Lactococcus lactis expressing IL-6 supplementation promotes the Tr17 regulatory cell differentiation in the gut and alleviates the metabolic and inflammatory dysfunction in an experimental model of diet-induced type 2 diabetes.

Obesity and metabolic syndrome are linked to chronic inflammation and insulin resistance (IR) in adipose tissue (AT), contributing to type 2 diabetes (T2D). Regulatory T cells expressing RORγt and Foxp3 (Tr17 cells) have immunosuppressive functions, but the role of IL-6 in their differentiation and in obesity-induced T2D is unclear. This study investigated whether recombinant Lactococcus lactis expressing IL-6 (L. lactis-R) could elicite Tr17 cells in the gut and improve metabolic dysfunction. The contribution of interleukin-10 (IL-10), which promotes anti-inflammatory M2 macrophages, was also examined. In vitro, IL-6 generates CD4+Foxp3+ T cells from Foxp3GFP mice into Tr17 cells positive for CCR6 receptor expression. In C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks, L. lactis-R supplementation did not affect body weight or AT mass, but reduced fasting blood glucose, improved insulin sensitivity, restored intestinal barrier integrity, and significantly decreased bacterial translocation. L. lactis-R supplementation also increased Tr17 cells in the colon and caused their accumulation in visceral AT, associated with a higher proportion of anti-inflammatory M2 macrophages. Furthermore, adoptive transfer of Tr17 cells into IL-10-deficient mice improved insulin sensitivity, reinforced the epithelial barrier, and increased adiponectin levels, demonstrating their protective role against obesity-induced T2D. In conclusion, L. lactis-R supplementation attenuates bacterial translocation, reduces metainflammation, and improves insulin resistance in T2D. These findings highlight the critical role of IL-10-producing Tr17 cells in maintaining intestinal and metabolic homeostasis and suggest that targeting this pathway may represent a promising therapeutic strategy for obesity-associated metabolic disorders such as T2D.