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| Author(s): |
Thaílla Cristina Faria Pacheco
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2024-12-10 |
| Examining board members: |
Daniela Carlos Sartori;
Pedro Manoel Mendes de Moraes Vieira
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| Advisor: | Daniela Carlos Sartori |
| Abstract | |
Obesity and type 2 diabetes (T2D) are characterized by chronic low-grade inflammation designed of metainflammation, particularly in visceral adipose tissue (VAT), where macrophages play a significant role in insulin resistance. Natural or recombinant probiotics have shown beneficial effects on metabolic diseases, mainly through modulation of the gut microbiota, maintenance of colonization against pathogenic bactéria and induction of immunoregulatory mechanisms. IL-6, a pleiotropic cytokine, is involved in immune system regulation and energy metabolism. Recently, IL-6 has been associated with the generation of RORγt+ Foxp3+ regulatory T cells (known as Tr17 cells), which exhibit strong suppressive activity and are predominantly present in the colon. In this context, this study aimed to assess whether the recombinant probiotic Lactococcus lactis, genetically modified to express IL-6, represents a potential immunobiotic to prevent or attenuate inflammatory and metabolic parameters associated with obesity and T2D after high-fat diet (HFD) intake. Initially, we demonstrated that IL-6 induced in vitro differentiation of Tr17 cells, significantly increased CCR6 expression, and elevated the production of IL-10 and IL-17 by these cells. Subsequently, in the HFD-induced obesity and T2D model, we observed a significant reduction in Tr17 cells in the cecal lymph node (CLN) and cytokines, such as IL-6 and IL-10, in the colon. To better understand the role of IL-6, IL-6-deficient mice (IL-6-/-) fed with HFD were used; these mice showed no changes in total body weight, body composition or adiposity index, but had increased hyperglycemia, glucose intolerance and elevated serum cholesterol levels. On the other hand, supplementation with L. lactis expressing IL-6 improved the glycemic and lipid profile, evidenced by lower glycemia, improved glucose tolerance and reduced serum cholesterol levels compared to diabetic WT animals without supplementation. Additionally, L. lactis expressing IL-6 supplementation caused reduced intestinal permeability and promoted intestinal epithelial cell proliferation. Furthermore, supplementation with L. lactis expressing IL-6 restored the Tr17 cell population in the CLN and VAT and induced the polarization of macrophages to the M2 profile in VAT. Finally, we investigated the potential role of IL-10 as a mechanism of action for Tr17 cells. IL-10 deficient mice (IL-10-/-) exhibited higher insulin resistance, lower levels of adiponectin, increased intestinal permeability and bacterial translocation in the VAT, as well as a significant decrease in M2 macrophages in the VAT compared to WT mice supplemented after HFD. However, the adoptive transfer of Tr17 cells to IL-10-deficient mice and supplementation partially reversed metabolic and inflammatory dysfunction, including a significant increase in adiponectin levels, reduced serum cholesterol levels, lower bacterial translocation and a significant increase in M2 macrophage population in VAT. In summary, the data suggest that L. lactis expressing IL-6 is a promising strategy to reduce metainflammation and improve insulin sensitivity associated with intestinal Tr17 cell differentiation and IL-10 production in the HFD-induced T2D experimental model. (AU) | |
| FAPESP's process: | 22/09797-8 - Study of the effects of Lactococcus lactis expressing IL-6 on the intestinal Th17 response and prevention of obesity-induced experimental T2D |
| Grantee: | Thaílla Cristina Faria Pacheco |
| Support Opportunities: | Scholarships in Brazil - Master |