Obesity induced gut dysbiosis contributes to disease severity in an animal model of multiple sclerosis

Abstract

BackgroundMultiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS. The etiology of MS is complex, and results from the interaction of multiple environmental and genetic factors. Although human leukocyte antigen-HLA alleles such as HLA-DR2 and –DR3 are considered the strongest genetic factors, the environmental factors responsible for disease predisposition are not well understood. Recently, diet and gut microbiota have emerged as an important environmental factors linked to the increased incidence of MS. Especially, western diets rich in protein and fat have been linked to the increased incidence of obesity. Numerous clinical data indicate a role of obesity and gut microbiota in MS; however, the mechanistic link between gut microbiota and obesity in the pathobiology of MS remains unclear. The present study determines the mechanisms driving MS severity in the context of obesity utilizing a high-fat diet (HFD) induced obese HLA-DR3 class-II transgenic mouse model of MS.MethodsHLA-DR3 transgenic mice were kept on a standard HFD diet or Normal Chow (NC) for eight weeks. Gut microbiota composition and functional analysis were performed from the fecal DNA of mice. Experimental autoimmune encephalomyelitis-EAE (an animal model of MS) was induced by immunization with the proteolipid protein-PLP91-110 peptide in complete Freud’s Adjuvant (CFA) and pertussis toxin.ResultsWe observed that HFD-induced obesity caused gut dysbiosis and severe disease compared to mice on NC. Amelioration of disease severity in mice depleted of gut microbiota suggested an important role of gut bacteria in severe EAE in obese mice. Fecal microbiota analysis in HFD mice shows gut microbiota alterations with an increase in the abundance of Proteobacteria and Desulfovibrionaceae bacteria and modulation of various bacterial metabolic pathways including bacterial hydrogen sulfide biosynthetic pathways. Finally, mice on HFD showed increased gut permeability and systemic inflammation suggesting a role gut barrier modulation in obesity induced disease severity.ConclusionsThis study provides evidence for the involvement of the gut microbiome and associated metabolic pathways plus gut permeability in obesity-induced modulation of EAE disease severity. A better understanding of the same will be helpful to identify novel therapeutic targets to reduce disease severity in obese MS patients.

Exploring the interplay between antiretroviral therapy and the gut-oral microbiome axis in people living with HIV

“…This is further corroborated by the observed shifts in the microbiome in a variety of disease states and chronic in ammatory conditions [6,7]. For instance, both gut and oral dysbiosis have been linked to obesity, as evidenced in laboratory investigations and patient cohorts [8,9,10]. We and others have previously reported that different ART regimens could have distinct modulating effects on the gut microbiome due to the anti-microbial properties of speci c antivirals [5,11,12].…”

Snapshot into the Type-2-Diabetes-Associated Microbiome of a Romanian Cohort

“…These OTUs were significantly correlated with different clinical parameters including HbA1c, the lipid profile and hypertension. Microbes considered to be associated with dysbiosis such as Bilophila [ 33 ], Sutterella [ 34 ] and Desulfovibrionaceae [ 35 ] were correlated with a worse clinical tableau in the case of T2D patients. Conversely, the presence of F. prausnitzii in the T2D microbiome was associated with improved metabolic parameters such as LDL and HDL.…”

Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms that Disturb the Hallmarks of Health in Polycystic Ovary Syndrome

“…Many of these factors can cause dysbiosis (an imbalance of the composition, metabolism or distribution of the microbiome associated with an unhealthy outcome) and have been investigated for their role in a wide range of human diseases (274). These include obesity, diabetes, gestational diabetes, metabolic syndrome, cardiovascular disease, inflammatory bowel disease, multiple sclerosis, dementia, PCOS, and many others (275,276). Lifestyle-related disturbance to the balanced microbial ecosystem contributes to a variety of diseases, depending on the level of exposure, length of exposure, combination of exposures, and individual disease susceptibility (274).…”