A microbial compound in the gut leads to anxious behaviors in mice


Date:
February 14, 2022
Source:
California Institute of Technology
Summary:
A new study shows how a particular molecule, produced by gut
bacteria, affects brain function and promotes anxiety-like behaviors
in mice.



FULL STORY ========================================================================== [Mouse (stock | Credit: (c) Szasz-Fabian Jozsef / stock.adobe.com] Mouse
(stock image).

Credit: (c) Szasz-Fabian Jozsef / stock.adobe.com [Mouse (stock | Credit:
(c) Szasz-Fabian Jozsef / stock.adobe.com] Mouse (stock image).

Credit: (c) Szasz-Fabian Jozsef / stock.adobe.com Close A Caltech-led
team of researchers has discovered that a small-molecule metabolite,
produced by bacteria that reside in the mouse gut, can travel to the
brain and alter the function of brain cells, leading to increased
anxiety in mice. The work helps uncover a molecular explanation for
recent observations that gut microbiome changes are associated with
complex emotional behaviors.


==========================================================================
The research was conducted primarily in the laboratory of Sarkis
Mazmanian, Luis B. and Nelly Soux Professor of Microbiology and
affiliated faculty member with the Tianqiao and Chrissy Chen Institute
for Neuroscience at Caltech. A paper describing the study appears on
February 14 in the journal Nature.

Decades of research have shown that the communities of bacteria that
inhabit the intestines of animals (the microbiome) influence the immune
system and metabolism; studies in the last few years have linked the
microbiome to brain function and mood. People with certain neurological conditions have distinctly different gut bacteria communities. Further,
studies in mice have shown that manipulating these communities can alter neurodevelopmental and neurodegenerative states, either ameliorating or exacerbating symptoms.

"It's been really difficult to show causation between something that's happening in the gut and the brain, rather than just associations between
the disease states and the presence or absence of certain microbes,"
says Brittany Needham, first author of the new study and a postdoctoral
scholar in the Mazmanian lab. "We were interested in trying to understand
the molecular messages that are going between the gut and the brain,
and how these signals may lead to changes in behavior." This study
focused on a bacterial metabolite (a by-product of microbes) called 4-ethylphenyl sulfate, or 4EPS. Initially produced by microbes in the intestines, 4EPS is then absorbed into the bloodstream and circulates throughout the body in both humans and mice. In 2013, the Mazmanian
lab showed that this particular molecule was present in higher levels
in mice with altered neurological development, specifically, a mouse
model of autism and schizophrenia. Though other aspects of the altered microbiome differed from the healthy microbiome, 4EPS levels were by far
the most different. Additionally, in a screen of human blood samples from
231 individuals, 4EPS levels were about seven times higher in children
on the autism spectrum than in neurotypical children.

In this work, the team focused on the effects of 4EPS on mouse models
of anxiety. While anxiety disorders in humans are complex, animal models provide a way to study the precise changes in the brain and body that lead
to anxious behaviors. "Anxiety" in mice is measured by their willingness
to explore or hide in a new space as well as the time spent in a risky environment. Bold mice will explore a new space, sniffing around, but
anxious mice will hide, as if facing a predator, instead of exploring.



==========================================================================
The study compared two groups of laboratory mice: one group was colonized
with a pair of bacteria that were genetically engineered to produce 4EPS;
the control group of mice were colonized with bacteria that were identical except lacked the ability to produce 4EPS. Then, the mice were introduced
to a new arena, and researchers measured each mouse's behavior.

The mice with 4EPS spent much less time exploring the area and more time
hiding as compared to their non-4EPS counterparts, indicating higher
levels of anxiety. Brain scans of the 4EPS mice also showed that some of
the brain regions associated with fear and anxiety were more activated in addition to overall changes in brain activity and functional connectivity.

