Friday, April 26, 2013

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.


Tom Hennessy said...

Lecithin from eggs and meat result in DIFFERENT effects than the lecithin found in plants so one might wonder whether the TMAO raises or lowers with the different sources of choline , plant versus animal sources?

"These results show that compared with egg-PC, omega3-PC can prevent or alleviate obesity-related disorders through the suppression of fatty acid synthesis, enhancement of fatty acid beta-oxidation, and increase of the serum adiponectin level in OLETF rats"

Anne Buchanan said...

Thanks. Yes, interesting. Another variable would be the specific microbes colonizing a given gut.

I think it's such early days in terms of trying to get a handle on the effects of intestinal -- and other -- microbes on health and disease that it's premature to draw conclusions. And as with most everything else, simple answers will be tempting but less credible than complex ones.

Anne Buchanan said...

Ah, that is to say microbes that colonize our bodies, the subject of current microbiome research.

Tom Hennessy said...

"would be the specific microbes colonizing a given gut"

Yes , but , if one looks at the 'fertiliser' FOR the microbiome , as a garden analogy. They have shown when the diet is high in iron the bacteria which use iron have an increased proliferation. So would the choline be affected by BOTH the high iron diet from meat and the source of choline , meat source versus plant source ?
"It is well known that pathogens increase growth rate by up to 8,000 times when exposed to increased levels of iron."
"An increase in iron levels, which happens during active IBD, inhibits the growth of probiotic bacteria, including Lactobacillus."

Meat eating , a high iron diet , is favorable to pathogenic bacteria.
"Dietary Heme Alters Microbiota"
"Increased amount of Gram-negative bacteria"

A high iron diet oxidizes Phosphatidylcholine , (oxPC) and Phosphatidylcholine has been tested in Colitis.
"Phosphatidylcholine for Steroid-Refractory Chronic Ulcerative Colitis:
A Randomized Trial"
"80% of phosphatidylcholine recipients discontinued steroid therapy"

Anne Buchanan said...

It's tempting to predict a simple dose response to specific foods and specific microbes but I would suggest that there's not going to be a single simple answer, because every microbiome is different, and response to what microbes do will vary.

And it occurs to me to wonder why cattle on antibiotics gain weight.

Tom Hennessy said...

Hmmm .. I actually looked at a study awhile ago.

"Evaluation of several potential bioactive agents for reducing protozoal activity in vitro"

Anne Buchanan said...

Thanks, Tom. It will be interesting to see what the accumulating data have to show. And surely there will be many more studies.

Tom Hennessy said...

Microbiomes between animals in the wild and those in zoos might be different too. Feeding meat to giraffes gives them encephalopathy. It might also show a different microbiome?
"The nutritional contribution to bovine spongiform encephalopathy."

One might wonder whether the diet supplied to mice , approved by the NIH , also will skew research , like it did this guys ?
"Defined iron-deficient diets, rather than chow diets, did not develop uroporphyria"

Tom Hennessy said...

The abstract I included doesn't speak specifically to the 'problem' the researchers found when they were doing the two studies. They were studying the porphyria and they found the chow they were using was skewing the research , hence the chow they created which didn't skew the research. That's why they mentioned something OTHER than the iron was causing the problem. Any chow supplied usually includes meat.

Tom Hennessy said...

Studying roller derby combatants , concluded, one passes 'outer' microrganisms around. Antiperspirants , are marketed specifically with iron chelators , to remove iron from bacteria. If one has MORE iron IN the body , would one be more inclined to have an iron based OUTER microbiome , as shown in IBD?
"Pathogens increase growth rate by up to 8,000 times when exposed to increased levels of iron"

Are the outer organisms too , different, with a low iron diet ?
"We decreased the Fe content of the diet to about 6·7 mg/d, without compromising the energy and protein content of the diet."

Richard F. said...

This whole TMAO thing is basically a bunch of bunk. Chris Kresser has been writing about these studies since early last month and apparently, each one is less credible than the one before it. Here's his latest one published in the last few days: . He's devoted much of his last year of research to CVD, doling out pretty good information about recent studies.

Anne Buchanan said...

Great, thanks very much for the link. He's asking all the right questions.

Ken Weiss said...

Thanks for this perspective. We are not doing the studies and of course are not really qualified to judge their credibility, nor whether Dr Hazen would have any sort of rebuttle.

Instead of attempting to adjudicate any differences of view, or credibility of evidence, our point was to note the subtleties of causation that are, or are being suggested as, related to the complex diseases that are defying many attempts to clarify their risk factors.

This just is one recent example of claims that suggest that studies can explain why other causal associations were made, etc.