D. A. Harris1, R. Subramaniam1, T. Brenner1, A. Tavakkoli1, E. G. Sheu1 1Brigham And Women’s Hospital,General Surgery,Boston, MA, USA
Introduction: Immune dysregulation in obesity causes insulin resistance. Sleeve Gastrectomy (SG) leads to diabetes remission through weight-loss dependent and independent mechanisms. We developed a model of SG in both lean and obese mice to characterize the weight-loss dependent and independent, global and organ-specific, immune cell changes following SG.
Methods: C57Bl/6J mice were divided into 4 groups: lean sham and SG (n=10,9); diet induced obese sham and SG (n=7,11). Weights and food intake were measured daily. Oral glucose tolerance testing (OGTT) was performed at 2 weeks. B, T, myeloid, NK, NKT, innate lymphoid cell (ILC) populations from jejunal, ileal, cecal, liver, and splenic tissues were profiled at 4 weeks using a 31-antibody panel and time-of-flight mass cytometry (CyTOF). ViSNE analysis and t-tests were used for comparisons.
Results: SG enhanced glucose tolerance in obese and lean mice (OGTT: p<0.01, 30/60 min), but only led to weight loss in obese mice. CyTOF analysis demonstrated a 15% and 10% reduction in splenic CD19+CD11BnegCD21+CD23+ B cells in obese (p=0.002) and lean (p=0.05) SG mice, respectively, compared to shams (figure 1). Further, there was a 14% reduction in mature IGM+IGD+ B cells in both obese (p=0.03) and lean (p=0.02) SG animals. Interestingly in the jejunum of obese, SG animals, there is a conserved, 63% reduction in the same CD21+CD23+ B cell population (p=0.009).
Further, there were population level changes that were unique to the obese phenotype. SG led to an increase in multiple 11B+ B cell subsets including a 2-fold increase in CD21-CD23+ (p=0.022) and a 4-fold increase in CD21+CD23- (p=0.01) B cells compared to shams.
Changes were also seen across myeloid populations. There was a 5.6- and 4.8-fold increase in splenic neutrophils in obese (p=0.06) and lean (p=0.025) SG compared to shams. In obese SG there was a 4.3-fold increase in cecal neutrophils as well. Finally, there was an increase in splenic, M2 (arginase 1+) macrophage polarization in all tested macrophage populations in obese SG animals (p<0.05).
There were no sustained T, NK, NKT, or ILC population changes in spleen, intestine, or liver in either lean and obese SG groups compared to their respective shams.
Conclusion: SG induces both weight-loss dependent and independent immune cell changes. There is a conserved reduction in total and follicular B cells among these changes, which are associated with improved glucose handling and are independent of weight-loss. B cells have been implicated in diet-induced obesity and diabetes. Thus, their downregulation may play a central role in mediating metabolic improvements following surgery.
