Consumption of fish yielded substantially greater increases in circulating TMAO than eggs or beef. The higher Firmicutes to Bacteroidetes enrichment among men exhibiting a greater response to dietary TMAO precursor intake indicates that TMAO production is a function of individual differences in the gut microbiome.

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The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase ( MTHFR ), which encodes a key enzyme in one carbon (C1) metabolism. The MTHFR 677C > T polymorphism reduces the efficiency of methyl group production with possible adverse downstream effects on gene expression. In this study, the effects of prenatal and/or postnatal diets enriched in C1 nutrients on ASD-like behavior were evaluated in Mthfr -deficient mice. Differences in intermediate pathways between the mice with and without ASD-like behaviors were tested. The findings indicate that maternal and offspring Mthfr deficiency increased the risk for an ASD-like phenotype in the offspring. The risk of ASD-like behavior was reduced in Mthfr -deficient mice supplemented with C1 nutrients prenatally. Specifically, among offspring of Mthfr +/- dams, prenatal diet supplementation was protective against ASD-like symptomatic behavior compared to the control diet with an odds ratio of 0.18 (CI:0.035, 0.970). Changes in major C1 metabolites, such as the ratios between betaine/choline and SAM/SAH in the cerebral-cortex, were associated with ASD-like behavior. Symptomatic mice presenting ASD-like behavior showed decreased levels of GABA pathway proteins such as GAD65/67 and VGAT and altered ratios of the glutamate receptor subunits GluR1/GluR2 in males and NR2A/NR2B in females. The altered ratios, in turn, favor receptor subunits with higher sensitivity to neuronal activity. Our study suggests that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior.

Mol. Nutr. Food Res. 2017, 61, 1600324. DOI: https://doi.org/10.1002/mnfr.201600324 Consumption of preformed trimethylamine‐N‐oxide (TMAO) in fish substantially increases circulating TMAO as compared to consumption of its precursors, choline (in eggs) and carnitine (in beef), which requires gut microbial processing prior to absorption. Lower microbial diversity and greater Firmicutes to Bacteroidetes enrichment heighten TMAO response to eggs and beef.