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      The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders

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      Immunology

      Wiley

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          Abstract

          <p id="d294387e179">The importance of the gut microbiome in the regulation of non‐infectious diseases has earned unprecedented interest from biomedical researchers. Widespread use of next‐generation sequencing techniques has prepared a foundation for further research by correlating the presence of specific bacterial species with the onset or severity of a disease state, heralding paradigm‐shifting results. This review covers the mechanisms through which a dysbiotic gut microbiota contributes to the pathological symptoms in an autoimmune neurodegenerative disorder, multiple sclerosis ( <span style="fixed-case">MS</span>). Although the central nervous system ( <span style="fixed-case">CNS</span>) is protected by the blood–brain barrier ( <span style="fixed-case">BBB</span>), it is unclear how gut dysbiosis can trigger potential immunological changes in the <span style="fixed-case">CNS</span> in the presence of the <span style="fixed-case">BBB</span>. This review focuses on the immunoregulatory functionality of microbial metabolites, which can cross the <span style="fixed-case">BBB</span> and mediate their effects directly on immune cells within the <span style="fixed-case">CNS</span> and/or indirectly through modulating the response of peripheral T cells to stimulate or inhibit pro‐inflammatory chemokines and cytokines, which in turn regulate the autoimmune response in the <span style="fixed-case">CNS</span>. Although more research is clearly needed to directly link the changes in gut microbiome with neuroinflammation, focusing research on microbiota that produce beneficial metabolites with the ability to attenuate chronic inflammation systemically as well as in the <span style="fixed-case">CNS</span>, can offer novel preventive and therapeutic modalities against a wide array of inflammatory and autoimmune diseases. </p>

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          Most cited references 36

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          T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

          Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
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            Effects of gut microbes on nutrient absorption and energy regulation.

            Malnutrition may manifest as either obesity or undernutrition. Accumulating evidence suggests that the gut microbiota plays an important role in the harvest, storage, and expenditure of energy obtained from the diet. The composition of the gut microbiota has been shown to differ between lean and obese humans and mice; however, the specific roles that individual gut microbes play in energy harvest remain uncertain. The gut microbiota may also influence the development of conditions characterized by chronic low-level inflammation, such as obesity, through systemic exposure to bacterial lipopolysaccharide derived from the gut microbiota. In this review, the role of the gut microbiota in energy harvest and fat storage is explored, as well as differences in the microbiota in obesity and undernutrition.
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              Is Open Access

              Characteristics of compounds that cross the blood-brain barrier

               William Banks (2009)
              Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.
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                Author and article information

                Journal
                Immunology
                Immunology
                Wiley
                00192805
                June 2018
                June 2018
                February 27 2018
                : 154
                : 2
                : 178-185
                Affiliations
                [1 ]Department of Pathology, Microbiology and Immunology; University of South Carolina School of Medicine; Columbia SC USA
                Article
                10.1111/imm.12903
                5980216
                29392733
                © 2018

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