Rheumatoid arthritis (RA) is a common autoimmune disease with emerging environmental and microbiome risk factors. The western diet is typically deficient in magnesium (Mg), and there is some evidence suggesting that Mg may have anti-inflammatory properties. But the actual role of Mg supplementation in arthritis or in T cell subsets has not been explored.
MethodsWe investigated the role of a high Mg diet in two different mouse models of RA induced with the KRN serum, and collagen-induced arthritis. We also characterized the phenotypes of splenocytes, gene expression, and an extensive intestinal microbiome analyses including fecal material transplantation (FMT).
FindingsThe high Mg diet group was significantly protected with reduced arthritis severity and joint damage, and reduced expression of IL-1β, IL-6, and TNFα. The high Mg group also had increased numbers of Foxp3+ Treg cells and IL-10-producing T cells. The high Mg protective effect disappeared in IL-10 knockout mice. FMT from the high Mg diet mice recreated the phenotypes seen in the diet-treated mice, with reduced arthritis severity, increased Foxp3+ Treg, and increased IL-10-producing T cells. Intestinal microbiome analyses using 16S rDNA sequencing revealed diet-specific changes, including reduced levels of RA-associated Prevotella in the high Mg group, while increasing levels of Bacteroides and other bacteria associated with increased production of short-chain fatty acids. Metagenomic analyses implicated additional pathways including L-tryptophan biosynthesis and arginine deiminase.
InterpretationWe describe a new role for Mg in suppressing arthritis, in expanding Foxp3+ T reg cells and in the production of IL-10, and show that these effects are mediated by the intestinal microbiome. Our discoveries suggest a novel strategy for modifying the intestinal microbiome to treat RA and other autoimmune and inflammatory diseases.
KeywordsRheumatoid arthritis
High magnesium diet
Microbiome
Treg
IL-10
Inflammation
Autoimmunity
AbbreviationsIL-10 KOB6.129P2-IL10tm1Cgn/J
IL17-GFPGFP-inducible C57BL/6-Il17atm1Bcgen/J
KRN miceKBxN TCR transgenic mice
CIAcollagen-induced arthritis
KSIAKRN serum-induced arthritis
Mg500Mg 500 ppm (normal Mg diet)
Mg2800Mg 2800 ppm (high Mg diet)
TregFoxp3+ regulatory T cells
Tr1IL10-producing regulatory T cell
TfhT follicular helper cell
ASVamplicon sequence variants
LDAlinear discriminant analysis
LEfSelinear discriminant analysis effect size (LEfSe) analysis
FMTfecal material transplant
© 2023 The Author(s). Published by Elsevier B.V.
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