eBioMedicine

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.

We 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).

The 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.

We 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.

Rheumatoid arthritis

High magnesium diet

Microbiome

Treg

IL-10

Inflammation

Autoimmunity

B6.129P2-IL10tm1Cgn/J

GFP-inducible C57BL/6-Il17atm1Bcgen/J

KBxN TCR transgenic mice

collagen-induced arthritis

KRN serum-induced arthritis

Mg 500 ppm (normal Mg diet)

Mg 2800 ppm (high Mg diet)

Foxp3+ regulatory T cells

IL10-producing regulatory T cell

T follicular helper cell

amplicon sequence variants

linear discriminant analysis

linear discriminant analysis effect size (LEfSe) analysis

fecal material transplant

© 2023 The Author(s). Published by Elsevier B.V.