Background/Purpose: Early-life nutrition can have a profound effect on late-life disease development. Most current studies focus on macro-nutrition (calorie, carbohydrate, fat, and protein), and much less is known about the role that early life micro-nutrition plays in diseases of adults.  One notable exception is that prenatal folic acid supplementation dramatically decreases the incidence of spina bifida and other neural tube defects.  In mouse models, supplementing ‘methyl donors’ in the diet of pregnant mice (dams) affects the incidence of diabetes and obesity in their offspring. These changes have been attributed to changes in the DNA methylation status of selected genes. 

Previously, we have demonstrated that feeding dams a prenatal diet supplemented with methyl donors (MDS) during mating and pregnancy decreases the levels of selected CD4+ T cell pro-inflammatory chemokines and cytokines in F1 mice by changing the DNA methylation pattern of those genes. CD4⁺ T cells are critical in arthritis pathogenesis, and many of the pro-inflammatory cytokines and chemokines required for arthritis development are regulated by DNA methylation. Recent studies have shown that RA is characterized by a perturbed extracellular redox environment. Based on our preliminary data, we hypothesize that the prenatal MDS diet will decrease inflammation in the collagen-induced arthritis (CIA) model of RA by modulating redox metabolites and CD4⁺ T cell function.

Methods: Female DBA/J mice received either a control diet or MDS diet during pregnancy and lactation.  Pups borne to these mice (F1 Control or F1 MDS) were maintained on those diets after birth and until they were weaned at 4 weeks.  After weaning, all mice were fed a standard (NIH 31) diet.  Arthritis was then induced, and paw swelling was measured.  Cytokines and redox metabolites were measured in the serum at specified time points, and mice were sacrificed for in vitro analysis of CD4+ T cell function. 

Results: Both F1-MDS and F1-Control mice developed arthritis 30 days after collagen injection, and the mean arthritis score was decreased by at least 2 points at day 45 after injection (p<0.05).  At 55 days after injection, CD4⁺ T cells from F1-MDS mice expressed decreased levels of TNF-α (p=0.04), IL-17 (p=0.04), and IL-6 (p=0.02) protein. Levels of the chemokine CCR7 were also decreased in CD4⁺ T cells from F1-MDS mice (p=0.02).  The serum redox potential in CIA mice is more oxidizing (-77 mV) than in non-CIA mice (-83 mV) (p<0.01). After CIA induction, the redox potential was maintained at a more homeostatic level (-85 mV) in F1-MDS mice, and the redox potential was more oxidizing (-77 mV) in F1-Control mice (p<0.01). 

Conclusion: The pre-natal MDS diet decreases disease severity, as measured by paw swelling in the CIA model of RA.  The diet caused decreases in serum levels of pro-inflammatory cytokines and expression of pro-inflammatory genes in CD4+ T cells.  Many of these genes are methylation sensitive.  These results demonstrate that a pre-natal diet enriched in methyl donors can decrease disease severity in a mouse model of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/prenatal-methyl-rich-diet-decreases-inflammation-in-collagen-induced-arthritis/