Impact of symbiotic protists on intestinal T cell homeostasis and inflammation.

Project Summary The gut microbiome exerts a tremendous influence on the function of the immune system at homeostasis and during inflammatory insults. Most research has focused on how individual bacteria or particular bacterial configurations interact with the immune system, but the microbiota contains other forms of microbial life, including protists. Several species of common and non-pathogenic protists in mice, from the genus Tritrichomonas, induce a type 2 immune response in the small intestine without causing overt pathology. In addition, other species of Tritrichomonads were later discovered that promote Th1 and Th17 cells in the colon. However, it is unclear if these differences in mucosal immunity are related to species- specific effects or other factors. The phylogenetic relationship between intestinal Tritrichmonas species is poorly understood as their genomes remain unsequenced. Furthermore, the immune landscape and microbiota composition varies greatly between the small intestine and colon, which further complicates comparisons between these Tritrichomonas species and their immune effects. To overcome these obstacles, we isolated two species of Tritrichomonads that elicit either a Th1 or Th2 immune response in the small intestine. In Aim 1, we will generate high-quality genomes for each protist and measure their output of key immunomodulatory metabolites. In Aim 2, we will characterize the effects of these two protists on the adaptive immune system. We will determine immune mechanisms that respond to each species of Tritrichomonas. Finally, in Aim 3, we will determine how these two Tritrichomonads impact Crohn’s Disease in a mouse model. These studies will establish key genomic tools and insights into Tritrichomonas species and mechanisms that influence on intestinal immunity. Furthermore, this project will evaluate the possible benefits of these symbiotic protists on Crohns’s disease, leading to novel therapeutic approaches to treat IBD.