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.
Dr. Davis wrote: «…demonstrated that a commercial probiotic (VSL#3)…»
For the benefit of anyone contemplating probiotics, it might be worth pointing out that being a paper published in 2015, the trial would have been using the legacy (2002-2016) De Simone formulation of VSL#3. Subsequent to the departure of Claudio De Simone, the post-2016-05 product has been the subject of litigation, with this class action arising just two weeks ago.
What used to be authentic VSL#3 may or may not now be called Visbiome®, and I’m not aware that the Undoctored program has taken a position on it.
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Very interesting indeed! I have high blood levels if homocysteine (above 16 at one point). My endocrinologist has had me on Folinic plus to reduce it, sighting the cardiac issues as the reason. It had not corrected it much until i switched to the “wheat belly” lifestyle in March of this year. My May blood test showed it at 12, a good drop from previous test but still a little high. I had lost about 25 lbs at that time. I have now lost 50 lbs to date but have been stalled at 231 lbs for the last month. I am reading up on SIBO and with new information it’s looking very likely to be an issue. (5 years ago i had a ruptured appendix that resulted in an abdominal infection. I was given leviquin by IV for 6 days and orally for another 2 weeks. It caused some real side effects. In fact, i firmly believe it was what caused my AFIB. I’m certain it disrupted my gut flora.)Thanks for bringing this important topic to light. I have been making the L. Reuteri yogart for abiut a month now and it is providing some if the benefits but not all. SIBO could be at the root of all this. Any feedback would be appreciated.
VanEichel wrote: «Very interesting indeed! I have high blood levels if homocysteine (above 16 at one point). My endocrinologist has had me on Folinic plus to reduce it, sighting the cardiac issues as the reason.»
Homocysteine seems to be yet-another marker that is usually alerting to a real problem, but is not itself a target for shoving around with meds, or even supplements / metabolic interventions (unless they are addressing the root cause).
re: «It had not corrected it much until i switched to the “wheat belly” lifestyle in March of this year.»
That would seem to be a bingo, and suggests that if dysbiosis was playing a role, switching to a grain-free real-foods diet probably corrected a large part of it. If the program you adopted was based on the original 2011 book, the 2014+ program, described in Wheat Belly Total Health, or the 2017 Undoctored, might provide more gains, having added, among other things gut flora cultivation.
re: «I have now lost 50 lbs to date but have been stalled at 231 lbs for the last month.»
There are a number of usual suspects for that. Some of them are covered in this video: Why can’t I lose weight?
re: «I was given leviquin by IV for 6 days and orally for another 2 weeks. It caused some real side effects.»
The published side effects for levofloxacin read like a SIBO symptom list.
re: «In fact, i firmly believe it was what caused my AFIB.»
The Undoctored subscription site has a Protocol for a-fib, which is a refinement of approaches developed on the prior Cureality and Track Your Plaque sites.
re: «SIBO could be at the root of all this. Any feedback would be appreciated.»
The site also has an evolving Protocol for SIBO, and because SIFO is a common co-morbidity, there’s an Advanced Topic for it that as well, which will likely become a Protocol at some point.
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Dr Davis:
“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.”
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I wonder about those studies. In so many of these papers the devil is in the detail and you can’t necessarily trust what’s in the abstract. For instance, the many papers that loudly proclaim that they’re “proof” a low-carb diet is ineffective or no better than a low-fat diet for weight loss and heart health. Mike Eades has analysed a number of these on his blog and demonstrated that their “low-carb” or “Atkins” diets are actually high-carb, just slightly lower in carbs than their low-fat diet. The bias of the researchers is often blatant. In one study that Mike analysed the low-fat cohort were given regular group counseling sessions with dietitians to keep them on the diet whereas the low-carb group were given one instruction session at the start and a handout and sent on their way. Gee, I wonder which diet the researchers wanted to come out on top? Despite the lack of coaching the low-carb group outperformed the low-fat group on every measure. However unless you have access to the full paper you don’t know this and usually it’s hidden behind a paywall.
I did a PubMed search on homocysteine and heart disease. The first paper that popped up claimed no connection between homocysteine levels and CVD after treatment with B vitamins. Looking at the authors’ affiliations revealed the dreaded letters CTSU. The Clinical Trials Service Unit at Oxford University is funded by the drug industry to the tune of hundreds of millions of $ to hold the primary data on statin trials and are the only ones allowed by the drug companies to see that data. They regularly issue pronouncements hailing statins as wonder drugs or denouncing anyone who questions their use. It’s therefore no surprise that they should come out with a negative report on a competing therapy that could derail the gravy train.
In regard to these negative trials what I’d want to know is
– how randomised were the treatment and control groups
– what was the starting Hcs level before treatment
– how much folate, B6 & B12 did they use and was it the methylated variety
– what was the Hcs level after treatment
Needless to say the abstract of the CTSU trial didn’t reveal any of this and of course the full paper is behind a paywall. They may have used trivial amounts of the vitamins or accepted as “low” a post-treatment Hcs level that’s still too high. The “normal” levels of Hcs are usually given as 5-15 when in fact levels greater than 7 are known to contribute to brain shrinkage and are probably damaging your blood vessels as well. So I’m very sceptical about those negative trials.