Evaluation of the intestinal microbioma profile and of the therapeutic potential of intervention strategies in the immunopathogeny of type 1 and 2 Diabetes

• Grant number: 18/14815-0
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Duration: May 01, 2019 - April 30, 2025
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Daniela Carlos Sartori
• Grantee: Daniela Carlos Sartori
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Celio Lopes Silva ; Flaviano dos Santos Martins ; João Santana da Silva ; Maria Cristina Foss de Freitas ; Niels Olsen Saraiva Câmara ; Rita de Cassia Aleixo Tostes Passaglia ; Vânia Luiza Deperon Bonato
• Associated research grant: 12/10395-0 - Role of NLRs receptors in immunoregulation mechanisms of the type 1 and 2 diabetes: identification of potential therapeutic targets, AP.JP
• Associated scholarship(s): 23/03750-2 - Cultivation and growth of probiotics (natural and recombinant) for application in experimental models of DM1 and DM2, BP.TT; 21/14793-9 - EXTERNAL MEMBRANE VESICLES (OMVS) OF AKKERMANSIA MUCINIPHILA AS A THERAPEUTIC INTERVENTION IN TYPE 2 DIABETES EXPERIMENTAL, BP.PD; 22/02762-4 - Effect of the administration of Lactococcus lactis expressing HSP65 on the induction of tolerance mediated by regulatory T cells and on the immunoregulation of DM1 in an experimental model., BP.DR; + associated scholarships 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, BP.MS; 21/13597-1 - Evaluation of the therapeutic potential of Lactococcus lactis expressing IL-17 in Obesity-induced type 2 Diabetes, BP.DR; 22/03449-8 - Cultivation and growth of probiotics (natural and recombinant) for application in experimental models of DM1 and DM2, BP.TT; 20/05514-6 - Evaluation of the immunomodulatory potential of the Akkermansia muciniphila probiotic as preventive/therapeutic strategy in T1D, BP.PD; 19/22688-0 - Probiotics (natural and recombinant) cultivation and growth and their application in DM1 and DM2 experimental models, BP.TT; 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, BP.MS - associated scholarships

Abstract

The etiology of DM is multifactorial related to genetic, environmental, food and metabolic factors. Several findings reveal an association between diet, gut Dysbiosis and the activation of immunological mechanisms, which results in the pathophysiology of type 1 and type 2 Diabetes Mellitus (T1D and T2D). It is shown that probiotics control the gut Dysbiosis, improve the intestinal permeability and provide an epithelial barrier function. More recent studies have evidenced that probiotics also exert a variety of local and systemic immunomodulatory effects through mucosal immunity stimulation, short chain fatty acid production and generation of regulatory T lymphocytes. In this context, we found reduced abundance of probiotic bacteria, in special Akkermansia muciniphila and Bifidobacterium sp., during the T1D. The administration of the inulin prebiotic was able to increase the A. muciniphila in the gut and to confer protection to this disease. Based on these evidence, through preclinical studies, we will to evaluate the effect of recomposition/modulation strategies of gut microbiome using these natural probiotics, recombinant (Lactococcus lactis hsp65 and IL-6) and prebiotics, such as to determine the immunoregulatory mechanisms that could prevent the onset or delay the progression of T1D and T2D. A longitudinal study will also be conducted in newly diagnosed diabetic patients to identify changes in the intestinal microbiome and correlate with clinical and immunological parameters during the disease progression in order to elucidate new biomarkers for diagnosis or treatment. The search for immunoregulation alternatives based on probiotics is very promising, since its production would have a low cost and would be safe for therapeutic application. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ELIAS-OLIVEIRA, JEFFERSON; LEITE, JEFFERSON ANTONIO; PEREIRA, ITALO SOUSA; GUIMARAES, JHEFFERSON BARBOSA; MANSO, GABRIEL MARTINS DA COSTA; SILVA, JOAO SANTANA; TOSTES, RITA CASSIA; CARLOS, DANIELA. NLR and Intestinal Dysbiosis-Associated Inflammatory Illness: Drivers or Dampers?. FRONTIERS IN IMMUNOLOGY, v. 11, AUG 11 2020. (18/14815-0, 12/10395-0)

SILVA, CARLA B. P.; ELIAS-OLIVEIRA, JEFFERSON; MCCARTHY, CAMERON G.; WENCESLAU, CAMILLA F.; CARLOS, DANIELA; TOSTES, RITA C.. Ethanol: striking the cardiovascular system by harming the gut microbiota. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 321, n. 2, p. H275-H291, AUG 2021. (18/14815-0, 13/08216-2)

COSTA, FREDERICO R. C.; LEITE, JEFFERSON A.; RASSI, DIANE M.; DA SILVA, JOSIANE F.; ELIAS-OLIVEIRA, JEFFERSON; GUIMARAES, JHEFFERSON B.; FOSS-FREITAS, MARIA C.; CAMARA, NIELS O. S.; PONTILLO, ALESSANDRA; TOSTES, RITA C.; et al. LRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabete. CELL REPORTS, v. 35, n. 8, MAY 25 2021. (12/10395-0, 18/14815-0, 13/08216-2)