We Are Not Field Mice
become an important treatment target for multiple conditions, and perhaps offer some “cures”
hitherto undiscovered.
As Valentin Fuster, MD, PhD, physician-inchief of the Mount Sinai Medical Hospital and
peutic approach, but as a concept
that has been around pretty much
since the dawn of civilization. “If
you think about it, much of traditional medicine is focused around
dietary interventions from different
sources of materials that the body
can convert,” he said. Now, we’re
just gaining a better understanding of what it’s really all about.
Dr. Tang is the director of the
Cleveland Clinic’s Center for Clinical Genomics, and the first author
on many of the TMAO studies
done in Dr. Hazen’s laboratory
at the Cleveland Clinic’s Lerner
Research Institute.
Meanwhile, there is a flurry of
questions and issues surrounding
FMT. How do you determine donor
suitability? Different trials are using
different ‘product,’ so how do you
compare across trials or show
reproducibility? From where do you
sample in the body? How do you
ensure you’re not inadvertently
introducing harmful pathogens?
There are several industry entities
trying to answer these questions in
the hopes of bagging an FDA approval and cornering the market on
a predictable poop product.
Rodents make up about 90% of all the animals used in research, the
majority of which are mice.1 Mice are relatively easy to maintain, are
highly fertile, and have genetic similarity to humans, which makes them
ideal candidates for genetic manipulation and study. But mice come in
different shapes and sizes, and these differences are relevant when attempting to draw conclusions about human health from animal studies.
Germ-free mice have no resident microorganisms. Gnotobiotic mice
could either be germ free or only known to carry certain strains of bacteria or microorganisms. There are also laboratory mice raised in specificpathogen-free environments, which means they are free of a specific
list of disease-causing pathogens and opportunistic and commensal
organisms by routine testing. And then there are plain old field mice.
These mice models offer important avenues for demonstrating
the functions of the gut microbiota and have been instrumental in
propelling the field of microbiome research forward. Germ-free mice
are used extensively in microbiome research because the ability to
carefully control the microbial composition in these mice allows for
mechanistic testing showing causality, as well as the study of microbemicrobe interactions and microbe-host interactions.
In early breakthrough experiments, the role of the gut in weight
regulation was demonstrated when germ-free mice fed a high-fat diet
had reduced adiposity compared to conventionally-raised mice fed the
same diet.2 In another experiment, when germ-free mice were colonized
with fecal content from conventionally-raised mice, they gained weight
without increasing caloric intake.
Yet another study showed that when germ-free mice were colonized
with fecal matter from human twins discordant for obesity, those mice who
received fecal matter from the obese twin gained weight compared to
those who got thin-twin feces. Interestingly, when the mice were housed
together such that microbial transfer could occur (via coprophagia or
ingestion of feces), the microbiota profile of the obese mice started to shift
toward the more lean metabolic phenotype. The kicker: this occurred if—
and only if—the formerly obese mice were fed a diet high in fiber and low
in saturated fat, emphasizing the contribution of diet to the story.
As well, the microbiota of the lean mice had greater efficiency to ferment short-cha in fatty acids, such as butyrate, proprionate, and acetate,
which are produced when dietary fiber is fermented in the colon and are
important for colonic and metabolic health.
So, clearly mice models offer important opportunities to study the
contributions of the gut to health and disease. However, the same microbiome that the mice are allowing us to study is actually a barrier to
the translatability of laboratory experiments in mice to humans, as recently outlined by Peter Libby, MD, recently in Circulation Research.3
Inbred strains of mice commonly used in research tend to
have a more categorical immune system than humans. In the
pathogen-free environment, the laboratory mouse immune systems
aren’t challenged or exposed. Humans, on the other hand, endure
constant exposure to pathogenic and commensal microbes that
serve to train and change their microbial environment. Mice engage
in coprophagia, thereby perpetuating their microbial environments.
Humans don’t. And the list goes on.
To sum: while mice models are wildly useful to deciphering the mysteries of the human microbiome, as well as other organ systems, basic
scientists sometimes underestimate the “enormous distance; effort; and
expenditure” that lies between their successful lab experiment and “the
reality of clinical translation,” said Dr. Libby.
“Ultimately, cardiovascular science will continue its impressive advance by combining the rigor and control of laboratory
experimentation with the much muddier reality of human patients
and populations: the delight and challenge we encounter in daily
practice,” wrote Dr. Libby. ■
REFERENCES
REFERENCES
1. Drekonja D, et al. Ann Intern Med.
2015;162:630-8.
2. Moayyedi P. Curr Opin Gastroenterol.
2016;32:282-6.
