Obesity Modulated Gut Microbiota Exacerbate Disease Severity in HLA-Class II Transgenic Mouse Model of Multiple Sclerosis

Abstract Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS where interaction among multiple environmental and genetic factors influence disease outcome. HLA class II alleles such as HLA-DR2 and –DR3 are considered strongest genetic factors linked with MS, whereas recently gut microbiota have emerged as an important environmental factor linked to MS. Additionally, obesity has been shown to promote MS disease severity. However, the mechanistic link between gut microbiota and obesity in pathobiology of MS is unknown. HLA-DR3 transgenic mice on a high-fat diet (HFD) to induce obesity, resulted in severe EAE compared to normal chow diet (NCD). Antibiotic-mediated gut microbiota depletion and fecal transplant studies established that the microbiota is necessary and sufficient for obesity to potentiate EAE severity. Obesity-associated microbiota alterations included increases in bacterial genes linked with hydrogen sulfide (H 2S)-metabolism, with concordant increases in fecal H 2S. Further, mice on HFD showed increased gut permeability and systemic inflammation compared with NCD group. Altogether, this study provides evidence for involvement of the gut microbiome and associated H 2S-metabolism microbial genes in obesity induced modulation of EAE severity. Dissection of these pathways will help to identify novel therapeutic targets to reduce disease severity in obese patients. The Author acknowledge funding from the National Multiple Sclerosis Society grant (RG 5138A1/1T), National Institutes of Health/NIAID (1R01AI137075), the University of Iowa Environmental Health Sciences Research Center, NIEHS/NIH (P30 ES005605), and a gift from P. Heppelmann and M. Wacek to AM.