Multiple sclerosis (MS) is a devastating autoimmune neuroinflammatory disease with a strikingly increasing incidence world-wide, implicating the influence of environmental factors. While genetics of MS are beginning to be understood, they can account for at most ~30% of the disease risk. The remainder of the disease risk is accounted for by environmental factors and gene-by-environment (GE) interactions. Mechanisms of GE in MS are not well understood, and are difficult to study in humans. Mounting evidence implicates a novel environmental risk factor for MS: dysregulation of the gut microbiome. In this application, we propose to take a genome-wide approach to identify gene microbiome interactions in a novel and powerful mouse genetics system. These studies cannot be carried out in humans, and they will provide important mechanistic understanding of GE in autoimmune disease of the CNS, and deliver cause vs. effect distinctions that are lacking in epidemiologic studies.
Incidence of autoimmune diseases, such as multiple sclerosis (MS), is on the rise in most developed countries, and these diseases represent a significant health care burden. This rising incidence most likely represents various environmental factors that influence disease in genetically susceptible individuals. While genetics of MS are beginning to be understood, how genetics interact with environmental factors remains an open question that is very difficult to address in human studies. Changes in the gut microbiome (the collection of trillions of bacteria that colonize the gut) represent a potential environmental risk factor in MS. We propose to use an animal model of MS to understand interactions between genetics and this environmental factor, employing a well-controlled powerful mouse genetics system. The gut microbiome represents a new frontier in human health and disease, as it could be used both diagnostically and therapeutically. However, cause and effect are difficult to separate in human studies, and our mouse studies will provide a critical frame work for the interpretation and application of the results from human studies.
| Krementsov, Dimitry N; Asarian, Loredana; Fang, Qian et al. (2018) Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity. Front Immunol 9:1622 |
