Effects of prebiotic inulin supplementation on butyrate production and immunoregulation of type 1 diabetes in an experimental model

Author(s)

Jhefferson Barbosa Guimarães

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2021-09-13

Examining board members

Daniela Carlos Sartori; Joilson de Oliveira Martins

• Advisor: Daniela Carlos Sartori

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the progressive loss of self-tolerance to insulin-producing pancreatic β-cell antigens, which leads to selective destruction of these cells by activated autoreactive lymphocytes as a result of inflammation in the pancreatic islets (insulitis). Several studies have demonstrated the relationship between the breakdown of intestinal immune tolerance and various diseases, such as obesity, allergies, inflammatory bowel diseases, rheumatoid arthritis and type 1 and 2 diabetes. Supplementation with the prebiotic inulin can modulate the intestinal microbiota, favoring the increase of bacteria probiotics that, when metabolizing this fiber, produce short-chain fatty acids (SCFA), which are important in immunoregulation and maintenance of intestinal homeostasis. Thus, this study aimed to evaluate whether supplementation with the prebiotic inulin protects the development of DM1 in mice in the multiple dose model induced by streptozotocin (STZ). Additionally, we aimed to elucidate whether the beneficial effect is mediated by the modulation of the intestinal microbiota and SCFA production. Monitoring of clinical, metabolic and histopathological parameters was performed in diabetic mice supplemented or not with inulin. The animals supplemented with inulin had total protection against the development of DM1, since 100% of the animals did not develop the disease after administration of STZ (STZ+INU). After inulin supplementation, the animals exhibited body weight gain, improved glycemic control, reduced pancreatic inflammatory infiltrate and normalization of serum insulin levels compared to diabetic animals on standard diet (STZ+DP). The STZ+INU animals showed greater mucus production in the colon associated with the prevalence of genera Bifidobacterium, Clostridium cluster IV and Akkemansia muciniphila in the intestinal microbiota. In the cecal lymph node (LC) of STZ+INU animals, we observed a decrease in CD4+Foxp3+ Treg cells expressing CCR4+. In parallel, we demonstrated a significant increase in the gene expression of tolerogenic dendritic cell markers such as retinaldehyde dehydrogenase (Aldh1e2) and indoleamine 2,3-dioxygenase (IDO) enzyme, as well as increased production of butyrate in the fecal content of the colon of animals supplemented with inulin. In pancreatic tissue, we verified an increase in Treg Foxp3+CCR4+ cells and protein expression of CCL17. Together, our findings showed the efficacy of inulin supplementation as a nutritional intervention in the prevention of type 1 diabetes in an experimental model, through the migration of Treg cells via CCR4 to the pancreas and high production of butyrate by the intestinal microbiota. (AU)

• FAPESP's process: 19/13858-0 - Effect of administration of Bifidobacterium longum, with or without inulin prebiotic, on the production of AGCC and on the immunoregulation of DM1 in an experimental model
• Grantee: Jhefferson Barbosa Guimarães
• Support Opportunities: Scholarships in Brazil - Master