More Evidence Links Gut Bacteria to Dementia

Pauline Anderson

February 06, 2019

HONOLULU —  Depletion of certain gut bacteria, and an elevated level of other bacteria, are associated with an increased risk for dementia, a new study suggests.

"Although our study has numerous limitations, the results suggest that the gut microbiome could be a new target for the management of dementia," study author Naoki Saji, MD, PhD, Vice Director, Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology in Japan, told Medscape Medical News.

Doctors should urge patients to "take care of their gut," said Saji.

The study was presented here at the International Stroke Conference (ISC) 2019, and published online January 30 in Scientific Reports.

The gut microbiome refers to microorganisms that live in the digestive tract; there are about a thousand different species of bacteria, comprising trillions of cells. Recent research has correlated certain changes in gut bacteria with inflammatory and autoimmune conditions, and studies have shown that changes in diet can alter gut bacteria.  

The gut microbiome has become a hot topic for many experts, including Saji. His research interests include associations between dementia and cerebrovascular and cardiovascular diseases. He supports the hypothesis that these diseases share common risk factors.

Results of previous research suggest a relationship between the gut microbiome and cardiovascular diseases. "I thought that a relationship between dementia and gut microbiome might be also possible," said Saji.

The new study included 128 outpatients visiting a memory clinic at their institution; participants had a mean age of 74.2 years and 59% were female.

Researchers collected information on demographics, risk factors, and activities of daily living, and assessed cognitive function using neuropsychological tests and brain MRI scans.

As well, from fecal samples, they determined gut microbiota using terminal restriction fragment length polymorphism (T-RFLP) analysis. This, said Saji, is a well-established and reliable method of classifying gut microbiota.

Investigators divided study participants into demented and nondemented groups. They used multivariable logistic regression models to identify factors independently associated with dementia.

Silent lacunar infarcts and cerebral microbleeds were more frequently seen on MRI scans of patients with dementia, the researchers report.

Decreased Bacteroides

The T-RFLP analysis revealed group differences in components of gut microbiota. For example, levels of Bacteroides (enterotype I), which are organisms that normally live in the intestines and can be beneficial, were decreased in demented compared with nondemented patients.

Other bacteria (enterotype III) were increased in the group with dementia.

Multivariable analyses showed that enterotype I (odds ratio [OR] 0.1, 95% confidence interval [CI] 0.02 - 0.4, P < .001) and enterotype III (OR 12.7, 95% CI 3.3 - 65.8, P < .001) were strongly associated with dementia, independent of traditional dementia biomarkers such as APOE ε4 genetic status; deficits in certain neurochemicals; and high scores on Voxel-Based Specific Regional Analysis System for Alzheimer's Disease (VSRAD).

Fecal concentrations of ammonia, indole, skatole, and phenol were higher in demented compared with nondemented patients.

These new results indicate that dysregulation of the gut microbiome is independently and strongly associated with dementia, commented Saji.

The study had a number of limitations. One is that the cross-sectional design could not establish a causal relationship between differences in the gut microbiome and dementia. As it had relatively few patients, the study may have been at risk of being underpowered, and the absence of enterotype II among demented patients may have affected the statistical interpretation.

Another possible limitation is selection bias, as the study was performed in a single hospital-based cohort, and possible confounding factors, such as the release of inflammatory biomarkers, and nutritional and dietary parameters, were not assessed. 

Despite these drawbacks, Saji noted that the odds ratios in the study were high.

Saji suggested there may be common underlying mechanisms in the effects of gut microbial composition on multi-organ arteriosclerosis.

Analyses of the gut microbiome may not only lead to better ways to manage dementia, but perhaps to a new therapy for the disease.

Saji pointed to a recent report from Kobayashi et al suggesting that Bifidobacterium breve A1 supplementation may improve cognitive function in adults with mild cognitive impairment (MCI).

The 24-week, open-label, single-arm study examined the cognitive effects of the oral supplementation in 27 subjects, 19 of whom completed the study.