1. JoVE Science Education Database. An Introduction to the Laboratory Mouse: Mus musculus. JoVE, Cambridge, MA, 2016.
2. Aron-Wisnewsky J, Clement K. Nat Rev Nephrol. 2016;12:169-81.
3. Libby P. Circ Res. 2015;117:921-5.
editor-in-chief of JACC, recently summarized, referring specifically to the gut metabolite TMAO:
“I’m not entirely certain how far this field will
go, but better we watch it.” n
REFERENCES:
1. Sonnenburg JL, Bäckhed F. Nature. 2016;535:56-64.
2. Backhed F, et al. Proc Natl Acad Sci U S A. 2004;101:15718-23.
3. Wang Z, et al. Nature. 2011;472:57-63.
4. Tang WH, et al. N Engl J Med. 2013;368:1575-84.
5. Koeth RA, et al. Nat Med. 2013;19:576-85.
6. Wang Z, et al. Eur Heart J. 2014;35:904-10.
7. Tang WH, et al. J Am Coll Cardiol. 2014;64:1908-14.
8. Gregory JC, et al. J Biol Chem. 2015;290:5647-60.
9. Tang WH, et al. Circ Res. 2015;116:448-55.
10. Warrier M, et al. Cell Rep. 2015. pii: S2211-1247(14)01065-1.
11. Zhu W, et al. Cell. 2016;165:111-24.
12. Senthong V, et al. J Am Coll Cardiol. 2016;67:2620-8.
13. Senthong V, et al. J Am Heart Assoc. 2016;5. pii: e002816.
14. Li Y, et al. Diabetes Care. 2015;38:e13-4.
15. Zheng Y, et al. Am J Clin Nutr. 2016;104:173-80.
16. Wang Z, et al. Cell. 2015;163:1585-95.
17. Libby P, et al. J Am Coll Cardiol. 2016;67:1091-103.
18. Estruch R, et al. N Engl J Med. 2013; 368:1279-90.
We Are Not Alone:
Intestinal Microbial Communities and the Congested Gut in Heart Failure
W.H. Wilson Tang, MD, is Director of the Cleveland Clinic’s Center for Clinical Genomics
and Professor of Medicine, at the Cleveland Clinic Lerner
College of Medicine. CSWN talks with him about his
review paper in JACC Heart Failure.
We Are Not Alone: Understanding the Contributions of
Intestinal Microbial Communities and the Congested Gut
in Heart Failure. JACC Heart Fail. 2016;4:228-9. http://
heartfailure.onlinejacc.org/article.aspx?articleID=2491374
Sharing Your Microbes with Friends
It’s research not for the squeamish, and certainly fecal microbial transplantation (FMT) may be
the butt of many jokes, but it is
also an established and growing therapeutic approach. It is
considered a “miracle cure” for
patients with recurrent Clostridium
difficile infection (CDI), according
to Erica Sonnenburg, PhD, where
it has been tested in at least
two randomized clinical trials.
FMT delivers a bolus of healthy
microbes to the gut, which appear
to competitively exclude the bad
bugs. Treatment is associated
with symptom resolution in 85% of
patients, markedly higher than the
response other treatment options.1
Most recipients report improvement within 1 or 2 days and
require only a single treatment.
FMT has also been tested
in inflammatory bowel disease
(IBD), but with less stellar results.
The technique has received a
great deal of media attention
with several websites offering
“do it yourself” instruction. While
the reported results in IBD show
promise, the results don’t appear
to match those seen with CDI and
there is a dearth of randomized
trial data available.
“At present there are insufficient data to recommend FMT in
36 CardioSource WorldNews
IBD, and patients certainly should
not be administering this themselves,” wrote Paul Moayyedi,
MD, PhD, the director of the
Division of Gastroenterology at
McMaster University in Hamilton,
Ontario, Canada, in a recent
review on the topic.2
While there are some “glimmers of hope,” Erica Sonnenburg,
PhD, thinks we still need a better
understanding of what a normal
microbial community looks like
before we can fully understand
how to transplant bugs to repair
an abnormal community.
“It could be the type of thing
where somebody has inflammatory
bowel disease and we do a typing
of their microbiota, and say, ‘OK, a
fecal transplant will probably work
for you because you have these
hallmarks’…but we just don’t know
those rules yet.”
FMT has also been tested in
several cardiometabolic diseases.
Again, the results are promising (improved insulin sensitivity,
increased gut richness, increased
abundance of butyrate-producing
bacteria), but whether FMT will
one day be a reliable treatment for
CMDs is unanswered.
In a video interview with
CSWN, W.H. Wilson Tang, MD,
viewed FMT not just as a thera-
August 2016