Functional medicine: Focusing on imbalances in core metabolic processes

Nutrition is one of the most important environmental factors modulating genes and phenotypes (nutrigenomics),^28,29 and recent studies on single nucleotide polymorphisms (SNPs) have reinforced the importance of considering the effect of genetic variation on dietary response (nutrigenetics).^29,30 While nutrigenomics and nutrigenetics have the potential to improve the health of large populations by personalizing dietary advice based on genotype and phenotype, genetic variation occurring within a specific biochemical pathway makes generalizing genotype-based dietary advice to other populations complex.

For instance, Greenlandic Inuit, the indigenous people inhabiting the Arctic regions of Greenland, have a low incidence of CVD, largely due to “non-European” genetic variants that lower their LDL, protecting them from the oxidative stress of their diet high in polyunsaturated fats.^31,32 In a study of European adults, phenotypic and phenotypic-­plus-genotypic information did not enhance the effectiveness of the personalized nutrition advice, demonstrating that more research is needed in larger populations.³³

Another specific, complex example of gene-nutrient interaction is the pathophysiologic outcome of polymorphisms in the MTHFR gene.³⁰ MTHFR is a rate-limiting enzyme involved in folate and homocysteine metabolism, DNA and RNA biosynthesis, and DNA and protein methylation. MTHFR polymorphisms are common in otherwise healthy people, but some have been reported to increase chronic disease susceptibility via MTHFR deficiency. The most common MTHFR variant is the SNP rs1801133 that reduces enzyme activity to ~30% in homozygotes (677TT), which can lead to reduced folate bioavailability and mild-to-moderate hyperhomocysteinemia depending on one’s dietary folate intake and food fortification.

One FM focus at variance with current recommendations. FM’s approach to homocysteine and MTHFR genotyping for nutritional assessment, dietary counseling, and supplement advice contrasts with recommendations from meta-analyses^34-36 and guidelines from the American Heart Association and USPSTF.^37,38 While USPSTF does recommend all women planning or capable of pregnancy take 0.4 to 0.8 mg of folic acid daily to prevent neural tube defects,³⁹MTHFR polymorphism screening to guide supplementation is not recommended during pregnancy given conflicting studies and uncertain clinical significance.⁴⁰ Moreover, while it is generally agreed that the MTHFR C677T polymorphism, and in particular the homozygous MTHFR 677TT genotype, is an independent risk factor for hyperhomocysteinemia, neither variant genotype was an independent coronary artery disease risk factor in several large studies.^41-43

Future research is needed to help optimize probiotic dose, duration, route of administration, and whether microbial communities outperform single-species probiotics.

However, study populations with generally high folate consumption or fortified foods may be a main confounding variable.⁴⁴ For example, in a recent meta-analysis of an elderly population, the T-allele of the MTHFR C677T variant increased pooled stroke risk. While this increased stroke risk is highest in homozygotes, the association was statistically significant only in the Chinese cohort—a group that generally has poor dietary intake of folate and B12.⁴⁵ Therefore, both MTHFR genotype and baseline folate level are important determinants of folate therapy efficacy in stroke prevention, and this may explain why US studies have not clearly identified a patient subset most likely to benefit.⁴⁶ Future high-quality studies should measure baseline folate, target populations with ­moderate-to-severe hyperhomocysteinemia with specific MTHFR polymorphisms, and compare high- and low-dose B vitamins or use 5-­methylfolate (the active form of folate).

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