risk independent of traditional risk factors and
cardiorenal indices.7
• In a mouse model, atherosclerosis susceptibility
(as defined by plaque burden) was transmitted
using fecal microbial transplantation.8
• Plasma TMAO levels are elevated in patients
with chronic kidney disease and are associated
with poorer survival and CVD risks, and chronic
choline or TMAO feeding in mice resulted in
impaired renal function.9
• The TMAO-generating enzyme flavin monooxygenase 3 (FMO3) is a key regulator of cholesterol/
lipid metabolism and inflammation.10
• TMAO levels correlated with thrombosis potential in > 4,000 patients and increased platelet activation. In mice fed an excess of choline, gut-generated TMAO heightened platelet hyper-reactivity
and thrombosis potential in vivo.11
• In a prospective study, fasting TMAO levels were
independently predictive of coronary vessel
atherosclerotic burden as quantified by SYNTAX
scores and lesion characteristics,12 while another
study showed that elevated TMAO increased
mortality risk among patients with stable CAD
managed with optimal medical treatment.13
• Dietary phosphatidylcholine intake has been
linked to an increased risk of type 2 diabetes in
three U.S. populations14 and to increased all-cause
and CVD mortality in >100,000 women and
men—especially in those with diabetes—who
were followed for over a quarter century while
enrolled in the Nurses’ Heath Study and the
Health Professionals Follow-up Study.15
• OK, so how do you change the situation? Inhibiting microbial TMA formation reduces the formation of atherosclerotic lesions.16 A compound
called 3,3-dimethyl-1-butanol (DMB) inhibits
TMA and DMB is found naturally in many foods
included in the Mediterranean diet plan, including some balsamic vinegars, cold-pressed extra
virgin olive oils, grapeseed oils, and red wine.
“I think the coolest thing about the thrombosis
paper in Cell11 was that we pretty much showed
that you could transfer an elevated risk of thrombosis by taking gut microbes from a high TMAOproducing, thrombosis-prone mouse and transplanting them into germ-free mice,” said Dr. Hazen in an
interview. “It’s such a weird idea to think our gut
microbes are impacting how much we might be at
risk for hemorrhaging after an injury, or, literally,
thrombosis potential. These studies show our risk
for MI and stroke are linked to our diets and dependent on our gut microbes.”
Of course, the million-dollar question is: what
do you do with a high TMAO level? (There is
now a commercially available clinical assay for
34
CardioSource WorldNews
It’s a Microbial World After All
While we find bacteria both in and
on the body, the vast majority of our
bug-mates reside in the colon. So cozy
are they as residents, that much has
been made of our being more microbe
than human: an early estimate put the
ratio of bacteria to host cells in humans
at 10:1, bugs winning handily.1 Turns
out, however, that this early estimate
—made in 1972—was an educated but
rough calculation done by a microbiologist with an early interest in
gnotobiology (the science of organisms
raised in germ-free environments).
Now, a small group of researchers
from Israel and Canada have used more
modern means and knowledge to update this calculation.2 According to Ron
Milo, PhD, and graduate student, Ron
Sender, from the Weizmann Institute
of Science in Rehovot, Israel, and Shai
Fuchs, MD, PhD, from the Hospital
for Sick Children in Toronto, Canada,
a “standard reference man” weighing
about 70 kg (154 lbs) and standing about
170 cm (5’6”) in height, actually contains
on average about 30 trillion human cells
and 39 trillion bacteria. This puts the
bacteria to cell ratio at closer to 1:1, with
a fudge factor of ~25%. The numbers
are close enough that “each defecation
event, which excretes about one-third
of colonic bacterial content, may flip the
ratio to favor human cells over bacteria,”
wrote Sender et al.
