Page 38 - Today's Dietitian (February 2020)

TMAO: Marker, Causal Factor, or Something Else? A Function of Kidney Function?
Elevated TMAO levels are associated with CVD—especially athero- Blood TMAO level depends on several factors, including diet,
sclerosis—and other poor health outcomes, including the develop- the composition and function of the gut microbiota, permeabil-
ment or progression of hypertension, diabetes, and renal failure, ity of the gut-blood barrier—which controls bacterial metab-
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but is TMAO a causative factor or simply a marker of disease? The olites’ access to the bloodstream—genetic regulation of liver
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origins of this question come from a 2011 study from the Cleve- enzymes, and how fast we can excrete TMAO in our urine.
land Clinic, which found an association between elevated fasting Lowered excretion due to impaired kidney function may have
plasma levels of TMAO and choline and several types of CVD. The played a role in the results of a 2013 study that fed 40 healthy
associations held even after adjustment for traditional cardiac risk adults two large hard-boiled eggs, which contained about 250
factors and medications. mg choline, along with 250 mg supplemental choline that was
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While other studies have found associations between CVD and marked so it could be tracked in the body after ingestion. Blood
choline, TMAO, or both, some have not. For example, large popu- and urine levels of both total TMAO and marked TMAO rose after
lation studies in Japan, the Netherlands, and the United States, consumption, although after eight hours total TMAO levels were
including the Atherosclerosis Risk in Communities study, found lower than they were before the challenge. Interestingly, after
no link between dietary choline intake and CVD. Unfortunately, administering antibiotics and repeating the challenge, TMAO
these studies didn’t also measure circulating TMAO levels. A levels didn’t rise, which speaks to the role of the gut microbiota
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2017 systematic review and meta-analysis in the Journal of the in TMAO production. Also notable? While average TMAO levels
American Heart Association did find that high TMAO levels were were associated with cardiovascular events, they were inversely
a much stronger predictor of cardiovascular events than were associated with glomerular filtration rate (GFR). In other words,
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elevated levels of its nutrient precursors, including choline. Pro- people with impaired kidney function had trouble clearing TMAO
posed mechanisms include effects on cholesterol, the hormone from their systems.
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angiotensin II—which can raise blood pressure—and increased Caudill says this is a critical detail in TMAO association studies,
platelet clumping, possibly leading to blood clots. 16,17 because most people older than age 55 to 60 are going to have some
“In my view, I don’t think they have very good evidence that subclinical kidney impairment. “If your kidneys are slightly com-
TMAO is a causative element in the disease process,” says Marie promised, that’s going to lead to an elevation in TMAO.” Kidney
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Caudill, PhD, RD, a professor and researcher in the division of nutri- function aside, another potential wrinkle in association studies
tional sciences at Cornell University in Ithaca, New York. “We’re at is that some research suggests the wrong player in the choline-
association at this point. It’s so murky. Association isn’t causation, TMA-TMAO cycle is being targeted. A 2019 study assessed TMA
but we seem to go down that road anyway.” and TMAO levels in both healthy adults and cardiac patients—
The 2011 Cleveland Clinic study also added choline or TMAO to unusual, since the studies that have found associations between
the diets of a species of mice that were at elevated risk of developing TMAO and increased cardiovascular risk generally haven’t mea-
atherosclerosis, and found that the mice in fact developed athero- sured TMA levels. They found that the cardiac patients had TMA
sclerosis. However, this species of mice lacks the gene responsible levels twice as high as levels in the healthy subjects, and that those
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for the protein that drives reverse cholesterol transport, Caudill levels were inversely correlated with estimated GFR, again sug-
says. Reverse cholesterol transport is a process that removes excess gesting that impaired kidney function plays a role. Interestingly,
cholesterol from the tissues and delivers it to the liver, where it can despite the significantly higher TMA levels, the cardiac patients
be excreted or recycled. “They’re looking at an animal model that only had slightly higher TMAO levels that didn’t reach statistical
doesn’t express all the genes humans do,” she says. “When you add significance. The authors also found that TMA, but not TMAO,
that gene back in, TMAO has no adverse effect.” she says. had biological effects that could harm the circulatory system—
One headline-grabbing detail of some TMAO studies is that specifically, damaging the cells responsible for contracting the
vegans and vegetarians produce far less TMAO after consum- heart—and that treatment with TMAO actually protected these
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ing its precursor nutrients than do omnivores. For example, cells from damage. Moreover, many studies have found other
a 2017 study published in Circulation found that oral choline protective functions of TMAO, including keeping cells from losing
supplementation of approximately 450 mg choline per day for volume under stress. 16,17,23
two months—an amount far above the AI when added to an
omnivore diet—led to an increase in fasting blood TMAO levels Genetic and Microbial Influences
and a corresponding increase in clumping of blood platelets. Despite many researchers finding associations between TMAO
These increases were more pronounced in omnivores than they levels and CVD risk and hypothesizing about potential causal
were in vegans and vegetarians and were attenuated by aspirin mechanisms, no actual mechanisms have been determined.
therapy, possibly because aspirin alters the gut microbe com- Scientists haven’t yet identified a dedicated TMAO receptor on
munity and interferes with TMAO production. What’s notable cells, and little is known about which specific gut microbe spe-
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is that the percentage of platelet clumping varied widely within cies are the primary producers of TMA. So far, researchers only
each diet group after supplementation, suggesting that a third know which broader bacteria groups are associated with higher
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factor led to differences between individuals. or lower circulating TMAO levels.
In an editorial in AME Medical Journal, Caudill stressed that “We differ in our gut microbiota,” Caudill says. “Those who are
supplemental choline was a more potent substrate for TMA/ sick have a different gut microbiota than those who are well,” she
TMAO than the phosphatidylcholine from food. Furthermore, says. “Those who have colon cancer may have a completely dif-
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the study couldn’t measure hard disease endpoints. “The prob- ferent gut microbe population.”
lem with surrogate markers is they don’t predict death,” Caudill For example, Caudill’s group found that TMAO was elevated
says. “At the end of the day, what’s important is, does this reduce in women at higher risk of colon cancer in a study that used a
risk of disease or death?” subset of participants from the Women’s Health Initiative, but she

38 TODAY’S DIETITIAN • FEBRUARY 2020