When we think about the causes of neurological disorders and how to treat them, we think about targeting the brain. But is this the best or only way? Maybe not.
New research by scientists at
Baylor College of Medicine suggests that microbes in the gut may contribute to
certain symptoms associated with complex neurological disorders.
The findings, published in
the journal Cell, also suggest that microbe-inspired therapies may
one day help to treat them.
Dr. Mauro Costa-Mattioli,
professor and Cullen Foundation Endowed Chair in neuroscience and director of
the Memory and Brain Research Center at Baylor, discovered with his team that
different abnormal behaviors are interdependently regulated by the host’s genes
and microbiome. Specifically, the team found that in mouse models for
neurodevelopmental disorders, hyperactivity is controlled by the host’s
genetics, whereas social behavior deficits are mediated by the gut microbiome.
More importantly from a
therapeutic perspective, they found that treatment with a specific microbe that
promotes the production of compounds in the biopterin family in the gut or
treatment with a metabolically active biopterin molecule improved the social
behavior but not motor activity.
“We are the bearers of both
host and microbial genes. While most of the focus has traditionally been in
host genes, the gut microbiome, the community of microorganisms that live
within us, is another important source of genetic information,” Costa-Mattioli
said.
The work by Costa-Mattioli’s
group offers a different way of thinking about neurological disorders in which
both human and microbial genes interact with each other and contribute to the
condition. Their findings also suggest that effective treatments would likely
need to be directed at both the brain and the gut to fully address all
symptoms. Additionally, they open the possibility that other complex
conditions, such as cancer, diabetes, viral infection or other neurological
disorders may have a microbiome component.
Brain-gut-microbiome
crosstalk
“It’s very difficult to study
these complex interactions in humans, so in this study, we worked with a mouse
model for neurodevelopmental disorders in which the animals lacked both copies
of the Cntnap2 gene (Cntnap2-/- mice),” said co-first author Sean Dooling, a
Ph.D. candidate in molecular and human genetics in the Costa-Mattioli lab.
“These mice presented with
social deficits and hyperactivity, similar to those observed in autism spectrum
disorders (ASD). In addition, these mice, like many people with ASD, also had
changes in the bacteria that make up their microbiome compared to the mice
without the genetic change.”
Further experiments showed
that modulating the gut microbiome improved the social behavior in the mutant
mice, but did not alter their hyperactivity, indicating that the changes in the
microbiome selectively contribute to the animals’ social behavior.
“We were able to separate the
contribution of the microbiome and that of the animal’s genetic mutation on the
behavioral changes,” Dooling said. “This shows that the gut microbiome
shouldn’t be ignored as an important variable in studying health and disease.”
Equipped with this knowledge,
the researchers dug deeper into the mechanism underlying the microbiome’s
effect on the animal’s social deficits. Based on their previous work, the
investigators treated the mice with the probiotic microbe, L.
reuteri.
“We found that L.
reuteri also can restore normal social behavior but cannot
correct the hyperactivity in Cntnap2-/- mice,” said co-first author Dr. Shelly
Buffington, a former postdoctoral fellow in the Costa-Mattioli lab and now an
assistant professor at the University of Texas Medical Branch in Galveston.
However, the bigger surprise
came when the investigators administered to the asocial mice a metabolite or
compound they found was increased in the host’s gut by L.
reuteri. They discovered that the animals’ social deficits also
were improved after treating them with the metabolite instead of the bacteria.
“This provides us with at
least two possible ways to modulate the brain from the gut, with the bacteria
or the bacteria-induced metabolite,” said Buffington.
Bacteria
to heal your brain & beyond
Could this work inspire new
breakthroughs in treating neurological disorders? While it is still too early
to say for sure, the investigators are particularly excited about the
translational implications of their findings. “Our work strengthens an emerging
concept of a new frontier for the development of safe and effective
therapeutics that target the gut microbiome with selective probiotic strains of
bacteria or bacteria-inspired pharmaceuticals,” Buffington said.
“As we learn more about how
these bacteria work, we will be able to more precisely and effectively leverage
their power to help treat the brain and perhaps more,” Dooling added.
This research represents
important step forward in the field as many disorders, especially those
affecting the brain, remain very difficult to treat.
“Despite all the scientific
advances and the promise of gene manipulation, it is still difficult to
modulate human genes to treat diseases, but modulating our microbiome may be an
interesting, noninvasive alternative,” said Costa-Mattioli. Indeed, L.
reuteri currently is being tested in a clinical trial in Italy
in children with autism, and Costa-Mattioli aims to start his own trial soon.
“In my wildest dreams, I
could have never imagined that microbes in the gut could modulate behavior and
brain function. To think now that microbial-based strategies may be a viable
way to treat neurological dysfunction, is still wild, but very exciting.”
Source: https://www.bcm.edu/news/microbes-may-hold-the-key-for-treating-neurological-disorders
Journal article: https://www.cell.com/cell/fulltext/S0092-8674(21)00159-8
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