Probiotic Biotherapy to Ameliorate Alzheimers Disease
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. Its prevalence is increasing, and no known treatment can stop or slow its neurodegenerative progression. One out of three seniors dies from AD or another form of dementia, but military personnel and Veterans who experienced brain trauma in the course of their service are at even higher risk for developing AD. Recent statistics show that traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) increase the risk of developing AD by 60 percent. Although the precise mechanisms and pathological pathways of AD remain obscure, recent research indicates that the bacteria living in our intestine (gut microbiome) play an important role in regulating brain functions, including learning and memory (cognition). TBI has been shown to change the gut microbiome dramatically, and our preliminary data and other studies indicate that the gut microbiome of individuals with mild cognitive impairment (MCI) and AD also differs significantly from normal. Their bacteria show a reduced capacity to produce major beneficial metabolites like the short chain fatty acids (SCFAs) - acetate, propionate, and butyrate. Again, we do not yet know exactly how the differences in gut bacteria and SCFAs deficits contribute to AD pathology. Some hypothesize that disturbances in the gut’s microbial composition and SCFAs production increase the permeability of the intestinal wall, allowing highly inflammatory bacterial ingredients like lipopolysaccharides to leak and cause low-grade inflammation. Like AD and MCI, TBI and PTSD are associated with increased gut leakiness, low-grade inflammation, and gut microbiome disturbances (dysbiosis). Among SCFAs, butyrate is known to ameliorate AD. It manipulates target cells in several ways, but most commonly it activates free fatty acid receptor 2 (FFAR2) signaling. FFAR2 is expressed in intestinal epithelial, immune, and neuronal cells. Limited evidence in rodents and humans suggests that certain gut microbiome modulators like antibiotics, prebiotics, probiotics, and dietary ingredients affect cognitive function, but no single well-defined regimen to ameliorate AD is known. We hypothesize that consuming human-origin probiotics – bacteria known to support health - will reduce gut leakiness and inflammation to ameliorate AD. Mechanistically, we posit that the probiotics will enhance microbiome-butyrate-FFAR2 signaling in the intestine. Recently, we isolated and purified probiotics from infant gut and formulated a cocktail of five lactobacilli and five enterococci strains that show great promise in modulating the human and mouse gut microbiome and enhancing SCFAs/butyrate production. Most exciting, these probiotics improved cognitive function in old-obese mice. In the proposed studies, we will: (1) determine the efficacy of these probiotics in slowing AD progression in AD mouse models (APP/PS1) compared to non-treated groups and establish whether they ameliorate the AD by (2) reducing gut leakiness and inflammation and (3) enhancing microbiome-butyrate-FFAR2 signaling. Results will establish proof of concept that this human-origin probiotic cocktail increases butyrate production to reduce leaky gut and inflammation and ameliorate AD pathology. They will have immediate translational potential for human and clinical studies that may lead to the first effective treatment for people with, or at high risk for, AD, including military personnel and Veterans with TBI/PTSD. Overarching Challenges and Focus Areas: The proposed projects are related to the following Fiscal Year 2018 Peer Reviewed Alzheimer’s Research Program New Investigator Research Award Focus Areas: Quality of Life and Non-Pharmacological Interventions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910236
Entities
People
- Hariom L. Yadav
Organizations
- United States Army
- Wake Forest University