Genetically Modified Lactococcus lactis Hypersecreting IL-1Ra Improves Glucose Metabolism and Modulates the Gut Microbiota in an Obese Mouse Model

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder and typically develops later in life due to systemic dysfunction in metabolic homeostasis and various factors related to β-cell inflammation. Interestingly, recent studies have proposed that intra-islet expression of inflammatory cytokines, particularly interleukin (IL)-1β, contributes to the pathogenesis of T2DM and have shown that blockade of IL-1β signaling improves glycemia and β-cell secretory function. We recently successfully constructed a genetically modified lactic acid bacteria (gmLAB) strain that hypersecretes recombinant mouse IL-1 receptor antagonist (rmIL-1Ra), that is, NZ-IL1Ra. In this study, we investigated how NZ-IL1Ra affects glucose metabolism using a mouse pancreatic β-cell line and diet-induced obese mouse model. We found that rmIL-1Ra purified from NZ-IL1Ra suppresses the expression of mouse pancreatic β-cell genes related to inflammation. In addition, the results of oral glucose tolerance tests revealed that administration of NZ-IL1Ra improves glucose metabolism, but the extent depends on the route of administration. Finally, microbiota analyses revealed increases in the abundances of two genera of Lachnospiraceae. These microbiota changes might also affect glucose metabolism in mice. Taken together, our results suggest that administration of NZ-IL1Ra may be a useful tool for improving glucose metabolism.