Intestinal microbes and heart disease -- we are what we eat

And now another in our irregular series on the role of anything-but-genes in chronic disease.  We've posted about the possible role of inflammation in many late onset or chronic heart disease, diet and lifestyle in heart disease, inflammation in asthma, cleanliness in asthma, inflammation in macular degeneration, and so on.  Diseases, it must be noted, for which hundreds of millions of dollars have been spent on the search for risk factor genes.  The excuse for this, used by geneticists to garner many huge grants, and with little other rationale for obviously environmental problems, was that they'd find important (major) segments of the population that were genetically susceptible to these environments.  We need not here belabor the thinness (from the beginning) of that rationale, because there are more important things to think about.

Steak; Wikimedia

For decades, primarily thanks to findings from the Framingham Study, it has been accepted wisdom that red meat is a risk factor for heart disease.  Why?  Because eating red meat was thought to raise cholesterol, which leads to hardening of the arteries, and then cardiovascular disease.  That led the pork and chicken industries to promote their implied-safer products (e.g., "the other red meat!").  Eggs, too, were implicated for a while because the yolks are high in cholesterol, though they were taken off the danger list some time ago (unfortunately, too late for some of us, who have developed a reflex egg-aversion, but given the cycling of risk factors, maybe that egg-aversion is a good thing).

Recent meta-analyses were not able to confirm the association between saturated fat and cholesterol and cardiovascular disease, a rather stunning finding that suggested that there may be other, perhaps correlated, environmental factors involved.  Two recent stories by Gina Kolata in the New York Times present just such alternative risk factors.

Kolata's story on April 7 suggested that indeed it's not the saturated fat or the cholesterol in meat that's to blame but the response of microbes in the gut to a constituent of the meat, carnitine in particular.  In a paper published in Nature Medicine, researchers at the Cleveland Clinic propose that when we eat meat the microbes in our gut convert carnitine into trimethylamine (TMA), which the liver then converts into TMAO, trimethylamine N-oxide, thought to be the real culprit in cardiovascular disease (CVD) because it causes atherosclerosis, hardening of the arteries.

The researchers compared the response of meat eaters and vegans to ingesting carnitine, and found that vegans didn't produce TMAO. Studies have shown that microbial composition of the gut does indeed vary with diet, among other things (geography, pregnancy, etc.) and meat eating presumably feeds a subset of microbes that vegans don't host.  Theirs don't make TMAO.    

Hard boiled eggs; Wikimedia

Kolata's story in yesterday's Times reports that a constituent of eggs might also be converted into TMAO by microbes in the gut.  In a paper published in the New England Journal of Medicine on Wednesday, the same researchers propose that when we digest the phosphatidylcholine, or lecithin, in eggs, one of the constituents is choline.  Intestinal microbes convert choline into TMA which, again, the liver converts into TMAO.  Other major sources of lecithin include liver, beef and pork.

Damn!  Do we have to stop the meat and eggs again?

Researchers confirmed the middleman (or middle-microbe) effect of intestinal flora by having their subjects take an antibiotic that wiped out the gut bacteria before they ate hard-boiled eggs.  With the microbes gone, TMAO levels in the blood didn't rise.  Only when the microbes were back to normal levels did TMAO rise. 

So, yes, foods high in fat and cholesterol may be associated with risk of heart disease.  But it's not because of the fat and cholesterol per se, but because these substances are present in foods that also have the constituents that gut microbes convert into what seems to be a true risk factor for atherosclerosis, TMAO. Not to mention that gut microbes are heavily determined by what we eat, as well.

We've 'known' for decades that red meat was a heart disease risk factor, and it was clearly because of fat and cholesterol.  This became lore.  The beef industry provided beef with less fat, the pork industry sold us on 'the other red meat', the poultry industry crowed, especially when eggs went back on the list of foods okay to eat.  

Vegan food pyramid; Wikimedia

And there was clearly a genetic component to heart disease risk, and/or to obesity, because CVD seems to run in families, and obesity is a risk factor, and this made many genetics labs crow.  Except that it was confusing when people with no family history of heart disease or thin people had heart attacks.

Despite the billion dollar industry that investigating, preventing and treating heart disease has become, it remains the leading cause of death in the US and other countries.  Number one.  Clearly we're doing something wrong -- including throwing a lot of money away on genetic studies that we knew really were going nowhere fast.  The intestinal microbe connection might turn out to be a huge advance in our understanding of heart disease, and it might well be that simple dietary changes and pharmaceutical approaches to cultivating 'good' microbes in our gut will prevent heart disease in many people -- leading the pharmaceutical industry to be the big crowers this time around. Of course, we can expect the genetic industry to say that some people are susceptible to the bugs' in their guts, but others (once we do the GWAS, whole genome sequencing, and 'personalized genomic medicine') will be cleared to go for the Egg McBreakfasts (with bacon).

But, this isn't likely to be the next health-research miracle, even if it gets promoted as one.  We would caution that this explanation will account for only some heart disease, even if the findings, which would be quite valuable to know, hold up.  Just as with every other complex disease, there are multiple pathways to this trait.  Why, for example, is smoking such a clear major risk factor?  Heart disease will remain a heterogeneous trait, difficult to predict, and not always possible to prevent.  But still, it's always refreshing when some innovative researcher breaks free of group think and provides new ideas on perplexing subjects.

The greatest irony, or should we say the last laugh, goes to the bugs who continue to outwit us and take us to our graves.