Gut Microbiota Signature Altered in Alzheimer's Disease

Liam Davenport

October 11, 2018

BARCELONA, Spain — Alterations in gut microbiota in patients with Alzheimer's disease (AD) may be associated with increased bacterial endotoxins in the blood, a finding that may point the way to potential treatments, new research suggests.

A study of 55 participants showed that there were substantial, marked differences in the composition of the gut microbiota between patients with AD and their healthy peers and that these differences persisted over time.

Moreover, blood samples showed that serum levels of a common bacterial endotoxin were higher in patients compared to healthy control persons, a finding that may support current hypotheses of the inflammatory nature of AD.

However, study investigator Nicola Lopizzo, MSc, Laboratory of Biological Psychiatry, IRCCA Fatebenefratelli, Brescia, Italy, told Medscape Medical News that although between-group differences were seen in the microbiota, it is not possible to say at this stage what effects each alteration might have.

"Actually, we do not know so much about the gut bacteria and their functions. Although some of them are well characterized, others have been recently discovered," Lopizzo said.

Lopizzo said it is unclear what causes the differences in gut microbiota in those with and those without AD but noted that it is a key question. "All scientists who are studying the gut microbiota are trying to answer [this]," she said.

The findings were presented here at the 31st European College of Neuropsychopharmacology (ECNP) Congress.

Inflammation's Central Role

Previous studies indicate that changes in the gut microbiome occur not only in gastrointestinal disorders but also in those of the central nervous system, including AD.

In fact, inflammation is thought to play a central role in the development of AD, which is characterized by the accumulation of amyloid-beta peptides. It has been suggested that gut microbiota may be a potential source of this inflammation.

The hypothesis is that alterations in the gut microbiota may cause the intestinal barrier to become more permeable, allowing bacterial components such as gram-negative bacterial endotoxin lipopolysaccharide (LPS) to enter the circulation and cross the blood-brain barrier.

To examine possible changes in microbiome composition associated with AD, the researchers studied 30 patients with AD who had tested positive for amyloid-beta. They compared these patients to 25 matched control persons who had no cognitive impairment and who had tested negative for amyloid-beta.

The investigators collected blood and stool samples at baseline and again at 2 and 4 months. DNA was isolated from the stool samples, and the bacterial 16S DNA was sequenced.

The researchers found that at the genus level, Bifidobacterium, Blautia, Dialister, Subdoligranum, and Citrobacter were significantly more abundant in samples from patients with AD than from those without the disease (for all, P < .05).

In contrast, Prevotella, Roseburia, Parasutterella, Oxalobacter, and Akkermansia were significantly less abundant in AD patients (for all, P < .05).

At the phyla level, Cyanobacteria and Verrucomicrobia were more abundant in the healthy control group than in the patient group. At the class level, Acintobacteria was more abundant in the patient group than in the healthy control group. The opposite pattern was shown for Verrucomicrobiae (P <.05 for all).

At the order level, Bifisobacteriales was more abundant in the patients with AD, whereas Verrucomicrobiales was more common in those without AD. A similar pattern was seen for Bifidobacteriaceae and Verrucomicrobiaceae at the family level (P < .05 for all).

Gut Composition

Comparing the results with the samples taken during follow-up showed that the gut microbiota at both the phylum and genus levels was stable over time.

Blood samples revealed that serum levels of LPS were higher in the participants with AD than in those without the disease.

"Our data suggest the presence of a specific gut microbiota composition in association with Alzheimer's disease," the investigators write. They suggest that this may play a role in disease pathology by triggering a more permeable gut barrier.

As a result of their findings, they are now examining a wide panel of proinflammatory and anti-inflammatory cytokines, as well as gut microbiome metabolites, in search of correlations with the changes in composition seen in those with AD.

Regarding gut bacteria and their various functions, "we know that some taxa could be beneficial, such as Bifidobacterium, whereas others could be potentially harmful; for instance, Escherichia coli. But in a commonly considered harmful genus, we can find strains that are beneficial, such as E coli Nissle, and vice versa," Lopizzo noted.

"Moreover, the relationship between gut bacteria and their host is very complicated, and a strain that is beneficial for one person could be harmful for another," she said.

Exciting Area of Research

Commenting on the findings for Medscape Medical News, Heather Snyder, PhD, senior director of medical and scientific operations at the Alzheimer's Association, which supported the research, said that this is "an exciting and emerging area" of research.

"While we are just beginning to learn about how our brains may be influenced by our gut and our microbiome, this new report adds to research reported this summer at the Alzheimer's Association International Conference," Snyder said.

The meeting marked the first time multiple reports were presented by researchers working to understand this intersection, called the gut-liver-brain axis.

Recent research has taught "a great deal about how diet, particularly overall eating patterns, may be linked to brain health, cognitive decline, and possibly even dementia as we age," Snyder said. "We've also seen inflammation and its markers in the brain and other parts of the body associated with Alzheimer's and other dementias.

"Exactly how diet and gut microbes interact with the brain and influence the brain's health as a cause, trigger, or risk/protective factor is a relatively new area of investigation for Alzheimer's and other dementias," she added.

"We now have initial hints about the connection between the gut microbiome and the brain and the potential influence of the microbiome on brain health. Understanding these connections will likely give us valuable new insights into the biology that contributes to brain health and may open the door to possible ways to intervene," she said.

These may include targeting digestion, adjusting behavior and diet, developing therapies that target the biology, or some combination of all of these factors, said Snyder.

The research was supported by a grant from the Alzheimer's Association and a current research grant from the Italian Ministry of Health. The participants have disclosed no relevant financial relationships.

31st European College of Neuropsychopharmacology (ECNP) Congress. Abstract 117, presented October 7, 2018.

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