Cardiology News
Ongoing Research Points to Key Role of Gut
Microbes in Cardiovascular Health
Tracy Hampton, PhD
M
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When gut bacteria metabolize the meat component l-carnitine, they produce a substance called trimethylamine-N-oxide (TMAO) that promotes
artery blockage and thrombosis risk.
Adapted from Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X,
Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA,
Brown JM, Lusis AJ, Hazen SL. Gut microbial metabolite TMAO enhances platelet
hyperreactivity and thrombosis risk. Cell. 2016;165:111–124 with permission of the
publisher. Copyright © 2016, Elsevier.
cant contribution, even stronger than
clinical risk factors and genetics, to
individual variations in body mass index and blood levels of triglycerides
and HDL, but they have little effect
on LDL or total cholesterol levels,”
said Fu. Much more work is needed,
however, to fully map out the details
behind which bacterial types are detrimental and which are beneficial.
Hazen’s research is providing
some clues concerning the mechanisms that may be involved in at least
some of the links between gut bacteria and cardiovascular parameters.
His research team has shown that
when gut bacteria metabolize specific nutrients abundant in meat and
animal products including choline,
phosphatidylcholine, and l-carnitine,
they produce a substance called
Circulation. 2016;134:1687–1688. DOI: 10.1161/CIRCULATIONAHA.116.025623
trimethylamine-N-oxide (TMAO) that
promotes atherosclerosis.
“Looking at multiple inbred strains
of mice, we can observe that variations in TMAO levels across the different inbred strains account for about
the same contribution to variation in
atherosclerotic plaque development
as changes in cholesterol levels do,”
said Hazen. In the investigators’ recent work in humans, TMAO served
as the strongest tie to coronary artery atherosclerotic burden in headto-head comparisons with other laboratory parameters and traditional risk
factors.
The mechanisms through which
the TMAO pathway may affect cardiovascular health are quite extensive.
“Changes in sterol metabolism and
transport at the level of the gut, liver,
November 22, 2016
1687
THE PULSE
icrobes that normally reside in
the gut are receiving considerable attention as important
contributors to cardiovascular health
and disease. From digestion and
metabolism to pain perception and
cognition, there may be no aspect of
human biology that is free from the
effects of these organisms.
Regarding the cardiovascular
system, effects may result from microbial imbalances in the digestive
tract that promote systemic inflammation, and from byproducts generated from gut bacteria, as well,
as they metabolize certain dietary
components.
“Microbial transplantation studies
in animals show a causal contribution of gut microbes to processes
like thrombosis and atherosclerosis,” said Stanley Hazen, MD, PhD,
who is Chairman of the Department
of Cellular and Molecular Medicine
at the Cleveland Clinic. Studies have
also demonstrated causal effects on
metabolic disorders including obesity
and insulin resistance, but the magnitude of these effects in humans is
unclear. In addition, research suggests that the relative proportions
of specific bacterial taxa in the gut
microbiome may determine the propensity toward such conditions. For
example, Jingyuan Fu, PhD, an associate professor of genetics at the
University of Groningen in The Netherlands, and her colleagues recently
identified 34 bacterial taxa associated with body mass index and blood
lipids in the general population. “Gut
microbes seem to make a signifi-
Hampton
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and artery wall have been shown,”
said Hazen. “More recently, TMAO
has been shown to change platelet reactivity and responsiveness to known
clot-inducing agents, as well as to
promote arterial endothelial cell activation and inflammatory gene expression.” The TMAO pathway also fosters
fibrosis in end-organ tissues and facilitates kidney function decline, adverse
ventricular remodeling, and heart failure after long-term exposure.
“TMAO is no doubt just the tip of
the iceberg,” said Hazen. “There is
every reason to believe that numerous other microbial pathways exist
that impact cardiovascular disease
and metabolic phenotypes. We just
need to learn the participants and
players involved, and it will no doubt
result in numerous opportunities for
new and improved diagnostics and
therapeutics in the field of cardiometabolic diseases.”
Short-chain fatty acids (SCFAs),
which are generated when bacteria
ferment dietary fibers, may also play
an important role in the gut microbiome’s link to cardiovascular health.
“SCFAs not only serve as an energy
source for the host but also act as
signaling molecules to regulate inflammation,” explained Fu. “Research
has shown both in vivo and in vitro
that SCFAs have beneficial effects in
the host and could lower the risk of
cardiovascular disease.”
Many efforts are underway to develop therapeutic strategies that ma-
1688 November 22, 2016
nipulate gut bacteria to improve human health. “These strategies range
from dietary interventions, probiotics
and prebiotics, fecal transplantation,
and small-molecule drugs targeting
specific bacterial pathways,” said Fu.
Recent studies show that chronic
dietary changes that incorporate
healthy options reduce TMAO levels.
When Hazen and his colleagues compared how the guts of omnivores,
vegetarians, and vegans processed
l-carnitine, they found the omnivores’
gut bacteria led to generation of
TMAO and certain other metabolites,
whereas the vegetarians’ and vegans’ bacteria did not. Studies also
indicate that adhering to the Mediterranean diet boosts levels of SCFAs
and decreases TMAO.
In more focused research, a compound developed by Hazen’s team
that is also found in some vinegars
and olive oils effectively blocked the
gut bacterial pathway that produces
TMAO in mice and prevented atherosclerosis. Similarly, resveratrol, a
compound found in red wine that has
antioxidant properties, was found to
alter the ratio of different bacterial
types in the gut and attenuate TMAOinduced atherosclerosis. Existing
medications, including statins, are
also known to impact the gut microbiome, but their effects on TMAO remain to be determined.
TMAO and other microbial-dependent products that can be measured
in the blood might also be used as
cardiovascular diagnostic or prognostic markers. In several large clinical
studies, plasma levels of TMAO were
predictive of subsequent heart attack,
stroke, and death, even after adjustments for traditional risk factors.
Although much of this work is
generating promising clinical leads,
teasing out the details behind how the
complex gut microbiome affects the
cardiovascular system, and how to
use that information to meaningfully
improve health, will be no easy task.
There are ≈100 trillion microbes representing an estimated 5000 species
living in the human gastrointestinal
tract.
“We need to look at human health
and physiology in a new and more
global way, and appreciate that we
are actually walking communities,
comprised not only of Homo sapiens cells, but also trillions of microorganism inhabitants,” said Hazen.
“Our overall metabolism and how
we experience a meal, which is our
largest environmental exposure, is
linked not only to our genes, but to
the gut microbial filter. We live in the
‘bus exhaust’ of our microbes within,
and differences in disease susceptibility between us appear in part to
depend on the microbial products
we absorb into our bodies with every meal.” n
Circulation is available at
http://circ.ahajournals.org.
© 2016 American Heart Association, Inc.
Circulation. 2016;134:1687–1688. DOI: 10.1161/CIRCULATIONAHA.116.025623
Ongoing Research Points to Key Role of Gut Microbes in Cardiovascular Health
Tracy Hampton
Circulation. 2016;134:1687-1688
doi: 10.1161/CIRCULATIONAHA.116.025623
Downloaded from http://circ.ahajournals.org/ by guest on July 28, 2017
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