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

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Pacheco, Thailla Cristina Faria ; Barbosa, Sara Candida ; Elias-Oliveira, Jefferson ; Pereira, Italo Sousa ; Rodrigues, Vanessa Fernandes ; Machado, Melissa Santana Gonsalez ; Rios, Wendy Martin ; Ramos, Anderson dos Santos ; Pereira, Jessica Assis ; Nakama, Raquel Pires ; Tostes, Rita Cassia ; Bermudez-Humaran, Luis Gilberto ; Carlos, Daniela

• Tipo de documento: Artigo Científico
• Fonte: Life Sciences; v. 384, p. 18-pg., 2026-01-01.

Resumo

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 ROR gamma t 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 antiinflammatory 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 trans-location. 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. (AU)

• Processo FAPESP: 22/09797-8 - Estudo dos efeitos de Lactococcus lactis expressando IL-6 na resposta Th17 intestinal e prevenção do DM2 experimental induzido por obesidade
• Beneficiário: Thaílla Cristina Faria Pacheco
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/14815-0 - Estudo do perfil do microbioma intestinal e do potencial terapêutico de estratégias de intervenção na imunopatogenia do Diabetes tipo 1 e 2
• Beneficiário: Daniela Carlos Sartori
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2