased gut and mesenteric fat M1 macrophages (p < 0.05). Our data suggest that deficiency of the transcription factor BATF3 and lack of cDC1 alters the intestinal epithelial barrier, promotes the development of obesity, and increases susceptibility to DSS. In conclusion, BATF3-dependent cDC1 play an important role in maintaining the intestinal epithelial barrier and are protective for the development of obesity.