Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis

Kadowaki, Atsushi; Saga, Ryoko; Lin, Yaqiu; Sato, Wakiro; Yamamura, Takashi

doi:10.1093/brain/awz012

Cited by 60 publications

(56 citation statements)

References 63 publications

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“…In the process of analyzing the gut microbiome structures in the subgroups of MS, the multiomics data disclosed the intriguing differences between SPMS and RRMS, which is in line with our hypothesis that transition from RRMS to SPMS may be driven by alterations of the gut microbiome ( 37 ). Metagenomic functional data disclosed an increase in microbial genes involved in DNA mismatch repair in SPMS as compared to RRMS, which we presumed to be caused by excessive oxidative stress.…”

Section: Discussionsupporting

confidence: 82%

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

Takewaki

Suda

Sato

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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134

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Multiple sclerosis (MS), an autoimmune disease of the central nervous system, generally starts as the relapsing remitting form (RRMS), but often shifts into secondary progressive MS (SPMS). SPMS represents a more advanced stage of MS, characterized by accumulating disabilities and refractoriness to medications. The aim of this study was to clarify the microbial and functional differences in gut microbiomes of the different stages of MS. Here, we compared gut microbiomes of patients with RRMS, SPMS, and two closely related disorders with healthy controls (HCs) by 16S rRNA gene and whole metagenomic sequencing data from fecal samples and by fecal metabolites. Each patient group had a number of species having significant changes in abundance in comparison with HCs, including short-chain fatty acid (SCFA)-producing bacteria reduced in MS. Changes in some species had close association with clinical severity of the patients. A marked reduction in butyrate and propionate biosynthesis and corresponding metabolic changes were confirmed in RRMS compared with HCs. Although bacterial composition analysis showed limited differences between the patient groups, metagenomic functional data disclosed an increase in microbial genes involved in DNA mismatch repair in SPMS as compared to RRMS. Together with an increased ratio of cysteine persulfide to cysteine in SPMS revealed by sulfur metabolomics, we postulate that excessive DNA oxidation could take place in the gut of SPMS. Thus, gut ecological and functional microenvironments were significantly altered in the different stages of MS. In particular, reduced SCFA biosynthesis in RRMS and elevated oxidative level in SPMS were characteristic.

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Section: Discussionsupporting

confidence: 82%

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

Takewaki

Suda

Sato

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

134

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“…The pathological and clinical outcome of CNS diseases can also be affected by the intestinal microflora in the context of autoimmunity (120)(121)(122)(123)(124). This relationship has been particularly well established for the response to bacteria, including pathogens and commensals, within the intestinal compartment and its effects on the CNS, a connection that was recently termed the gut-brain axis.…”

Section: Other Central Nervous System Diseasesmentioning

confidence: 99%

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

Zhang

et al. 2020

Front. Immunol.

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Gamma-delta (gd) T cells are a subset of T cells that promote the inflammatory responses of lymphoid and myeloid lineages, and are especially vital to the initial inflammatory and immune responses. Given the capability to connect crux inflammations of adaptive and innate immunity, gd T cells are responsive to multiple molecular cues and can acquire the capacity to induce various cytokines, such as GM-CSF, IL-4, IL-17, IL-21, IL-22, and IFN-g. Nevertheless, the exact mechanisms responsible for gd T cell proinflammatory functions remain poorly understood, particularly in the context of the central nervous system (CNS) diseases. CNS disease, usually leading to irreversible cognitive and physical disability, is becoming a worldwide public health problem. Here, we offer a review of the neuroinflammatory and immune functions of gd T cells, intending to understand their roles in CNS diseases, which may be crucial for the development of novel clinical applications.

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“…In the recent study published by the present author with others, evidence that CCR9 + CD4 + memory T (Tm) cells represent a key regulatory lymphocyte involved in SPMS pathogenesis was provided (Fig. ) . A reduction in CCR9 + Tm cells in human peripheral blood and the deviation of their phenotype to an inflammatory Th17 phenotype in patients with SPMS were shown.…”

mentioning

confidence: 65%

“…1). 5 A reduction in CCR9 + Tm cells in human peripheral blood and the deviation of their phenotype to an inflammatory Th17 phenotype in patients with SPMS were shown. CCR9 + Tm cells expressed high levels of C-MAF; produced disease-protective cytokines, interleukin (IL)-4 and IL-10; expressed CCR6, a CNS homing receptor; and upregulated lymphocyte activation gene 3 in the cerebrospinal fluid during relapses of MS.…”

mentioning

confidence: 99%

Gut microbiota‐dependent CCR9⁺CD4⁺ T cells are reduced and altered to an inflammatory phenotype in secondary progressive multiple sclerosis

Kadowaki

2019

Clinical & Exp Neuroim

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Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis

Cited by 60 publications

References 63 publications

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

Gut microbiota‐dependent CCR9⁺CD4⁺ T cells are reduced and altered to an inflammatory phenotype in secondary progressive multiple sclerosis

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Gut microbiota-dependent CCR9+CD4+ T cells are altered in secondary progressive multiple sclerosis

Cited by 60 publications

References 63 publications

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

Alterations of the gut ecological and functional microenvironment in different stages of multiple sclerosis

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

Gut microbiota‐dependent CCR9+CD4+ T cells are reduced and altered to an inflammatory phenotype in secondary progressive multiple sclerosis

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Gut microbiota‐dependent CCR9⁺CD4⁺ T cells are reduced and altered to an inflammatory phenotype in secondary progressive multiple sclerosis