More evidence of role gut bacteria may play in Alzheimer’s decline

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A fascinating new study has shed more light on how the trillions of microbes in our gut could be affecting our brain health. The animal research found mice engineered to develop Alzheimer’s developed significantly fewer signs of neurodegeneration when raised with no gut bacteria, suggesting the microbiome may play a crucial role in the development of neurodegenerative disease.

A landmark study published in 2017 reported a strange relationship in mice between gut bacteria and the accumulation of a toxic protein linked to Alzheimer’s disease. The research found mice engineered to develop amyloid protein plaques showed fewer brain amyloid aggregations when bred to carry no gut bacteria.

This new research follows that study with an investigation into the relationship between the microbiome and tau accumulation, the other major pathogenic sign of Alzheimer’s disease. The research also looked into what actual differences in neurodegeneration could be detected between mice with and without gut microbiomes.

The first test looked at mice raised in entirely sterile environments from birth. Called germ-free mice, these animals grow without developing any kind of gut microbiome. When engineered to express high volumes of tau proteins these germ-free mice were found to have significantly less neurodegeneration at 40 weeks of age compared to animals raised under normal conditions.

The next test looked at normally raised mice given strong doses of antibiotics to eliminate their microbiomes at two weeks of age. Here things started getting a little more complicated, with sex-based differences between the animals becoming apparent.

When male mice were given antibiotics at two weeks of age they developed less brain damage by 40 weeks of age than expected. However, female mice did not show similar protective effects, with antibiotics not reducing levels of brain damage at 40 weeks.

“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,” said senior author on the study David Holtzman. “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.”

Following clues from prior studies the researchers also looked at the influence of several specific gut bacterial metabolites on neurodegeneration. The main focus was on short chain fatty acids (SCFAs) such as acetate, butyrate, and proprionate.

When these metabolites were added to the drinking water of germ-free mice, the animals subsequently developed significant levels of neurodegeneration. But the next mystery was how these SCFAs could be triggering neuroinflammation when key brain immune cells carry no receptors to respond to these particular metabolites.

Here the researchers hypothesize a kind of chain reaction of events could be occurring, with peripheral circulating immune cells being activated by the SCFAs and then subsequently inciting immune activity in the brain. And this mechanism may be how gut bacteria play a role in triggering neurodegeneration.

Of course, these findings are still years away from giving us concrete insights into how we could therapeutically manipulate the microbiome to treat neurodegenerative disease. Simply reducing the levels of gut bacteria that produce these SCFA isn’t feasible, since these metabolites are crucial to other healthy physiological functions. In fact, a recent hypertension study found engineered fiber supplements designed to increase SCFA production in the gut could effectively lower a person’s blood pressure.

Holtzman is still confident there may be ways to manipulate the microbiome and slow, or even prevent, neurodegeneration. But we certainly still have plenty more to learn before you’ll find a proven probiotic treatment for Alzheimer’s.

“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?” Holtzman speculated. “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.”

The new study was published in Science.

Source: Washington University School of Medicine in St. Louis

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