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
• Start date: May 01, 2019
• End date: April 30, 2026
• 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): 24/06798-9 - INVESTIGATION OF THE EFFECT OF OUTER MEMBRANE VESICLES (OMVs) FROM AKKERMANSIA MUCINIPHILA ON M2 MACROPHAGE DIFFERENTIATION AND FUNCTION VIA TLR2/TLR9 AND THEIR THERAPEUTIC POTENTIAL IN TYPE 2 DIABETES., BP.PD; 24/23656-3 - Evaluation of the role of butyrate via the GPR109 receptor in the differentiation of follicular regulatory T lymphocytes and immunoregulation of DM1 in an experimental model, BP.MS; 24/13834-1 - Probiotics (natural and recombinant) cultivation and growth and their application in DM1 and DM2 experimental models, BP.TT; + associated scholarships 24/13737-6 - Construction of a biorepository of biological samples from patients with type 1 diabetes for analysis of the functional profile of dendritic cells and evaluation of the intestinal microbiota, BP.TT; 23/12630-0 - Evaluation of the role of IL-22 in the modulation of type 1 diabetes by Akkermansia muciniphila supplementation, BP.IC; 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; 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

(9)

(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)

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)

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)

LEITE, JEFFERSON ANTONIO; MENEZES, LUISA; MARTINS, ELOISA; RODRIGUES, TAMARA SILVA; TAVARES, LUCAS; EBERING, ANNA; SCHELMBAUER, CARSTEN; CEBINELLI, GUILHERME C. MARTELOSSI; ZININA, VALERIYA; GOLDEN, ARTEMIY; et al. AIM2 promotes T_H17 cells differentiation by regulating RORγt transcription activity. ISCIENCE, v. 26, n. 11, p. 19-pg., 2023-10-14. (18/14815-0, 17/05264-7, 19/19435-3)

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. NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes. CELL REPORTS, v. 35, n. 8, p. 15-pg., 2021-05-25. (13/08216-2, 12/10395-0, 18/14815-0)

MANSO, GABRIEL MARTINS DA COSTA; ELIAS-OLIVEIRA, JEFFERSON; GUIMARAES, JHEFFERSON BARBOSA; PEREIRA, ITALO SOUSA; RODRIGUES, VANESSA FERNANDES; BURGER, BEATRIZ; FANTACINI, DAIANNE MACIELY CARVALHO; DE SOUZA, LUCAS EDUARDO BOTELHO; RODRIGUES, HOSANA GOMES; BONATO, VANIA LUIZA DEPERON; et al. Xenogeneic mesenchymal stem cell biocurative improves skin wounds healing in diabetic mice by increasing mast cells and the regenerative profile. REGENERATIVE THERAPY, v. 22, p. 11-pg., 2023-01-09. (19/22013-3, 18/14815-0)

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)

NORONHA, NATALIA YUMI; MARTINS, LUZANIA DOS SANTOS; WATANABE, LIGIA MORIGUCHI; PINHEL, MARCELA AUGUSTA DE SOUZA; RODRIGUES, GUILHERME DA SILVA; SCHNEIDER, ISABELLE MELLO; NICOLETTI, CAROLINA FERREIRA; DELFINO, HEITOR BERNARDES PEREIRA; CARLOS, DANIELA; NONINO, CARLA BARBOSA. Ability of Hypocaloric Diets to Change Nutrient-Phyla Associations after 8 Weeks of Intervention. OBESITIES, v. 4, n. 2, p. 10-pg., 2024-06-01. (12/10395-0, 18/14815-0, 18/24069-3, 20/08687-9)

MACHADO, MELISSA S. G.; RODRIGUES, VANESSA F.; BARBOSA, SARA C.; ELIAS-OLIVEIRA, JEFFERSON; PEREIRA, ITALO S.; PEREIRA, JESSICA A.; PACHECO, THAILLA C. F.; CARLOS, DANIELA. IL-1 Receptor Contributes to the Maintenance of the Intestinal Barrier via IL-22 during Obesity and Metabolic Syndrome in Experimental Model. MICROORGANISMS, v. 12, n. 8, p. 14-pg., 2024-08-01. (18/14815-0, 22/06787-1)

GUIMARAES, JHEFFERSON BARBOSA; RODRIGUES, VANESSA FERNANDES; PEREIRA, ITALO SOUSA; MANSO, GABRIEL MARTINS DA COSTA; ELIAS-OLIVEIRA, JEFFERSON; LEITE, JEFFERSON ANTONIO; WALDETARIO, MARIANA CAMILA GONCALVES MIRANDA; DE OLIVEIRA, SARAH; GOMES, ARILSON BERNARDO DOS SANTOS PEREIRA; FARIA, ANA MARIA CAETANO; et al. Inulin prebiotic ameliorates type 1 diabetes dictating regulatory T cell homing via CCR4 to pancreatic islets and butyrogenic gut microbiota in murine model. Journal of Leukocyte Biology, v. 115, n. 3, p. 14-pg., 2023-11-21. (19/13858-0, 18/14815-0)