Abstract It is known that patients with type 1 autoimmune diabetes (T1D) have altered gut microbiota, and potentially pathogenic bacteria, which are increased, have been much studied. However, less is known of the impact on the host immune system, and in particular on immune regulation, of the bacterial species, which are significantly reduced. We hypothesized that the reduced bacterial species are associated with the lack of immune tolerance in T1D, especially the bacterial species that are commonly present in both the gut and oral cavity. Taking advantage of availability of germ free animals and a pure V dispar strain from human oral cavity, we tested this hypothesis by using V. dispar to colonize germ-free (GF) mice and assessed the effect of V. dispar on immune cells. It is intriguing that we found that V. dispar promoted Treg cells in most of the peripheral lymphoid tissues examined and the majority of the Treg cells expressed neuropilin-1 and a higher frequency of the Tregs were IL-10 producers. These in vivo effects of V. dispar could also be mirrored in vitro with direct contact of immune cells to V. dispar. V. dispar induced Tregs are ready to suppress naturally primed diabetogenic T cells in vitro. More importantly, V. dispar ameliorated the severity of insulitis in NOD mice. Further, V. dispar produce high level of short chain fatty acids (SCFAs) acetate and propionate. In addition, V. dispar markedly improved gut permeability. Moreover, the induction of Tregs and IL-10 producers, as well as improvement of gut permeability by V. dispar were found when tested in both GF-NOD and GF-B6 mouse strains, suggesting that V. dispar has a general immune regulatory effect.. Our preliminary data are compelling, and lead us to hypothesize that V. dispar are important in maintaining immune regulation, and hence immune tolerance. We propose the 3 specific aims to test our hypothesis using GF NOD and GF B6 mice, as well as the mouse strains in which dendritic cells or Tregs or short chain fatty acid (SCFA) receptor are specifically targeted (commercially available). Our approach using V. dispar as a model system will also signpost the study of other bacteria species that were markedly reduced in the gut of patients with T1D. If our hypothesis is proved to be correct, our study will help with the design of future novel therapy for T1D and other autoimmune disorders, for which, we will “return“ to human studies.