Central Nervous System Demyelinating Disease Protection by the Human Commensal Bacteroides fragilis Depends on Polysaccharide A Expression

Section of Neurology, Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(7):4101-8. DOI: 10.4049/jimmunol.1001443
Source: PubMed


The importance of gut commensal bacteria in maintaining immune homeostasis is increasingly understood. We recently described that alteration of the gut microflora can affect a population of Foxp3(+)T(reg) cells that regulate demyelination in experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We now extend our previous observations on the role of commensal bacteria in CNS demyelination, and we demonstrate that Bacteroides fragilis producing a bacterial capsular polysaccharide Ag can protect against EAE. Recolonization with wild type B. fragilis maintained resistance to EAE, whereas reconstitution with polysaccharide A-deficient B. fragilis restored EAE susceptibility. Enhanced numbers of Foxp3(+)T(reg) cells in the cervical lymph nodes were observed after intestinal recolonization with either strain of B. fragilis. Ex vivo, CD4(+)T cells obtained from mice reconstituted with wild type B. fragilis had significantly enhanced rates of conversion into IL-10-producing Foxp3(+)T(reg) cells and offered greater protection against disease. Our results suggest an important role for commensal bacterial Ags, in particular B. fragilis expressing polysaccharide A, in protecting against CNS demyelination in EAE and perhaps human multiple sclerosis.

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Available from: Javier Ochoa-Repáraz, May 01, 2014
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    • "Notably, B. fragilis treatment rescued some behavioral defects, including stereotyped behavior (compulsive marble burying), communication deficits (ultrasonic vocalizations), and anxiety behaviors (open-field exploration) (Hsiao et al., 2013). B. fragilis has been shown to augment the development and function of the immune system (Mazmanian et al., 2008; Ochoa-Repá raz et al., 2010; Round and Mazmanian, 2010); however, treatment with B. fragilis did not restore several aspects of immune dysfunction in an animal model of autism (Hsiao et al., 2012, 2013). Instead, levels of serum metabolites found to be altered in mice with ASD-related behaviors were restored to normal levels. "
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    ABSTRACT: Animals share an intimate and life-long partnership with a myriad of resident microbial species, collectively referred to as the microbiota. Symbiotic microbes have been shown to regulate nutrition and metabolism and are critical for the development and function of the immune system. More recently, studies have suggested that gut bacteria can impact neurological outcomes-altering behavior and potentially affecting the onset and/or severity of nervous system disorders. In this review, we highlight emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system. While understanding and appreciation of a gut microbial impact on neurological function is nascent, unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially novel etiologies for psychiatric and neurodegenerative disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):565-576. DOI:10.1016/j.chom.2015.04.011 · 12.33 Impact Factor
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    • "However, in follow-up studies, it was demonstrated that antigens from particular bacteria such as B. fragilis could also have a protective effect [42]. It was suggested that the presence or absence of polysaccharide A might be decisive for beneficial or harmful outcomes of EAE [42]. Also in MS not the mere presence of gut microbiota could be a key criterion for the development of or the protection against the disease, but a state of dysbiosis in favor of an autoimmune response directed against CNS antigens. "
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    ABSTRACT: Background The etiology of multiple sclerosis (MS) has remained unclear, but a causative contribution of factors outside the central nervous system (CNS) is conceivable. It was recently suggested that gut bacteria trigger the activation of CNS-reactive T cells and the development of demyelinative disease. Methods C57BL/6 (B6) mice were kept either under specific pathogen free or conventional housing conditions, immunized with the myelin basic protein (MBP)–proteolipid protein (PLP) fusion protein MP4 and the development of EAE was clinically monitored. The germinal center size of the Peyer’s patches was determined by immunohistochemistry in addition to the level of total IgG secretion which was assessed by ELISPOT. ELISPOT assays were also used to measure MP4-specific T cell and B cell responses in the Peyer’s patches and the spleen. Ear swelling assays were performed to determine the extent of delayed-type hypersensitivity reactions in specific pathogen free and conventionally housed mice. Results In B6 mice that were actively immunized with MP4 and kept under conventional housing conditions clinical disease was significantly attenuated compared to specific pathogen free mice. Conventionally housed mice displayed increased levels of IgG secretion in the Peyer’s patches, while the germinal center formation in the gut and the MP4-specific TH17 response in the spleen were diminished after immunization. Accordingly, these mice displayed an attenuated delayed type hypersensitivity (DTH) reaction in ear swelling assays. Conclusions The data corroborate the notion that housing conditions play a substantial role in the induction of murine EAE and suggest that the presence of gut bacteria might be associated with a decreased immune response to antigens of lower affinity. This concept could be of importance for MS and calls for caution when considering the therapeutic approach to treat patients with antibiotics.
    PLoS ONE 06/2014; 9(6):e99794. DOI:10.1371/journal.pone.0099794 · 3.23 Impact Factor
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    • "Moreover, our unexpected results, which did not show a decrease in microbial load but instead a tendency towards an increase, are discordant with previous studies using either qPCR [10], [12] or culture methods [34], [35], [36], [37] (Table S1). These authors reported, as expected, a significant decrease in microbial load after 3 to 7 days antibiotic intake. "
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    ABSTRACT: From birth onwards, the human gut microbiota rapidly increases in diversity and reaches an adult-like stage at three years of age. After this age, the composition may fluctuate in response to external factors such as antibiotics. Previous studies have shown that resilience is not complete months after cessation of the antibiotic intake. However, little is known about the short-term effects of antibiotic intake on the gut microbial community. Here we examined the load and composition of the fecal microbiota immediately after treatment in 21 patients, who received broad-spectrum antibiotics such as fluoroquinolones and β-lactams. A fecal sample was collected from all participants before treatment and one week after for microbial load and community composition analyses by quantitative PCR and pyrosequencing of the 16S rRNA gene, respectively. Fluoroquinolones and β-lactams significantly decreased microbial diversity by 25% and reduced the core phylogenetic microbiota from 29 to 12 taxa. However, at the phylum level, these antibiotics increased the Bacteroidetes/Firmicutes ratio (p = 0.0007, FDR = 0.002). At the species level, our findings unexpectedly revealed that both antibiotic types increased the proportion of several unknown taxa belonging to the Bacteroides genus, a Gram-negative group of bacteria (p = 0.0003, FDR<0.016). Furthermore, the average microbial load was affected by the treatment. Indeed, the β-lactams increased it significantly by two-fold (p = 0.04). The maintenance of or possible increase detected in microbial load and the selection of Gram-negative over Gram-positive bacteria breaks the idea generally held about the effect of broad-spectrum antibiotics on gut microbiota.
    PLoS ONE 04/2014; 9(4):e95476. DOI:10.1371/journal.pone.0095476 · 3.23 Impact Factor
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