Homocysteine has been a perplexing issue for decades, ever since Dr. Kilmer McCully explored excessively high homocysteine levels in children that were associated with impaired growth, seizures, anemia and accelerated atherosclerosis, a condition labeled “homocystinuria” due to the abnormally high levels of homocysteine found in urine. Dr. McCully then speculated that less severe elevations of homocysteine in other people without homocystinuria could underlie numerous other health conditions, particularly atherosclerosis.
Since this initial speculation, increased blood levels of homocysteine have indeed been shown in observational studies to predict up to several-fold increased risk for heart disease, stroke, depression, and cancer. (Although the data are observational, the associations have been consistent across numerous studies with sizably increased risk such that these associations, unlike so many other conclusions reached via observational evidence, are probably true.) It has also been shown that increased homocysteine levels can be reduced through supplementation with B vitamins folate, B6, B12, and riboflavin (vitamin B2, especially relevant to people with the MTHFR variant C677T).
Next logical question: Does supplementation with B vitamins in people with higher levels of homocysteine reduce heart attack and stroke?
No, they do not. Fifteen randomized, placebo-controlled studies compared homocysteine-reducing B vitamin regimens with placebo, regimens that did indeed reduce homocysteine levels substantially and were conducted for as long a seven years, have demonstrated no reduction in cardiovascular events, stroke, or mortality.
What to make of this tangle? Is there a missing piece? Is homocysteine just a marker for some other process unresponsive to B vitamins? Could it be that other factors are associated with higher homocysteine levels such as subclinical (mild) hypothyroidism or kidney dysfunction are confounding the results? Are there not-yet-identified other nutrients or dietary factors that are present? How much do common MTHFR variants play in blunting the beneficial effects?
The answers remain unclear. While correcting deficiencies of B vitamins, especially folate and B12, is indeed helpful for overall health (including use of methyl forms for people with the MTHFR C677T variant), tracking or reducing homocysteine is not something worth achieving, given the failure to reduce cardiovascular risk by doing so.
But I’d like to highlight an interesting preliminary observation that intersects with the homocysteine and B vitamin conversation: Many species of bowel flora microbes are vigorous producers of B vitamins such that substantial quantities are produced, enough to help prevent deficiencies if/when oral intake is compromised. (This may explain why most vegans and vegetarians who obtain no dietary intake of B12 do not always develop overt and severe deficiencies—bowel flora may partially compensate.) The B vitamins produced in the most substantial quantities by bowel flora species such as Lactobacillus plantarum? Folate, B6, and B12.
Isn’t that curious? The same B vitamins that reduce homocysteine are also the B vitamins most plentifully produced by bowel flora. Put 2 + 2 together: Could higher homocysteine levels really be a marker for dysbiosis, e.g., overproliferation of Firmicutes, as occurs in overweight people with insulin resistance, that do not produce B vitamins coupled with a relative lack of species that produce B vitamins? And could the failure to reduce cardiovascular risk with B vitamin supplementation be due to the failure to address dysbiosis and SIBO? After all, SIBO is proving to be, also in preliminary studies, a cardiovascular risk factor.
Another preliminary study has demonstrated that a commercial probiotic (VSL#3) can increase levels of B vitamins and reduce homocysteine, but cardiovascular outcomes were not tracked. But it tells us that homocysteine is indeed under the influence of bowel flora composition. Does that mean that the increased cardiovascular and other risks associated with higher homocysteine blood levels are better addressed not with oral B vitamin supplementation, but with 1) correction of dysbiosis with 2) restoration of a greater proportion of B vitamin-producing species?
Stay tuned. As with so many issues that appear to be varied manifestations of disrupted bowel flora, so it is looking that way for homocysteine, as well. We shall be exploring this issue further in our discussions in our Undoctored Inner Circle.