Dissecting the Influence of the Gut Microbiota on the Brain in AD

The major goal of this project is to identify microbes and metabolites that affect brain aging and to understand how microbes program cells in the brain towards dysfunction and Alzheimer’s disease. In the brain, there are 4 major cell types, neurons, microglia, astrocytes, and oligodendrocytes, which can be affected by the gut microbiota. In Aim 1, we will investigate whether bacteria in the gut can affect the programming of these 4 cell types in the brain to switch them from a healthy to a dysfunctional state. In Aim 2, we will search for microbial metabolites that may affect cells in the brain in the hopes of uncovering novel therapeutics to protect the brain in aging and in Alzheimer’s disease.

The gut microbiota contains trillions of microbes that promote health by producing vitamins, defending against bad bacteria, or training the immune system. The gut microbiota also affects the brain by secreting substances that can affect the immune system or mood. In aging, the gut microbiota becomes destabilized and can contribute to disease. We are investigating how age-related microbiota changes contribute to Alzheimer’s disease, and are trying to find ways to control the microbiome to promote healthy brain aging. There are four major cell types in the brain, (1) neurons, which conduct the signals that are responsible for memory, mood, and thought, (2) microglia, which are the primary immune cell in the brain and clear up debris and invading microbes, (3) astrocytes, which play a supportive role for neurons, clear debris, and contribute to immune responses in the brain, and (4) oligodendrocytes, which create a protective electrical insulation for neurons. In aging, these cells can become dysfunctional and acquire toxic states that lead to memory loss. New studies suggest that the gut microbiota can alter the states of cells in the brain, but little is known about how this happens. In this project, we will test whether gut microbiota from AD patients, or two groups of bacteria that are altered in aging, control the programming of these cells towards health or disease. These studies may lead to new ways to prevent and treat Alzheimer’s disease.

Little is known about why neurons, microglia, astrocytes, and oligodendrocytes in the brain become dysfunctional in Alzheimer’s disease, but our new studies suggest that the gut microbiota may be a contributing source for this dysfunction. An innovative aspect of this project is that we will investigate how the gut microbiota affect genes that can program cells in the brain towards health or disease. Another innovative aspect is the investigation of bacterial metabolites on epigenetic programming, which may be important bacterial signals to the brain in AD.

Our project may increase our understanding of how the gut microbiota controls brain function in AD. Identification of bacterial metabolites that have a beneficial effect on maintaining cellular function in aging and AD provides a clear path forward for the development of novel strategies to prevent and treat AD.