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Gut microbes contribute to recurrent ‘yo-yo’ obesity

New research in mice may
in the future help dieters keep the weight off

Date:

November 29, 2016

Source:

Weizmann Institute of Science

Summary:

Researchers have shown
in mice that intestinal microbes — collectively termed the gut microbiome —
play an unexpectedly important role in exacerbated post-dieting weight gain,
and that this common phenomenon may in the future be prevented or treated by altering
the composition or function of the microbiome.

Following a successful
diet, many people are dismayed to find their weight rebounding — an
all-too-common phenomenon termed “recurrent” or “yo-yo”
obesity. Worse still, the vast majority of recurrently obese individuals not
only rebound to their pre-dieting weight but also gain more weight with each
dieting cycle. During each round of dieting-and-weight-regain, their proportion
of body fat increases, and so does the risk of developing the manifestations of
metabolic syndrome, including adult-onset diabetes, fatty liver and other
obesity-related diseases.

As reported today in Nature,
researchers at the Weizmann Institute of Science have shown in mice that
intestinal microbes — collectively termed the gut microbiome — play an
unexpectedly important role in exacerbated post-dieting weight gain, and that
this common phenomenon may in the future be prevented or treated by altering
the composition or function of the microbiome.

The study was
performed by research teams headed by Dr. Eran Elinav of the Immunology
Department and Prof. Eran Segal of the Computer Science and Applied Mathematics
Department. The researchers found that after a cycle of gaining and losing
weight, all the mice’s body systems fully reverted to normal — except the
microbiome. For about six months after losing weight, post-obese mice retained
an abnormal “obese” microbiome.

“We’ve shown in
obese mice that following successful dieting and weight loss, the microbiome
retains a ‘memory’ of previous obesity,” says Elinav. “This
persistent microbiome accelerated the regaining of weight when the mice were
put back on a high-calorie diet or ate regular food in excessive amounts.”
Segal elaborates: “By conducting a detailed functional analysis of the
microbiome, we’ve developed potential therapeutic approaches to alleviating its
impact on weight regain.”

The study was led by
Christoph Thaiss, a Ph.D. student in Elinav’s lab. Thaiss collaborated with
master’s student Shlomik Itav of the Elinav lab, Daphna Rothschild, a Ph.D.
student of Segal’s lab, as well as with other scientists from Weizmann and
elsewhere.

In a series of
experiments, the scientists demonstrated that the makeup of the
“obese” microbiome was a major driver of accelerated post-dieting
weight gain. For example, when the researchers depleted the intestinal microbes
in mice by giving them broad-spectrum antibiotics, the exaggerated post-diet
weight gain was eliminated. In another experiment, when intestinal microbes
from mice with a history of obesity were introduced into germ-free mice (which,
by definition, carry no microbiome of their own), their weight gain was
accelerated upon feeding with a high-calorie diet, compared to germ-free mice
that had received an implant of intestinal microbes from mice with no history
of weight gain.

Next, the scientists
developed a machine-learning algorithm, based on hundreds of individualized
microbiome parameters, which successfully and accurately predicted the rate of
weight regain in each mouse, based on the characteristics of its microbiome
after weight gain and successful dieting. Furthermore, by combining genomic and
metabolic approaches, they then identified two molecules driving the impact of
the microbiome on regaining weight. These molecules — belonging to the class
of organic chemicals called flavonoids that are obtained through eating certain
vegetables — are rapidly degraded by the “post-dieting” microbiome,
so that the levels of these molecules in post-dieting mice are significantly
lower than those in mice with no history of obesity. The researchers found that
under normal circumstances, these two flavonoids promote energy expenditure
during fat metabolism. Low levels of these flavonoids in weight cycling
prevented this fat-derived energy release, causing the post-dieting mice to
accumulate extra fat when they were returned to a high-calorie diet.

Finally, the
researchers used these insights to develop new proof-of-concept treatments for
recurrent obesity. First, they implanted formerly obese mice with gut microbes
from mice that had never been obese. This fecal microbiome transplantation
erased the “memory” of obesity in these mice when they were
re-exposed to a high-calorie diet, preventing excessive recurrent obesity.

Next, the scientists
used an approach that is likely to be more unobjectionable to humans: They
supplemented post-dieting mice with flavonoids added to their drinking water.
This brought their flavonoid levels, and thus their energy expenditure, back to
normal levels. As a result, even on return to a high-calorie diet, the mice did
not experience accelerated weight gain. Segal said: “We call this approach
‘post-biotic’ intervention. In contrast to probiotics, which introduce helpful
microbes into the intestines, we are not introducing the microbes themselves
but substances affected by the microbiome, which might prove to be more safe and
effective.”

Recurrent obesity is
an epidemic of massive proportions, in every meaning of the word. “Obesity
affects nearly half of the world’s adult population, and predisposes people to
common life-risking complications such as adult-onset diabetes and heart
disease,” says Elinav. “If the results of our mouse studies are found
to be applicable to humans, they may help diagnose and treat recurrent obesity,
and this, in turn, may help alleviate the obesity epidemic.”

Also taking part in
the study were Mariska Meijer, Maayan Levy, Claudia Moresi, Lenka Dohnalova,
Sofia Braverman, Shachar Rozin, Dr. Mally Dori-Bachash and Staff Scientist
Hagit Shapiro of the Immunology Department, Staff Scientists Drs. Yael Kuperman
and Inbal Biton, and Prof. Alon Harmelin of the Veterinary Resources
Department, and Dr. Sergey Malitsky and Prof. Asaph Aharoni of the Plant and
Environmental Sciences Department — all of the Weizmann Institute of Science,
as well as Prof. Arieh Gertler of the Hebrew University of Jerusalem and Prof.
Zamir Halpern of the Tel-Aviv Sourasky Medical Center.

Story Source:

Materials provided by Weizmann Institute of Science. Note:
Content may be edited for style and length.

Journal Reference:

1.    Christoph A. Thaiss, Shlomik Itav, Daphna
Rothschild, Mariska Meijer, Maayan Levy, Claudia Moresi, Lenka Dohnalová, Sofia
Braverman, Shachar Rozin, Sergey Malitsky, Mally Dori-Bachash, Yael Kuperman,
Inbal Biton, Arieh Gertler, Alon Harmelin, Hagit Shapiro, Zamir Halpern, Asaph
Aharoni, Eran Segal, Eran Elinav. Persistent microbiome alterations
modulate the rate of post-dieting weight regain. Nature, 2016;
DOI: 10.1038/nature20796

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