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Researchers at �����о��� Medical School have added a detailed layer of evidence to the theory that the microbiome and Alzheimer’s disease are closely associated. Published in , the open access journal of the American Society of Microbiology, the study by Beth McCormick, PhD, and John Haran, MD, PhD, establishes a critical bridge connecting specific bacteria species, dysregulation of inflammation pathways in the intestines and different types of dementia prevalent in the elderly.

“This is the first study to show that patients with Alzheimer’s disease have distinctly different microbiomes than patients with other forms of dementia,” said Dr. McCormick, vice chair and professor of microbiology & physiological systems and founding director of the �����о��� Center for Microbiome Research. “While this isn’t enough to say that microbiome dysregulation causes Alzheimer’s, this research does point to a very strong and specific connection between the two that may potentially have clinical implications.”

Key to the mBio study was the collection of a broad representation of patient microbiomes to sequence and study. Dr. Haran, associate professor of emergency medicine and microbiology & physiological systems and clinical director of the Center for Microbiome Research, studies the practice of infection control in nursing homes. He is interested in the consequences of giving antibiotics to the elderly, as they can throw a healthy microbiome into imbalance and cause disease.

“There have been some studies done that have investigated the microbiota-gut-brain axis and Alzheimer’s disease on a very superficial level but none of these have looked deeply at the clinical variants,” said Haran. “Using patient samples and machine learning, we were able to take this research forward and isolate specific bacterial species that affect a certain pathway in the intestines known to be responsible for maintaining physiological balance in the gut. With this study, we have a better understanding of the connection between the microbiome and Alzheimer’s disease.”

Haran and McCormick, along with colleagues, including Doyle Ward, PhD, associate professor of microbiology & physiological systems, and Vanni Bucci, PhD, assistant professor of biology at �����о��� Dartmouth, analyzed 300 microbiome samples from 108 nursing home residents over a five-month period. Of these study participants, 51 had no dementia, 24 had Alzheimer’s disease and 33 had other types of dementia. Whole genome sequencing was performed to isolate which bacterial species were present in each sample. Machine learning was then used to obtain finer resolution over clinical variables, such as medications that might impact the composition of the microbiome, and functional studies were performed to identify the specific molecular pathway being disrupted in those study participants with Alzheimer’s disease.

Researchers found that those with Alzheimer’s disease exhibited similar microbiome patterns. Specifically, these participants experienced a loss of a particular type of bacteria, (butyrate-producing bacteria), and a gain of bacteria known to cause pro-inflammatory states—neither of which were present in participants with no dementia or other types of dementia.

The researchers also showed how the microbiome of those people with Alzheimer’s adversely affected inflammatory balance in the intestines by dysregulating and lowering P-glycoprotein levels (P-gp). Found on the cell surface, P-gp is normally responsible for waste removal, pumping foreign matter, debris and toxins out of the cell. This helps the body’s immune system discern good bacteria from harmful bacteria. In the presence of good bacteria, P-gp helps suppress inflammation. Conversely, when it encounters potential pathogens, it alerts the immune system by activating inflammatory pathways in the intestine.

Interestingly, bacterial species selected from Dr. Bucci’s computer model, when compared to study participants with Alzheimer’s disease and those without, accurately predicted inflammation through the loss of the P-gp protein.

“Dysregulation of this important protein contributes directly to inflammatory disorders of the intestine,” said McCormick. “Since Alzheimer’s disease is thought to be linked to chronic bacterial infections as a possible influencer, our findings fill a critical knowledge gap by finally describing a potential nexus for the microbiome and intestinal inflammation that may underlie this neurodegenerative disease.

“The modulation of intestinal homeostasis by increasing bacteria that activate inflammation versus those that help suppress it may be the link between the microbiome and Alzheimer’s disease.”