Obesity induced changes in gut microbiota contribute to disease severity in animal model of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS), affecting nearly one million Americans. The etiology of MS is complex and results from the interaction of multiple environmental and genetic factors. Although human leukocyte antigen-HLA genes especially certain HLA-class II alleles such as HLADR2 and DR3 are recognized as the strongest genetic factors associated with predisposition to MS, the environmental factors responsible for disease predisposition are not well understood. Recently, diet and gut dysbiosis have emerged as an important environmental factor linked to the increased incidence of MS. Especially, western diet rich in protein and fat have been linked to the increased incidence of obesity. Numerous clinical data indicate a role of obesity and gut dysbiosis in MS, however the mechanistic link between gut microbiota and obesity in pathobiology of MS remains unclear. In the present study, utilizing HLADR3 transgenic experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we showed that High Fat Diet (HFD) induced obesity caused gut dysbiosis and increased EAE severity. Amelioration of disease severity in mice depleted of gut microbiota using broad spectrum antibiotics validate an important role of gut bacteria in severe EAE induced in obese mice. Fecal microbiota analysis in HFDinduced obese mice shows gut microbiota alterations with an increase in the abundance of Proteobacteria and Desulfovibrionaceae bacteria and metabolic pathways associated with sulfur metabolism, lipopolysaccharide, and long chain fatty acids biosynthesis. Taken together, this study provides evidence for involvement of the gut microbiome and associated metabolic pathways in obesity induced modulation of EAE disease severity and a better understanding of the same will advance our ability to identify novel therapeutic targets to reduce disease severity in obese patients.