Are Supplements Isotopically-Depleted?
Synthetic nutrients & their implications.
While undertaking work during my Master’s thesis at the Zubarev lab, I had the opportunity to accurately measure the isotopic composition of amino acid residues from living tissue. By growing E. coli in media where there is a singular carbon and nitrogen source, we could infer the isotopic composition of the various chemicals used as nutrient for the bacteria. What is intriguing is that both carbon-13 (13C) and nitrogen-15 (15N) values present in the amino acids of their tissue deviated from physiological levels. This implies that the substrate used to grow the E. coli almost certainly had isotopic compositions outside of those generally considered natural.
For our particular purposes, this fact was not important. However, I was interested in what this meant for the isotopic compositions of the synthetically produced and naturally derived compounds we used — compounds that are routinely used as nutritional supplements. Because bacteria synthesise their own amino acids de novo, the isotopic composition of said amino acids should yield reliable information about their food source.1 For example, E. coli grown on ‘isotopically normal’ NH4Cl exhibited δ15N levels of ~–100‰2. For reference, our tissues typically lie in the range of approximately +5‰ and +20‰. This suggests that the synthetically produced NH4Cl is significantly isotopically distinct from natural processes.
Similar results were found for δ13C as well, where E. coli grown on ‘isotopically normal’ D-glucose synthesised amino acids that yielded ~-40‰.3 Again, this suggests that isolated, concentrated nutrients have the potential of being comprised of isotopes in unnatural abundances — either enriched or depleted. In our particular case, none of this mattered, but I could not help but think about the potential of nutritional supplements actually being depleted in heavy isotopes rather than enriched — as is often assumed. Really, there is no particular reason why synthetics should be enriched in heavy isotopes rather than depleted. What did appear clear to me, though, is that synthetically derived nutrients likely deviate significantly from their natural counterparts in isotopic composition.
This does not mean that supplements are ‘bad’, or that they are heavy isotope ‘bombs’. What it does suggest is that the isotopic composition of particularly synthetically produced nutrients possibly deviate significantly from their natural forms that our bodies have evolved to work with. This may not be such a big deal as our metabolic network appears to have evolved to buffer isotopic shifts, maintaining a type of isotopic homeostasis.
What is more concerning from my perspective is not necessarily the abundance of heavy isotopes in synthetically produced compounds4, but the location within the molecule itself. Natural processes appear to go to great lengths to enrich or deplete molecules in highly specific locations due to their subtle, yet critical effects. For example, a recent breakthrough has confirmed a decades-old hypothesis regarding the action of thiamine (vitamin B1) as a cofactor in critical enzymatic processes.5 Previously, it was thought that thiamine could not transition through a carbene as they are far too reactive to stabilise the enzyme-substrate complex, however, recent evidence has confirmed the astounding ability for thiamine to overcome this with subtle quantum mechanical effects. Given how delicate quantum effects can be, might isotope substitutions be able to meddle with these types of intricate processes?
While this is all speculation, it rests on the observed fact that, in particular, synthetically produced NH4Cl contains a 15N signature that significantly deviates from natural abundances. There is no reason to suspect that other synthetically produced compounds commonly used as nutritional supplements would not encounter the same issue. Again, this may be a non-issue in many cases, but with a growing appreciation for quantum effects in biology, even subtle isotopic effects could play disproportionate effects.
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This is especially true of carbon and nitrogen as in our circumstances, we controlled the only source of these nutrients. Hydrogen was present in most of the nutrient used, however, making tracing its source much more difficult.
This notation means that the sample is ~100‰ (or 10%) more depleted in 15N than the international standard based on atmospheric nitrogen samples where 15N comprises ~0.36765%.
This is particularly interesting if the D-glucose was derived from maize, as maize utilises the C4 photosynthetic pathway, promoting accumulation of greater amounts of 13C relative to C3 plants. To my knowledge, the vast majority of commercially available D-glucose is derived from maize.
Although, obviously this is also a concern.
Raviprolu, V. T., Gregory, A., Banda, I., McArthur, S. G., McArthur, S. E., Goddard, W. A., 3rd, Musgrave, C. B., 3rd, & Lavallo, V. (2025). Confirmation of Breslow’s hypothesis: A carbene stable in liquid water. Science advances, 11(15).