Science: Gut bacteria affect brain health

There is growing evidence that the trillions of microbes that normally live in our guts, the so-called gut microbiome, have a profound impact on
how our bodies function.
Members of this microbial community produce vitamins that help us digest food, prevent the overgrowth of harmful bacteria, regulate the immune system, among other benefits
.
Now, according to researchers at Washington University School of Medicine in St.
Louis, a new study shows that the gut microbiome also plays a key role
in our brain health.

The study, conducted in mice, found that gut bacteria (in part by producing compounds such as short-chain fatty acids) influence the behavior of immune cells throughout the body, including those in the brain, which damage brain tissue and exacerbate neurodegeneration
in diseases such as Alzheimer's disease.
The findings, published Jan.
13 in the journal Science, open up possibilities
for remodeling the gut microbiota as a way to prevent or treat neurodegenerative diseases.

Senior authors David M.
Holtzman, M.
D.
, Barbara Burton and David M.
Holtzman, PhD, said: "We gave the young mice antibiotics for just one week, and we saw permanent changes in their gut microbiota, immune response, and degree of neurodegeneration associated with a protein called tau
.
Excitingly, manipulating the gut microbiome could be a way to have an impact on the brain without having to implant anything
directly into the brain.
”

There is growing evidence that the gut microbiome of people with Alzheimer's disease may be different from
that of healthy people.
But it's unclear whether these differences are a cause or a consequence of the disease, or both, or what effect altering the microbiome might have on the course of the disease
.

To determine whether the gut microbiome might play a causal role, the researchers altered the gut microbiome
of mice susceptible to Alzheimer's disease-like brain injury and cognitive impairment.
The mice were genetically engineered to express a mutated form of the human brain protein tau, which accumulates at 9 months of age and causes neuronal damage and brain atrophy
.
They also carried a variant of the human APOE gene, a major genetic risk factor
for Alzheimer's disease.
People who carry one copy of the APOE4 variant are 3 to 4 times
more likely to develop the disease than people with the more common APOE3 variant.

In addition to Holtzman, the research team included gut microbiome expert and co-author Jeffrey I.
Gordon, Ph.
D.
, and Dong-Oh Seo
, Ph.
D.

When the genetically modified mice were raised under sterile conditions from birth, they did not acquire a gut microbiome, and their brains were much less damaged at 40 weeks of age than mice with normal mouse microbiota
.

When these mice were housed under normal, non-sterile conditions, they developed a normal microbiota
.
However, taking a course of antibiotics at two weeks of age permanently altered the bacterial composition
of their microbiota.
For male mice, it also reduced significant brain damage
at 40 weeks of age.
The researchers said that the protective effect of changes in the microbiota in male mice carrying APOE3 mutations was more pronounced in male mice carrying the high-risk APOE4 variant, possibly because the harmful effects of APOE4 offset some of the protection
.
Antibiotic therapy had no significant effect
on neurodegeneration in female mice.

Holtzman said: "Through studies of brain tumors, normal brain development and related topics, we have learned that immune cells in the brains of men and women respond very differently
to stimuli.
So when we manipulated the microbiome, we saw gender differences in response, which isn't too surprising, though it's hard to say what exactly this means for
men and women with Alzheimer's disease and related conditions.
”

Further experiments linked three specific short-chain fatty acids — compounds produced by the metabolism of certain types of gut bacteria — to neurodegenerative diseases
.
All three fatty acids were deficient in mice whose gut microbiota had been altered by antibiotic treatment, and undetectable
in mice without gut microbiota.

These short-chain fatty acids appear to trigger neurodegeneration by activating immune cells in the blood, which in turn somehow activates immune cells in the brain, damaging brain tissue
.
When middle-aged mice without a microbiome were fed these three short-chain fatty acids, their brain immune cells became more active, and their brains showed more signs of
tau-related damage.

"This study may provide important insights into how the microbiome affects tau-mediated neurodegenerative diseases and suggest that treatments that alter gut microbes may influence the onset or progression of neurodegenerative diseases.
"

These findings provide a new way to prevent and treat neurodegenerative diseases that alter the gut microbiome
through antibiotics, probiotics, specialized diets, or other means.

"What I want to know is, if you take a mouse that is genetically destined to develop neurodegenerative disease and manipulate the microbiome before the animal starts showing signs of damage, can you slow or prevent neurodegenerative disease?" Holtzman asked
.
"This is equivalent to starting treatment
in late middle age when cognitive abilities are still normal but on the verge of impairment.
" If we can start treatment in these genetically sensitized adult animal models before neurodegeneration begins to become apparent, and prove that it works, that could be a recipe we can test in humans
.
”

Journal Reference:

1. Dong-oh Seo, David O’Donnell, Nimansha Jain, Jason D.
   Ulrich, Jasmin Herz, Yuhao Li, Mackenzie Lemieux, Jiye Cheng, Hao Hu, Javier R.
   Serrano, Xin Bao, Emily Franke, Maria Karlsson, Martin Meier, Su Deng, Chandani Desai, Hemraj Dodiya, Janaki Lelwala-Guruge, Scott A.
   Handley, Jonathan Kipnis, Sangram S.
   Sisodia, Jeffrey I.
   Gordon, David M.
   Holtzman.
   ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy.
   Science, 2023; 379 (6628) DOI: 10.
   1126/science.
   add1236