To assess cognitive function, the researchers used the Mini-Mental State Examination (MMSE) and Digit Symbol Substitution Test (DSST). They measured mental condition and quality of life for gastrointestinal symptoms using the Profile of Mood States 2nd Edition (POMS2), and the Gastrointestinal Symptom Rating Scale (GSRS).

The study found MMSE scores were significantly increased and GSRS scores significantly improved during the intervention.

However, Saji is not convinced supplementation alone is the answer, and noted that this is a controversial area.

Very Controversial

Costantino Iadecola, MD, professor of neurology at Weill Cornell Medical College and director of the Feil Family Brain and Mind Research Institute, New York City, agreed that research into supplementation "is very controversial."

For one thing, to change the composition of the gut microbiome, "you need to essentially create a niche; in other words, you have to create a home" for the new bacteria, Iadecola told Medscape Medical News.

That might be possible by first using antibiotics and then introducing probiotics, said Iadecola, but it's all very hypothetical at this point. "You can't reliably say what a certain species is doing" in the gut, he added.

Iadecola delivered a preconference presentation on hypertension, gut, and neurovascular dysfunction at the ISC 2019.

It's difficult for studies in this field to draw correlations, said Iadecola. "The microbiota is very variable and it can be modified by a wide variety of factors, for example, diet, gut motility, infections, and other immunological factors," he said.

Another drawback to research into the human microbiota is that "we don't really know all the bacteria species that are in our gut," said Iadecola.

Dietary Role?

Can diet alone boost beneficial gut bacteria enough to affect cognition? Some studies have suggested there may be such an advantage to the Mediterranean diet, which focuses on eating foods like fish, fruits, vegetables, nuts, and whole grains, and staying away from unhealthy fats and sugars, said Saji.

Iadecola noted, though, that it may not be this diet per se that affects cognitive function, but its lack of saturated fats.

The traditional Japanese diet (Washoku), which features harmonious presentations of rice and other dishes made with seasonal and colorful ingredients, may play a role too, said Saji. His colleague recently published a report suggesting that a "super" Washoku diet can positively change the gut microbiome compared with a more modern diet.

Saji cautioned, however, that while some diets may alter gut bacteria, "the outcome regarding health is not confirmed yet."

Iadecola agreed that Saji's new study of gut microbiota highlights the interest this topic is garnering.

"It reflects this kind of obsession with this probiotic stuff, with the microbiota," he said. "But like everything else in science, there's a peak of interest, which I call the bandwagon effect when everyone gets in on it," and then eventually interest drops off.

Interest seems to be still expanding, though. The Alzheimer's Association International Conference (AAIC 2018) in Chicago last summer featured a number of studies that investigated how the digestive system, including gut and liver functions, may be related to changes in the brain, and to brain disorders such as dementia.

According to the Alzheimer's Association, scientists have reported that some species in the microbiome can promote protein build-up in the brain. This may be significant as accumulation of amyloid and tau proteins are hallmarks of Alzheimer's disease (AD).

And recent reports from experiments in AD mouse models suggest that changing the bacterial profile in the digestive tract, by changing their diet, may reduce amyloid plaques, lower inflammation, and improve memory.

Meanwhile, an increasing body of evidence suggests that altered metabolism of certain lipids may be an important factor in the development of AD. Several genes associated with Alzheimer's, including APOE ε4, are involved in lipid transport or metabolism.

The study was supported by the Research Funding of Longevity Sciences; NARO Bio-oriented Technology Research Advancement Institution project (Advanced integration research for agriculture and interdisciplinary fields); and the Toyoaki Scholarship Foundation. Saji reports grants from NARO Bio-oriented Technology Research Advancement Institution project, the BMS/Pfizer Japan Thrombosis Investigator Initiated Research Program, the Toyoaki Scholarship Foundation, the National Center for Geriatrics and Gerontology, and the Japan Agency for Medical Research and Development (AMED). Iadecola has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2019: Poster WP569. Presented February 6, 2019.

Scientific Reports. Published online January 30, 2019. Abstract

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