Butyrate-producing gut bacteria are a promising target for preventing and treating memory loss associated with Alzheimer’s disease, according to research presented recently at the Alzheimer’s Association International Conference (AAIC) in Amsterdam, Netherlands.

The research in 3XTg mouse model demonstrated that oral administration of tributyrin mitigates age-associated loss of butyrate-producing bacteria and prevents the decline in cognitive and memory function associated with Alzheimer’s disease.

The work was led by Shirish Barve, Ph.D., chief research scientist at Norton Neuroscience Institute and Norton Research Institute, with a team from Norton Neuroscience Institute and the University of Louisville School of Medicine.

Gut microbiota are thought to contribute to neurodegenerative diseases by initiating and sustaining the development of neuroinflammation and neurodegeneration.

Specifically, one of the two mouse studies presented by the Norton Neuroscience Institute-UofL study team found that the oral administration of tributyrin prevented the age-associated loss of butyrate-producing bacteria in the gut in 3xTg-AD mice. These mice are genetically engineered to express Alzheimer’s disease related human transgenes and recapitulate specific aspects of neuropathological progression of Alzheimer’s disease.

The second study showed that the long-term administration of tributyrin, administered orally twice weekly, significantly prevented the loss of short-term, episodic memory and spatial memory in these 3xTg-AD mice.

The butyrate-Alzheimer’s connection

Previous cross-sectional studies observed a reduction in butyrate-producing bacteria in the microbiome of people with Alzheimer’s disease, suggesting that butyrate might have a   effect. In view of this the Norton Neuroscience Institute-UofL team pursued longitudinal studies and identified the causal relationship between the decrease in the butyrate-producing bacteria and development of neuropathological changes in Alzheimer’s disease.

The clinical translational goal of the Norton Neuroscience Institute-UofL studies was to evaluate the potential therapeutic effects of tributyrin — a butyrate prodrug, and to examine if oral tributyrin supplementation would counteract the decrease in butyrate bacteria and prevent the progression of neuropathology and impairment of cognitive and memory function, in the 3XTg mouse model of Alzheimer’s disease.

In the 18 months of the Norton Neuroscience Institute-UofL study, tributyrin supplementation, beginning at six months, significantly attenuated Alzheimer’s disease-associated neuropathology and prevented cognitive and behavioral deficits. Mice who did not receive tributyrin developed the anticipated neuropathology accompanied by significant short-term, episodic memory and spatial memory declines.

Interestingly, the observed beneficial prophylactic effect of tributyrin was independent of the beta-amyloid levels and senile plaque formation. However, tributyrin treatment effectively prevented formation of oxidative stress and tau hyperphosphorylation, both hallmarks of Alzheimer’s disease pathology.

The role of tributyrin

The Norton Neuroscience Institute-UofL team used tributyrin, a butyrate prodrug, rather than butyrate itself, because it has better pharmacokinetic properties and an established safety profile. Tributyrin is a triglyceride that is processed into butyrate in the intestine and liver.

“These data show long-term treatment with a butyrate prodrug has the potential to be integrated into treatment strategies to preserve cognitive function in patients in the prodromal phase of Alzheimer’s disease,” said Dr. Barve, who is known internationally for his research on the connection between the gut microbiome and brain.

The studies presented at the AAIC were:

• “Oral Tributyrin Supplementation Attenuates Alzheimer’s Disease-associated Neuropathology and Prevents Cognitive and Behavioral Deficits in the 3xTg-AD Mouse Model”
• “Tributyrin Oral Administration Significantly Attenuates the Loss of Intestinal Butyrate-producing Bacteria and the Ensuing Cognitive Dysfunction Associated with Alzheimer’s Disease Pathogenesis in 3xTg-AD Mouse Model”

Other researchers involved in the studies were Paula M. Chilton, Ph.D., senior research scientist, Norton Neuroscience Institute; Gregory E. Cooper, M.D, Ph.D., director, Norton Neuroscience Institute Memory Center; Smita S. Ghare, Ph.D., senior research scientist, Norton Neuroscience Institute; Christopher B. Shields, M.D., chairman, Norton Neuroscience Institute; and Scott R. Whittemore, Ph.D., senior research scientist, Norton Neuroscience Institute.