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CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice.

ABSTRACT: Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short-chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT) mice, into EAE-induced CD44WT mice, led to significant amelioration of EAE. High-throughput bacterial 16S rRNA gene sequencing, followed by clustering sequences into operational taxonomic units (OTUs) and biochemical analysis, revealed that EAE-induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE-induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). Further, data showed a significant change in the abundance of SCFAs, propionic acid, and i-butyric acid in EAE-CD44KO compared to EAE-CD44WT mice. In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota and SCFAs. Furthermore, our studies also demonstrate that the phenotype of gene knock-out animals may be shaped by gut microbiota.

SUBMITTER: Chitrala KN

PROVIDER: S-EPMC5704912 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice.

Chitrala Kumaraswamy Naidu KN Guan Hongbing H Singh Narendra P NP Busbee Brandon B Gandy Alexa A Mehrpouya-Bahrami Pegah P Ganewatta Mitra S MS Tang Chuanbing C Chatterjee Saurabh S Nagarkatti Prakash P Nagarkatti Mitzi M

European journal of immunology 20170606 7

Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short-chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT ...[more]

PMID: 28543188

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Project description:BackgroundIntravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism.MethodsWe measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11R?-/-). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11R?-/- mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells.ResultsIVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11R?-/- mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11R?-/- mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11R?-/- mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture.ConclusionThese results implicate IL-11 as an important immune effector of IVIg in the prevention of Th17-mediated autoimmune inflammation during EAE.

Project description:BackgroundConstipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).MethodsConstipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups.ResultsCompared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota.ConclusionsOur results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

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CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice.

Publications

CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice.

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