Looking closer at brain cells within these altered regions, the team
found that particular cells called oligodendrocytes were altered. These
cells are important in part because they produce a protein called myelin,
which acts as a protective coating around neurons and nerve fibers called axons, like insulation around an electrical wire. The team found that in
the presence of 4EPS, oligodendrocytes are less mature and consequently
produce less myelin, leading to thinner insulation around axons.

However, when the 4EPS mice were treated with a drug known to increase
myelin production in oligodendrocytes, the drug was able to overpower the negative effects of 4EPS -- the mice regained normal myelin production,
and the anxious behaviors were reduced.

In a related study appearing simultaneously in the journal Nature
Medicine, Needham showed that treating mice with an oral drug to soak
up and remove 4EPS from their systems led to reductions in anxious
behaviors. This result enabled a small clinical study that also
gave humans the drug in an open-label trial (no placebo or control
group). Sequestering 4EPS in the human gut led to reduced levels of 4EPS
in the blood and urine, and many of the 26 study participants displayed
overall decreased levels of anxiety.



========================================================================== "It's an exciting proof-of-concept finding that a specific microbial
metabolite alters the activity of brain cells and complex behaviors in
mice, but how this is happening remains unknown," says Mazmanian. "The
basic framework for brain function includes integration of sensory and molecular cues from the periphery and even the environment. What we show
here is similar in principle but with the discovery that the neuroactive molecule is of microbial origin. I believe this work has implications for
human anxiety or other mood conditions." The next steps for the work are
to examine the mechanisms through which 4EPS affects oligodendrocytes --
which proteins it may be interacting with, whether 4EPS is affecting
changes directly in the brain, or if it is affecting another part of
the body and those effects are making their way up to the brain. Also,
it will be critical to show that the human data have an effect in a well- powered and controlled clinical trial, which is now underway.

In addition to Needham and Mazmanian, Caltech co-authors are former
research technician Mark Adame; research technician Joseph Boktor;
former postdoctoral scholar Wei-Li Wu (now of National Cheng Kung
University in Taiwan); postdoctoral scholar Claire Rabut; EM scientist
Mark Ladinsky; lecturer in chemistry Son-Jong Hwang; graduate student
Jessica Griffiths; Pamela Bjorkman, David Baltimore Professor of Biology
and Bioengineering, Merkin Institute Professor, and executive officer
for biology and biological engineering; and Mikhail Shapiro, professor
of chemical engineering and Howard Hughes Medical Institute Investigator.

Additional co-authors are Masanori Funabashi of Stanford University
and Daiichi Sankyo RD Novare Co.; Zhuo Wang, Yumei Guo, and Daniel
Holschneider of USC; Jillian Haney and Daniel Geschwind of UCLA; Qiyun
Zhu of UC San Diego and Arizona State University; Rob Knight of UC San
Diego; and Michael Fischbach of Stanford University.

Funding was provided by the Center for Environmental Microbial
Interactions, the National Science Foundation, the Human Frontier Science Program, the National Institutes of Health, the Ministry of Science and Technology in Taiwan, the Heritage Medical Research Institute, and Lynda
and Blaine Fetter.

Sarkis Mazmanian is co-founder of Axial Therapeutics, which conducted
the clinical trial.

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided
by California_Institute_of_Technology. Original written by Lori
Dajose. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Brittany D. Needham, Masanori Funabashi, Mark D. Adame, Zhuo
Wang, Joseph
C. Boktor, Jillian Haney, Wei-Li Wu, Claire Rabut, Mark S. Ladinsky,
Son- Jong Hwang, Yumei Guo, Qiyun Zhu, Jessica A. Griffiths, Rob
Knight, Pamela J. Bjorkman, Mikhail G. Shapiro, Daniel H. Geschwind,
Daniel P.

Holschneider, Michael A. Fischbach, Sarkis K. Mazmanian. A
gut-derived metabolite alters brain activity and anxiety behaviour
in mice. Nature, 2022; DOI: 10.1038/s41586-022-04396-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220214121254.htm

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