Role of the Gut Microbiome in AD Pathology and the Potential of Probiotic Therapeutic Strategies

The human gut contains a myriad of microorganisms collectively referred to as the microbiome. We propose to investigate if the microbiome may modulate the progression of early Alzheimer’s disease (AD) pathology.

More than a century ago, the Nobel laureate Elie Metchnikoff postulated that “good gut bacteria” may delay senility and have beneficial effects for the symptoms of anxiety and depression associated with deteriorating cognition. Manipulation of the gut microbiome since has become common practice, with widespread consumption of probiotics, a concentrated bacterial cocktail. While the broad array of health benefits claimed for probiotics have failed to be substantiated in controlled clinical studies, findings have shown that the gut microbiome is essential for normal brain function. Signal molecules from the microbiome can enter the central nervous system (CNS) and modulate brain activities, sometimes producing profound effects in animal models. More recently, it has emerged that fecal transplants, used to redress microbial imbalances in the gut, also can impact patient mental functions.

The complex interaction between the microbiome and brain has come to be called the microbiota-gut-brain axis. While the beneficial aspects of probiotics appear to have been overstated, what has emerged is a clear realization that an abnormal microbiota-gut-brain axis can potentiate existing pathologies or even cause new disease. Particularly germane to AD has been recent revelations that the pathways of the microbiota-gut-brain axis include a comprehensive two-way communication system between the microbiome and brain. Findings suggest that under disease conditions, the “back and forth” between the brain and microbiome may become disrupted and reinforce harmful pathways that promote pathology. Abnormal brain activity can shift conditions in the gut and lead to a rise in gut bacteria linked to neuroinflammation and poor health outcomes. Changes in the gut microbiome lead, in turn, to increases in metabolites that exacerbate neuroinflammation, anxiety and depression in the brain.

We propose to investigate whether this pathological cycle may have a role in early AD. In preliminary studies we found that, compared with nontransgenic littermates, the gut of young pre-symptomatic transgenic AD mice have lower levels of bacteria thought to be protective. In this study, we propose to first characterize the changes in transgenic AD mice gut microbiome in high detail. Next, we plan to test whether shifts in gut microbiota can ameliorate or potentiate the progression of pathology in transgenic AD mice. Experiments will test the effects of fecal transplants, probiotics and bacterial metabolites on young transgenic AD mice. We believe confirmation of a role for the gut microbiome in AD pathology has the potential to reshape diagnostic and treatment strategies for early AD.