One source of over-estimation in
Thomas D. Luckey’s original work was
related to the proportion of bacteria in
fecal matter. He estimated that the guts
contain around 1014 bacteria, by assuming there were 1011 bacteria per gram
of “wet content” (stool), and scaling
that up by the one-liter volume of the
alimentary canal, which stretches from
the mouth to the anus. However, we
now know that most bacteria reside
only in the colon, which has a volume
of only about 0.4 liters.
Does this matter? Maybe not much,
but accuracy is always important in sci-
it.) It remains to be seen whether there is clinical benefit to altering diet to reduce TMAO or
whether we find other factors besides diet and
microbiota that influence TMAO levels or their
effect on the vasculature. But studies have already
shown that subjects adhering to a Mediterranean
diet have lower TMAO and this diet reduces
heart disease risks.
Dr. Hazen, who is also section head of Preventive Cardiology at the Cleveland Clinic, noted
that high blood TMAO levels serve as a strong
and independent predictor of incident CVD risk;
consequently, he thinks more aggressive global
preventive efforts with a high TMAO would seem
reasonable. To be clear, Dr. Hazen says much more
research is needed, and he and others are looking
at numerous gut-mediated pathways to atherogenesis and inflammation; it is just that TMAO is the
furthest along.
What About Inflammation?
Does TMAO link the gut and atherogenesis? It may be
part of the connection, but there is likely more, according to Peter Libby, MD, the Mallinckrodt Professor of
Medicine at Harvard Medical School, Boston, MA.
Oxidized lipids have been thought to be an important initiating stimulus for atherosclerosis; however,
the evidence to show this in humans is actually
“awfully slim,” he said in an interview. Besides being
a cardiologist at Brigham and Women’s Hospital in
Boston, MA, Dr. Libby is an editor of Braunwald’s
Heart Disease and a world leader in the area of atherogenesis, inflammation, and vascular biology.
“For want of better guesses, we all—including
ence. What better way to comply with
the Delphic maxim to ‘know thyself,’
said Sender and colleagues, than to
quantitatively examine the contents of
the human body?
Also, quality matters. In several
studies, individuals found to have low
microbiota quality are at higher risk
for cardiometabolic disease compared
to those with high microbial gene
counts. Moreover, folks with less rich
microbiota have a greater abundance
of “bad” bacteria types, while those
with greater gut richness have bacteria
types that are associated with better
metabolic outcomes.
While dietary interventions can
dramatically change the gut microbiota, the complexity and individuality
of each person’s microbiota makes
it difficult to estimate how powerful
dietary interventions might be.
REFERENCES
1. Luckey TD. Am J Clin Nutr. 1972; 25:1292-4.
2. Sender R, et al. Cell. 2016;164:337-40.
myself and all textbooks and review articles—show
that oxidized LDL is the initiating stimulus, but I
don’t think that the evidence that supports that is
rock solid,” said Dr. Libby.
“And that’s why it’s intriguing that we have a
greater understanding of the human microbiome,
not just in the gut but also in places like the periodontal space, and that an alternative or complementary hypothesis to the oxidized LDL hypothesis as a
trigger for inflammation in atherosclerosis might be
products of infectious agents.”
Dr. Libby suspects that leakage of gut microbial
products, due to impaired barrier function in the
intestinal epithelium, may switch on inflammatory signaling networks that can be identified and
targeted clinically.17
This doesn’t mean TMAO is out. On the contrary,
Dr. Hazen’s work has been “eye-opening” said Dr.
Libby, but he suspects there are other important aspects of the relationship we have with our commensal microbial organisms that interact with vascular
cells and inflammatory cells.
Any Recommendations?
Fecal microbial transplantation offers one possibility for repairing or rehabilitating a dysfunctional
microbiome, but—let’s face it—that’s not one likely
to be embraced by the masses any time soon [see
the sidebar Sharing Your Microbes with Friends].
Let’s all imagine being asked to come up with a
glossy ad campaign to support that service.
The appeal of fixing your health by fixing your
microbiome through dietary means is more than
enough of a catalyst to drive industry into a bug-
August 2016