Evidence from this meta-analysis and systematic review indicates that dietary Mg intake is inversely associated with serum CRP levels. Our findings are robust as the meta-analysis is based on both continuous and binary outcomes, and the results are supportive of each other. In addition, the study participants are comprised of male and female, adults and children with a wide age range, which improve the generalizability of the findings. In addition, the summarization of findings both from observational and intervention studies either in the meta-analyses or in the systematic review makes the available information on the association of Mg and serum CRP levels more aggregated.

Some limitations should also be considered when interpreting the results from this meta-analysis. First, most of the studies had just a single measure of exposure/effect sizes, for example, mean level of CRP, ORs or correlation coefficients. The different measures of exposure and effect size made it difficult or even impossible to pool the results and estimate the overall association. For example, we had to exclude two studies11, 23 from the meta-analysis because they reported mean CRP (s.d.), and/or OR (95% CI) on the basis of a continuous scale of Mg intake. Second, none of the primary studies considered the health impact of high Mg intake (hypermagnesemia, for example, serum Mg >1.9 mEq/l28). Anyway, no sufficient evidence to date indicates any substantial adverse effect of dietary Mg overdose, although two case studies reported that Mg intake above 6 mEq/l, a rare phenomenon in a general population, caused parathyroid gland dysfunction, respiratory, cardiac and CNS dysfunction.29, 30 Of note, an estimated 75% of Americans have daily Mg intakes less than the RDA.31

In addition, the possibility of residual confounding from primary studies cannot be completely excluded, although various potential confounders including lifestyle and demographic variables were well adjusted in the primary studies.

Five Mg intervention studies25, 26, 27, 32, 33 used different doses of Mg supplementation (50–450 mg/day) for relatively short durations (4 weeks to 4 months). These studies cannot be pooled because of the different measures of outcome across studies. Nevertheless, all these intervention studies reported a generally inverse association between Mg supplementation and serum CRP levels, which is consistent with the pooled estimate from observational studies. In addition, a study conducted in patients with cardiac surgery found a moderate inverse correlation between serum Mg concentration and preoperative CRP levels.34

Findings from this meta-analysis are biologically plausible. Studies indicate that Mg deficiency may increase CRP production mediated through interlinked chains of the following events. Inadequate dietary Mg intake depletes extracellular Mg ion and consequently leads to the activation of macrophages and influx of calcium ions into cells (adipocytes, neuronal and peritoneal cells). The increased calcium level in the cells causes enhanced Mg need to block the influx of calcium ion, which further leads to the increased stimulation of N-methyl-D-aspartic acid or N-methyl-D-aspartate receptors. The increased stimulation of N-methyl-D-aspartic acid or N-methyl-D-aspartate results in the opening of channels nonselective to cations, thus increasing calcium ions in neuronal cells.9 This leads to the release of neurotromediators (for example, substance P) and inflammatory cytokines. Major pro-inflammatory cytokines including IL-6 and tumor necrosis factor-alpha are released into the bloodstream and act as signaling molecules to promote the release of CRP from the liver as a part of the acute phase response, which further prolongs the inflammatory response in the body.1 CRP production by liver is regulated by tumor necrosis factor -alpha and IL-6.9 A well-documented link between Mg deficiency and acute inflammatory response in animal models characterized by leukocyte and macrophage activation, release of inflammatory cytokines and acute phase proteins, and excessive production of free radicals has also been reported in experimental settings.35, 36 Studies based on infrared spectrometry techniques have also demonstrated substantial alteration in secondary structures of human CRP in the presence of Mg ions.37

In summary, findings from this meta-analysis and systematic review indicate that dietary Mg intake is inversely associated with serum CRP levels. Our results suggest that the potential beneficial effect of Mg intake on the risk of chronic diseases may be, at least in part, explained by inhibiting inflammation. Because inflammation is a risk factor of various chronic diseases, increasing Mg intake is certainly of great public health significance.