Role of Macrophages and B Cells in the Resolution of T2DM Following Bariatric Sleeve Gastrectomy

Abstract

Sleeve gastrectomy (SG) results in significant improvements in glycemic control in obese patients with type 2 diabetes (T2DM). Animal models of diet-induced obesity have demonstrated roles for numerous immune cell subsets in the pathogenesis of insulin resistance, but the effects of SG on immunity are unknown. We hypothesized that SG improves insulin sensitivity by altering intestinal and splenic immune cell milieu. C57Bl/6J mice fed normal (lean) or high fat chow (obese) underwent SG (lean n=4; obese n=10) or sham (lean n=5; obese n=8) surgery. Oral glucose tolerance tests (OGTT) were performed at 2 weeks post-op. Major immune cell compartments in the jejunum, liver, and spleen were then profiled using the novel time-of-flight mass cytometry (CyTOF) platform. SG improved glycemic control by OGTT in lean and obese mice and multivariate viSNE analysis of CyTOF data demonstrated changes in B cell and macrophage populations after SG. SG reduced splenic CD19+CD21+CD23+ B cells by 27% (p=0.0009) in obese and 45% in lean mice (p=0.04) compared to shams. Further, obese-SG mice exhibited decrease in jejunal CD19+CD21+CD23+ B cells (p=0.009) and increase (p=0.03) in MHCIInegF4/80+CD11b+ splenic macrophages compared to obese-shams. Splenic and jejunal macrophages in obese-SG mice also exhibited elevated anti-inflammatory M2 polarization. We therefore conclude that SG improves glycemic control in association with decreased splenic follicular B cells in obese and lean mice, suggesting a weight-independent effect of surgery. In obese mice, SG also promotes increased anti-inflammatory M2 macrophage polarization, which may represent a downstream effector phenotype. Reduction of pathologic inflammation may therefore contribute to the metabolic benefits of SG and support a role for immune-targeted therapies for diabetes.