Author: Suzi Birnbaum
Featured image caption: This is the fifth figure from the Fotiou et al. article showing speculative pathways of where metabolites identified by NMR in C1 AF samples may fit into overall metabolism.
Described article can be accessed by clicking here.
It is not news that a maternal diet has influence on a fetus’ development. What a mother eats dictates what is available to the fetus, as her uterus is its only environment. While maternal nutrition has long been under the scrutiny of every expecting mother, nutritionist, doctor, and well-meaning stranger, less attention has been paid to the makeup of the amniotic fluid (AF). Instead, all research has focused on morphological development of the fetus. A recent paper published in Nature Scientific Reports by Fotiou et al. details one of the only studies on human AF. The authors make a point to highlight the large research gap that exists in the literature regarding to AF studies in humans. They cite only one other source, to their knowledge, that reports on AF metabolite composition of humans. This other study was performed by Felig et al. and published in 1972, with a focus on the effects of fasting on the AF content of expecting mothers (1). Other AF studies have been published between the Felig et al. paper and the current Fotiou et al. study, but they were done in mouse and pig models. While these animals are good systems for overall vertebrate AF studies, human studies are needed due to the specific nuances behind human fetal development.
The lack of human AF studies is not unsurprising given that amniocentesis (the procedure to extract AF) carries risk of miscarriage, and is considered an invasive procedure on the mother. It is likely to be hard to convince mothers to contribute AF samples for scientific research, if they do not see an immediate need to do so. The Fotiou et al. research group managed to get sixty-five human AF contributors in the second trimester, of which they assessed global metabolite composition by 1H NMR due to dietary differences. They published their work under the title, 1H NMR-based metabolomics reveals the effect of maternal habitual dietary patterns on human amniotic fluid profile. In addition to the NMR-metabolomics assessment of AR samples, each expecting mother’s diet was recorded by a survey.
The major result of the study was that maternal diet could be split into two groups that had statistically significant different ratios of certain metabolites. These groups were labeled C1 and C2; the C1 group was characterized by those who ate mostly refined carbohydrates, red meats, refined dairy products, “ready-to-eat foods” in comparison to mothers of the C2 group whose diet consisted of whole wheats, “vegetables, fruits, legumes, and nuts”.
The C1 group had higher “glucose, alanine, tyrosine, valine, citrate, cis-aconitate, and formate” and higher amounts of “histidine, phenylalanine, valine” while the C2 group displayed relatively high amounts of lipoproteins. These data were then subjected to Metabolite Set Enrichment Analysis (MSEA), a program used to put metabolomic data in biological relevance. The MSEA results of the AF samples were that biosynthetic pathways aminoacyl-tRNA (amino acid metabolism) and citric acid cycle metabolism were statistically significantly upregulated in the C1 group.
This result makes sense in terms of biological context as we would expect to see a statistically significant increase in anabolic pathways in the environment of a developing fetus. While the results of the study were rather straightforward, they opened up a host of questions. Looking at the increased metabolites in the C1 group, the authors cite the higher levels of glucose, alanine, tyrosine, phenylalanine, and histidine to support the glycolysis and protein synthesis in fetal tissue development. Furthermore, the authors cited the increased valine levels as potentially contributing to branched chain amino acid synthesis. According to the authors, the higher levels of citrate and cis-aconitate indicated higher rates of citric acid cycle metabolism.
The authors vaguely reference that the C1 diet (higher in red meats and various processed foods) results in higher levels of secondary metabolic pathways, as indicated by higher fumarate levels. They interpreted the differential fumarate level as a potential “marker of the biological consequences of the quality of dietary intake”. Not present in their results section but referenced in the discussion, Fotiou et al. analyzed maternal urine samples. With regards to the C1 cluster of diet and NMR data, the urine samples of C1 women were higher in alanine and urea. These results were in agreement with previous studies of urine studies in diets high in red meat and refined sugars. Even with all these speculations, the authors cited a need for further studying of these metabolites in C1 AF samples to fully understand the linkage between dietary roles in AF.
Looking at the C2 cluster of diet and NMR data, as previously stated, the only significantly increased biomolecule levels were that of lipoproteins. The authors gave no speculations as to what pathway could be affected by extra lipoproteins, or what the higher lipoprotein levels could be indicative of. Instead, the Fotiou et al. pointed to other studies that found strong hormonal influences on changing lipid levels in pregnant women (2,3). They reasoned that this evidence for high lipid variability in pregnant women obscured the significance of their data in the C2 cluster. They did, however, suggest that the abundance of lipoproteins in the AF were most likely due to a diet higher in “total lipid, monounsaturated and polyunsaturated fatty acid [intake]”.
This study certainly opened up more conversation than it could answer, as most ‘omics’ studies do. It is hard to draw any sort of conclusion from the results given because many more experiments could be applied to the raw data and/or samples to explore what the initial metabolomics data indicated. Fotiou et al. left ample room in their discussion for further speculations as to what the differing metabolite levels in the C1 and C2 AF NMR data could indicate. Specifically they left room for interpretation regarding diet makeup and AF makeup. Arguably the C1 diet is what many cultures and diet organizations across the world would consider to be unbalanced as it is heavy on red meat, processed foods, and refined carbohydrates. Yet due to food deserts and systemic imbalances of food availability, it is unfortunately the case that many individuals have access to what would classify as a C1 diet. Additionally, as evident by the obesity epidemic of the Western world (namely the United States) even those who have the resources available to eat more balanced diets would still fall under the C1 classification of diet, given the overwhelming presence of refined sugars, heavily processed foods, and red meat. These shifts in dietary influences on maternal diet on fetus development is crucial to study, which includes explorations in AF.
Hopefully less invasive procedures for AF studies will develop in the near future (for future studies and also for fetus health screenings). In the meantime, readers can extrapolate their own interpretations of the data. From the perspective of the BCM441 course, we could look at the higher glucose, aconitate, and cis-aconitate levels in the C1 group, and the higher lipoprotein levels in the C2 group, and try to form our own understanding of what may be causing their abundance in relation to the maternal diet.
- Felig, P., Kim, Y. J., Lynch, V. & Hendler, R. Amino acid metabolism during starvation in human pregnancy. J clin Invest 51,
- Lippi, G. et al. Lipid and lipoprotein profile in physiological pregnancy. Clin. Lab. 53, 173–177 (2007).
- Eshriqui, I. et al. Prepregnancy dietary patterns are associated with blood lipid level changes during pregnancy: A prospective
Cohort Study in Rio de Janeiro, Brazil. J. Acad. Nutr. Diet. 117, 1066–1079.e1 (2017).
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