Some Short-Chain Fatty Acids Made by Gut Microbes Increase Neuroinflammation in the Aging Brain

Researchers are attempting to determine exactly how the gut microbiome contributes to age-related chronic inflammation, particularly inflammation in the brain. This may be largely due to a few compounds produced by specific microbial species, some of which become more populous with age at the expense of beneficial microbes. The results noted here are an example of the output of this sort of research. Ultimately, this will lead to more deterministic ways of adjusting the gut microbiome in older individuals. At present the most effective approach is to transplant a fecal sample from a young individual, sidestepping our comparative ignorance of the fine details. It should be possible to improve upon this, however, given greater understanding of the interaction between the gut microbiome and 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.

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.

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.


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