Organ-specific autoimmune diseases like Type 1 Diabetes and Multiple Sclerosis result from the interplay between environmental and genetic factors. Recent studies indicate that activation of self-reactive T cells and alterations of immune regulatory pathways may occur at the intestinal level and maybe modulated by environmental factors that modify the gut environment such as diet and microbiota composition. Our goal is to determine whether the intestinal environment plays a role in the pathogenesis of autoimmune diseases such as T1D and MS and to promote immune tolerance in the gut through diet and microbiota modifications for preventions/ treatment of those extraintestinal autoimmune disorders.
Type 1 Diabetes (T1D) and Multiple Sclerosis (MS) are autoimmune diseases mediated by self-reactive T cells that destroy insulin-producing b cells and the myelin sheaths. Both genetic and environmental factors are involved in the pathogenesis of T1D and MS but the mechanisms governing the activation of autoimmune T cells are still largely unknown. Growing evidence supports the notion that the gut environment influences the pathogenesis of extra-intestinal autoimmune diseases such as T1D and MS. Specifically, an inflammatory intestinal environment induced by diet and/or commensal microbiota composition can promote activation of autoimmune T cells including islet-specific and myelin-specific self-reactive T lymphocytes within the gut mucosa and/or systemically, thereby triggering T1D or MS pathogenesis. Recently, our group found that humans affected by T1D and MS have alterations of gut mucosal immunity with inflammatory immunological profiles. Moreover, we demonstrated in pre-clinical models of T1D that an inflammatory gut environment promotes activation of self (islet)-reactive T cells by inducing loss of gut barrier continuity and abnormal interaction between immune cells and commensal gut microbiota leading to activation of self(islet)-reactive T cells and autoimmune diabetes.
We are currently investigating in humans and animal models of T1D and MS how gut inflammation, modification of the microbiota composition and intestinal and mucus barrier integrity affect the autoimmune pathogenesis of T1D and MS. Furthermore, we are exploiting the capacity of probiotic and prebiotic therapeutic approaches to modulate T1D pathogenesis in designed clinical trials.
Liang W, Enée E, Andre-Vallee C, Falcone M, Sun J, Diana J. Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota against Pancreatic Autoimmunity. Gastroenterology 2022 doi.org/10.1053/j.gastro.2021.12.272.
Fousteri G, Rodrigues EM, Giamporcaro G, Falcone M. A Machine Learning Approach to predict response to immunotherapy in Type 1 Diabetes. Cell Mol Immunol. 2021 March; 18(3):515-517. doi: 10.1038/s41423-020-00594-4.
Falcone M, Fousteri G. Role of the PD-1/PD-L1 dyad in the maintenance of pancreatic immune tolerance for prevention of Type 1 Diabetes. Front Endocrinol. 2020 Aug 19; 11:569
Antonini M, Lo Conte M, Sorini C, Falcone M. How the interplay between the commensal microbiota, gut barrier integrity and mucosal immunity regulates brain autoimmunity. Front Immunol. 2019 Aug 16; 10:1937
Sorini C, Cosorich I, Lo Conte M, De Giorgi L, Facciotti F, Lucianò R, Rocchi M, Ferrarese R, Sanvito F, Canducci F, Falcone M. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proc Natl Acad Sci U S A. 2019 Jul 23; 116(30):15140-15149.
Jofra T, Galvani G, Cosorich I, De Giorgi L, Annoni A, Vecchione A, Sorini C, Falcone M, Fousteri G. Experimental colitis in IL-10-deficient mice ameliorates in the absence of PTPN22. Clin Exp Immunol. 2019 Jun 13. doi: 10.1111/cei.13339. PMID: 31194881
De Giorgi L, Sorini C, Cosorich I, Ferrarese R, Canducci F, Falcone M. Increased iNKT17 cell frequency in the intestine of non-obese diabetic mice correlates with high Bacterioidales and low Clostridiales abundance. Front Immunol. 2018 Jul 30;9:1752.
Sorini C, Cosorich I, Falcone M. New therapeutic perspective in Type 1 Diabetes: dietary interventions prevent β cell-autoimmunity by modifying the gut metabolic environment. Cell Mol Immunol. 2017 Dec; 14 (12):951-953.
Cosorich I, Dalla-Costa G, Sorini S, Ferrarese R, Messina MJ, Dolpady J, Radice E, Mariani A, Testoni PA, Canducci F, Comi G, Martinelli V and Falcone M. High frequency of intestinal Th17 cells correlated with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017 Jul 12; Vol.3, no.7, e1700492