Pharmacologic inhibition of glycolysis prevents the development of lupus by altering the gut microbiome in mice
Ahmed S. Elshikha,
Yong Ge,
Josephine Brown,
Nathalie Kanda,
Mojgan Zadeh,
Georges Abboud,
Seung-Chul Choi,
Gregg Silverman,
Timothy J. Garrett,
William L. Clapp,
Mansour Mohamadzadeh,
Laurence Morel
Affiliations
Ahmed S. Elshikha
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA; The Laboratory of B Cell Immunobiology and the Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA
Yong Ge
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA; The Laboratory of B Cell Immunobiology and the Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA
Josephine Brown
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Nathalie Kanda
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA
Mojgan Zadeh
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA
Georges Abboud
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Seung-Chul Choi
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA
Gregg Silverman
The Laboratory of B Cell Immunobiology and the Division of Rheumatology, NYU School of Medicine, New York, NY 10016, USA
Timothy J. Garrett
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
William L. Clapp
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA
Mansour Mohamadzadeh
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA
Laurence Morel
Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health, San Antonio, TX 78229, USA; Corresponding author
Summary: Gut dysbiosis has been associated with lupus pathogenesis, and fecal microbiota transfers (FMT) from lupus-prone mice shown to induce autoimmune activation into healthy mice. The immune cells of lupus patients exhibit an increased glucose metabolism and treatments with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, are therapeutic in lupus-prone mice. Here, we showed in two models of lupus with different etiologies that 2DG altered the composition of the fecal microbiome and associated metabolites. In both models, FMT from 2DG-treated mice protected lupus-prone mice of the same strain from the development of glomerulonephritis, reduced autoantibody production as well as the activation of CD4+ T cells and myeloid cells as compared to FMT from control mice. Thus, we demonstrated that the protective effect of glucose inhibition in lupus is transferable through the gut microbiota, directly linking alterations in immunometabolism to gut dysbiosis in the hosts.
