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TRIF deficiency protects non-obese diabetic mice from type 1 diabetes by modulating the gut microbiota and dendritic cells. 2018

Elke Gülden, and Chen Chao, and Ningwen Tai, and James A Pearson, and Jian Peng, and Monika Majewska-Szczepanik, and Zhiguang Zhou, and F Susan Wong, and Li Wen
Section of Endocrinology, School of Medicine, Yale University, New Haven, CT, 06519, USA.

The incidence of type 1 diabetes (T1D) is determined by both genetic and environmental factors. In recent years, the gut microbiota have been identified to be an important environmental factor that could modify diabetes susceptibility. We have previously shown that Myeloid differentiation primary response gene 88 (MyD88), a major adaptor protein downstream of most innate immune Toll-like receptor (TLR) signaling, is important for mediating diabetes susceptibility in the non-obese diabetic (NOD) mouse model of human T1D. Here we report the role of TIR-domain-containing adapter-inducing interferon-β (TRIF) in T1D development, as TRIF is an important adaptor protein downstream of TLR3 and TLR4 signaling. We found that TRIF-deficient (TRIF-/-) NOD mice were protected from development of diabetes, but only when housed with TRIF-deficient (TRIF-/-) NOD mice. When housed with TRIF-sufficient wild type (WT, i.e., TRIF+/+) NOD mice, the mice developed diabetes. We further investigated the gut microbiota as a potential cause for the altered diabetes development. Interestingly, TRIF-/-NOD mice had a different microbiota composition compared to WT NOD mice, only if they were housed with TRIF-/-NOD mice. However, the composition of gut microbiota in the TRIF-/-NOD mice was indistinguishable from WT NOD mice, if they were housed with WT NOD mice. The difference in the gut microbiota in TRIF-/-NOD mice, due to cohousing, accorded with the diabetes development in TRIF-/-NOD mice. Comparing the gut microbiota in TRIF-/- and WT NOD mice, we identified changes in percentage of Sutterella, Rikenella and Turicibacter species. Moreover, bacteria from WT NOD mice induced significantly stronger inflammatory immune responses in vitro compared to those from TRIF-/-NOD mice. Further immunological analysis revealed impaired function of dendritic cells and reduced T cell activation and proliferation in TRIF-/-NOD mice. Our data show that TRIF-deficiency protects NOD mice from diabetes development through alteration of the gut microbiota and reduced immune cell activation; however, that protection is over-ridden upon exposure to WT NOD bacteria. Therefore exposure to different microbiota can modify disease susceptibility determined by genetic factors related to innate immunity.

UI MeSH Term Description Entries
D008213 Lymphocyte Activation Morphologic alteration of small B LYMPHOCYTES or T LYMPHOCYTES in culture into large blast-like cells able to synthesize DNA and RNA and to divide mitotically. It is induced by INTERLEUKINS; MITOGENS such as PHYTOHEMAGGLUTININS, and by specific ANTIGENS. It may also occur in vivo as in GRAFT REJECTION. Blast Transformation,Blastogenesis,Lymphoblast Transformation,Lymphocyte Stimulation,Lymphocyte Transformation,Transformation, Blast,Transformation, Lymphoblast,Transformation, Lymphocyte,Activation, Lymphocyte,Stimulation, Lymphocyte
D003713 Dendritic Cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as SKIN and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process ANTIGENS, and present them to T-CELLS, thereby stimulating CELL-MEDIATED IMMUNITY. They are different from the non-hematopoietic FOLLICULAR DENDRITIC CELLS, which have a similar morphology and immune system function, but with respect to humoral immunity (ANTIBODY PRODUCTION). Dendritic Cells, Interdigitating,Interdigitating Cells,Plasmacytoid Dendritic Cells,Veiled Cells,Dendritic Cells, Interstitial,Dendritic Cells, Plasmacytoid,Interdigitating Dendritic Cells,Interstitial Dendritic Cells,Cell, Dendritic,Cell, Interdigitating,Cell, Interdigitating Dendritic,Cell, Interstitial Dendritic,Cell, Plasmacytoid Dendritic,Cell, Veiled,Cells, Dendritic,Cells, Interdigitating,Cells, Interdigitating Dendritic,Cells, Interstitial Dendritic,Cells, Plasmacytoid Dendritic,Cells, Veiled,Dendritic Cell,Dendritic Cell, Interdigitating,Dendritic Cell, Interstitial,Dendritic Cell, Plasmacytoid,Interdigitating Cell,Interdigitating Dendritic Cell,Interstitial Dendritic Cell,Plasmacytoid Dendritic Cell,Veiled Cell
D003921 Diabetes Mellitus, Experimental Diabetes mellitus induced experimentally by administration of various diabetogenic agents or by PANCREATECTOMY. Alloxan Diabetes,Streptozocin Diabetes,Streptozotocin Diabetes,Experimental Diabetes Mellitus,Diabete, Streptozocin,Diabetes, Alloxan,Diabetes, Streptozocin,Diabetes, Streptozotocin,Streptozocin Diabete
D004198 Disease Susceptibility A constitution or condition of the body which makes the tissues react in special ways to certain extrinsic stimuli and thus tends to make the individual more than usually susceptible to certain diseases. Diathesis,Susceptibility, Disease,Diatheses,Disease Susceptibilities,Susceptibilities, Disease
D005260 Female Females
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D000068536 Firmicutes A phylum of predominantly GRAM-POSITIVE BACTERIA that includes the orders Bacillales and Clostridiales. Firmicutes and BACTEROIDETES are the two bacterial phyla that constitute the majority of the human gut MICROBIOTA.
D000069196 Gastrointestinal Microbiome All of the microbial organisms that naturally exist within the GASTROINTESTINAL TRACT. Enteric Bacteria,Gastric Microbiome,Gastrointestinal Flora,Gastrointestinal Microbial Community,Gastrointestinal Microbiota,Gastrointestinal Microflora,Gut Flora,Gut Microbiome,Gut Microbiota,Gut Microflora,Intestinal Flora,Intestinal Microbiome,Intestinal Microbiota,Intestinal Microflora,Bacteria, Enteric,Flora, Gastrointestinal,Flora, Gut,Flora, Intestinal,Gastric Microbiomes,Gastrointestinal Microbial Communities,Gastrointestinal Microbiomes,Gastrointestinal Microbiotas,Gut Microbiomes,Gut Microbiotas,Intestinal Microbiomes,Intestinal Microbiotas,Microbial Community, Gastrointestinal,Microbiome, Gastric,Microbiome, Gastrointestinal,Microbiome, Gut,Microbiome, Intestinal,Microbiota, Gastrointestinal,Microbiota, Gut,Microbiota, Intestinal,Microflora, Gastrointestinal,Microflora, Gut,Microflora, Intestinal
D000073556 Burkholderiales An order of gram-negative bacteria of the class BETAPROTEOBACTERIA which include highly pathogenic species such as BURKHOLDERIA; BORDETELLA; and RALSTONIA.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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