Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis

Dušan Radojević; Marina Bekić; Alisa Gruden-Movsesijan; Nataša Ilić; Miroslav Dinić; Aleksandar Bisenić; Nataša Golić; Dragana Vučević; Jelena Đokić; Sergej Tomić

doi:10.1080/19490976.2022.2127455

Myeloid-derived suppressor cells prevent disruption of the gut barrier, preserve microbiota composition, and potentiate immunoregulatory pathways in a rat model of experimental autoimmune encephalomyelitis

Gut Microbes. 2022 Jan-Dec;14(1):2127455. doi: 10.1080/19490976.2022.2127455.

Affiliations

¹ Group for Probiotics and Microbiota-Host Interaction, Laboratory for Molecular Microbiology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
² Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia.
³ Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Belgrade, Serbia.

Abstract

Over-activated myeloid cells and disturbance in gut microbiota composition are critical factors contributing to the pathogenesis of Multiple Sclerosis (MS). Myeloid-derived suppressor cells (MDSCs) emerged as promising regulators of chronic inflammatory diseases, including autoimmune diseases. However, it remained unclear whether MDSCs display any therapeutic potential in MS, and how this therapy modulates gut microbiota composition. Here, we assessed the potential of in vitro generated bone marrow-derived MDSCs to ameliorate experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats and investigated how their application associates with the changes in gut microbiota composition. MDSCs differentiated with prostaglandin (PG)E2 (MDSC-PGE2) and control MDSCs (differentiated without PGE2) displayed strong immunosuppressive properties in vitro, but only MDSC-PGE2 significantly ameliorated EAE symptoms. This effect correlated with a reduced infiltration of Th17 and IFN-γ-producing NK cells, and an increased proportion of regulatory T cells in the CNS and spleen. Importantly, both MDSCs and MDSC-PGE2 prevented EAE-induced reduction of gut microbiota diversity, but only MDSC-PGE2 prevented the extensive alterations in gut microbiota composition following their early migration into Payer's patches and mesenteric lymph nodes. This phenomenon was related to the significant enrichment of gut microbial taxa with potential immunoregulatory properties, as well as higher levels of butyrate, propionate, and putrescine in feces. This study provides new insights into the host-microbiota interactions in EAE, suggesting that activated MDSCs could be potentially used as an efficient therapy for acute phases of MS. Considering a significant association between the efficacy of MDSC-PGE2 and gut microbiota composition, our findings also provide a rationale for further exploring the specific microbial metabolites in MS therapy.

Keywords: Multiple sclerosis; gut microbiota; immunoregulatory mechanisms; microbial metabolites; myeloid-derived suppressor cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Butyrates / metabolism
Dinoprostone / metabolism
Encephalomyelitis, Autoimmune, Experimental*
Gastrointestinal Microbiome*
Multiple Sclerosis*
Myeloid-Derived Suppressor Cells* / metabolism
Myeloid-Derived Suppressor Cells* / pathology
Propionates / pharmacology
Putrescine / metabolism
Rats

Substances

Butyrates
Propionates
Dinoprostone
Putrescine

Grants and funding

This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia under Contract No. 451-03-68/2022-14/200042 and Contract No. 451-03-68/2022-14/200019, and by the Science Fund of the Republic of Serbia, PROMIS, #6062673, Nano-MDSC-Thera.