The study, in mice, found that gut bacteria — partly by producing
compounds such as short chain fatty acids — affect the behavior of
immune cells throughout the body, including ones in the brain that can
damage brain tissue and exacerbate neurodegeneration in conditions such
as Alzheimer’s disease. The findings, published in the journal Science, open up the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
“We gave young mice antibiotics for just a week, and we saw a permanent
change in their gut microbiomes, their immune responses, and how much
neurodegeneration related to a protein called tau they experienced with
age,” said the senior author. “What’s exciting is that manipulating the
gut microbiome could be a way to have an effect on the brain without
putting anything directly into the brain.”
Evidence is accumulating that the gut microbiomes in people with
Alzheimer’s disease can differ from those of healthy people. But it
isn’t clear whether these differences are the cause or the result of the
disease — or both — and what effect altering the microbiome might have
on the course of the disease.
To determine whether the gut microbiome may be playing a causal role,
the researchers altered the gut microbiomes of mice predisposed to
develop Alzheimer’s-like brain damage and cognitive impairment. The mice
were genetically modified to express a mutant form of the human brain
protein tau, which builds up and causes damage to neurons and atrophy of
their brains by 9 months of age. They also carried a variant of the
human APOE gene, a major genetic risk factor for Alzheimer’s. People with one copy of the APOE4 variant are three to four times more likely to develop the disease than people with the more common APOE3variant.
When such genetically modified mice were raised under sterile conditions
from birth, they did not acquire gut microbiomes, and their brains
showed much less damage at 40 weeks of age than the brains of mice
harboring normal mouse microbiomes.
When such mice were raised under normal, nonsterile conditions, they
developed normal microbiomes. A course of antibiotics at 2 weeks of age,
however, permanently changed the composition of bacteria in their
microbiomes. For male mice, it also reduced the amount of brain damage
evident at 40 weeks of age. The protective effects of the microbiome
shifts were more pronounced in male mice carrying the APOE3 variant than in those with the high-risk APOE4variant, possibly because the deleterious effects of APOE4canceled
out some of the protection, the researchers said. Antibiotic treatment
had no significant effect on neurodegeneration in female mice.
“We already know, from studies of brain tumors, normal brain development
and related topics, that immune cells in male and female brains respond
very differently to stimuli,” the senior author said. “So it’s not
terribly surprising that when we manipulated the microbiome we saw a sex
difference in response, although it is hard to say what exactly this
means for men and women living with Alzheimer’s disease and related
disorders.”
Further experiments linked three specific short-chain fatty acids —
compounds produced by certain types of gut bacteria as products of their
metabolism — to neurodegeneration. All three of these fatty acids were
scarce in mice with gut microbiomes altered by antibiotic treatment, and
undetectable in mice without gut microbiomes.
These short-chain fatty acids appeared to trigger neurodegeneration by
activating immune cells in the bloodstream, which in turn somehow
activated immune cells in the brain to damage brain tissue. When
middle-aged mice without microbiomes were fed the three short-chain
fatty acids, their brain immune cells became more reactive, and their
brains showed more signs of tau-linked damage.
The findings suggest a new approach to preventing and treating
neurodegenerative diseases by modifying the gut microbiome with
antibiotics, probiotics, specialized diets or other means.
“What I want to know is, if you took mice genetically destined to
develop neurodegenerative disease, and you manipulated the microbiome
just before the animals start showing signs of damage, could you slow or
prevent neurodegeneration?” the senior author asked. “That would be the
equivalent of starting treatment in a person in late middle age who is
still cognitively normal but on the verge of developing impairments. If
we could start a treatment in these types of genetically sensitized
adult animal models before neurodegeneration first becomes apparent, and
show that it worked, that could be the kind of thing we could test in
people.”
https://www.science.org/doi/10.1126/science.add1236