Inside Neuroscience: The Gut-Brain Connection and Neurodegenerative Diseases

The trillions of microbes in and on the human body are absolutely critical to physiological functioning: they help feed us, fight off disease, and play an essential role in the immune system. The gut microbiome has emerged in the past decade as an interest for neuroscientific research; the so-called microbiota-brain connection is a developing field of study to better understand the connection of gut microbes with the central nervous system. Put more simply: the gut microbiota can be linked to neurological conditions, from anxiety to Alzheimer’s disease (AD).

Jane A. Foster

“Microbes are actually symbiotic to our existence,” said Jane A. Foster, professor at McMaster University and moderator of “The Impact of Gut Bacteria on Brain Health” press conference at Neuroscience 2019. “The immune system is a key factor in how microbes communicate with the brain.” Research presented during the press conference explored the gut-brain connection with a view towards effective treatment in humans. In other words, “What are the potential microbiota-targeted therapies in neurological and psychiatric disorders?” Foster asked.

Linking Brain Inflammation and an Obesity-Causing Diet

Studies have shown that three major risk factors for AD — obesity, metabolic syndrome, and diabetes — may contribute to disease development via the gut-brain connection. A cell processing protein, soluble TNF (sTNF), is seen as a key mediator in this process. Researchers at the University of Florida Health used a rodent model with genetic predisposition toward amyloid beta, the “plaque” that forms as a result of AD.

The rodents were fed an obesity-causing high-fat, high-sugar diet for two months — leading to amyloid plaque and gut and brain inflammation. After the rodents were administered XPro1595 at four weeks into the test, which was delivered through the end of the two-month study, many of these features were reversed.

Malú Gámez Tansey

Malú Gámez Tansey, a professor of neuroscience and neurology at the University of Florida College of Medicine, McKnight Brain Institute, and the Fixel Center for Neurological Diseases, said, “A high-fat, high-sugar diet may trigger chronic inflammation and increase the risk and progression for AD in humans. Targeting soluble TNF with this new biologic may lower the risk by lowering the harmful inflammation without suppressing the immune system.” Researchers will follow up with an upcoming study in Australia in human subjects, which will provide the peptide over the course of three months and measure its effects on inflammatory markers.

Sex-Specific Differences in the Gut Microbiome, and the Effect on AD Pathology

Previous studies from Professor Sam Sisodia’s lab at the University of Chicago Medicine have shown that administering antibiotics that alter the gut microbiota in AD rodent models can positively impact disease pathology in the brain — but intriguingly, only in male rodents. Scientists at the University of Chicago Medicine continued this investigation using another mouse model of Alzheimer’s disease to understand the role of sex-specific gut microbiota in connection with a higher incidence of AD in female humans.

AD rodent models received an antibiotic cocktail from 14 days old for up to three months, after which the researchers observed that males and females had different gut microbiota profiles. The treatment caused decreased amyloid pathology in male mice, but not in female mice. Microglia (immune cells in the brain) were altered in male mice to be more neuroprotective rather than neurodegenerative. Thus, it appears that the gut microbiota served to “train” the associated microglia. Specifically, when the gut microbiota profile in antibiotic-treated male mice were restored back to normal by fecal microbiota transfer, the amyloid pathology increased with more neurodegenerative microglia.

Hemraj Dodiya

The results suggest that the gut microbiota speed up the pathology of AD and that antibiotics-mediated gut microbiota can reverse the process, but only in males. Hemraj Dodiya, a postdoctoral researcher, explained, “Our data establishes causality between gut microbiota and Alzheimer’s pathology. It also highlights an importance of considering both sexes in preclinical as well as clinical studies aiming to target the microbiome in AD and many other neurodegenerative conditions.” Ongoing research will further delve into these sex-specific differences in the gut microbiome.

Probiotics, Gut Health, and Improvement in Alzheimer’s

Does the introduction of health-promoting probiotics effect AD pathology? Researchers at the University of North Dakota, Grand Forks studied the intestinal dysbiosis (bacterial imbalance) in an AD rodent model and its connection to bacterial byproducts known as short chain fatty acids (SCFA) in the serum and brain. The researchers attempted to discover if using a probiotic that targeted gut health would in turn result in SCFA changes.

Harpreet Kaur

After the rodent received the probiotic there were, in fact, improvements in the gut microbiota. In turn, SCFA production was enhanced and behavior improved. “AD mice had a high anxiety level. Giving the probiotic supplementation decreased the anxiety levels. That clearly shows that manipulating the gut bacteria using probiotics had the ability to affect the brain,” said Harpreet Kaur, a postdoctoral research associate.

Researchers drew several conclusions: the fecal bacterial analysis they used to determine dysbiosis may be a non-invasive identifier for AD; AD patients who improve their gut health via probiotics may show improvement in symptoms; and SCFAs may one day be used as an effective AD treatment.

Preventing TBI Memory Loss With Probiotics

There are more than 2.8 million reported cases of traumatic brain injury (TBI) every year, a third of which are experienced by children. Many TBI sufferers also experience chronic dysfunction in the gut. Researchers at the University of California, Los Angeles wondered if gut microbes were also impacted by brain injury and what the precise relationship to gut-brain health might be.

Working with a rodent model, those that were exposed to brain injury had subsequent memory problems. Rodents that had been pretreated with probiotics (and continued treatment until the time of assessments) but still had brain injury did not experience the memory deficits — the probiotics prevented the loss and enhanced neuroplasticity in the hippocampus. Interestingly, probiotics did not restore the normative microbiome of the rodent but did create a new microbiome that was marked by SCFA producers.

Wellington Amaral

Wellington Amaral, a postdoctoral researcher, explained, “We believe that the gut does play a strong role in the pathology of TBI, and this may be a venue of interest for manipulations that can alleviate at least some of the symptoms of TBI.”

Looking Ahead

One of the biggest implications of this research is that treatment may one day become more personalized for maximum efficacy, explained Foster. “How can we use the peripheral immune system in these microbes as biomarkers to stratify individuals to get a better understanding of individual differences in psychiatric illness, which gets to the point of precision medicine where we can actually come up with therapies for sub-types of illnesses?”

This research may also expand beyond the gut, as microbes exist everywhere throughout the body. “This might be important when we look at biomarkers for clinical disorders ... These other surfaces might be of interest moving forward,” said Foster. Thus, the opportunities for study and treatment are ongoing.