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Antidepressant signal offers new insights into gut-brain axis

Researchers from a variety of disciplines work in St. Joe’s laboratories, conducting novel, fundamental science related to human health and disease. There, the recent discovery of a neural code that originates in the gut – one with a unique firing pattern – has opened a pathway towards the development of new medical interventions to treat depression.

Scientists at St. Joseph’s Healthcare Hamilton and McMaster University have discovered an underlying neural mechanism within the vagus nerve, which is activated by chemical and bacterial antidepressants. The vagus nerve relays mood-altering signals originating from the inner wall of the intestines – known as the gut lumen – to the brain. This communications channel is called the gut-brain axis.

Previous research on the gut-brain axis has shown that the vagus nerve connection is involved in activating the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) as well as a bacterial strain of Lactobacillus that exhibits antidepressant-like activity. But exactly how these chemical and bacterial antidepressants work has evaded scientists, until now.

For the first time, researchers have identified a unique neural firing pattern from both chemical (i.e., SSRIs) and bacterial (Lactobacillus) anti-depressant stimuli. The neural pattern (or code) was the same for all antidepressants – a decrease in the mean spike interval, increase in spike burst duration, decrease in the gap duration between bursts, and increase in intra-burst spike intervals.

The team used vagus nerve fibres to measure neural signals as chemical and bacterial stimuli were introduced. Senior study author, Wolfgang Kunze, designed the experiments while working in Australia. When Kunze joined St. Joe’s and McMaster, he was able to perform the experiments with his graduate students, including Christine West and Karen-Anne McVey Neufeld.

The study, which comprised a large part of West’s doctoral research, was published in October 2021 in the journal Nature Scientific Reports. First author Christine West completed her PhD in January 2021 and now works in medical operations at GlaxoSmithKline.

“The publication of this study not only represents the culmination of my doctoral work, but the result of a supportive collaboration with the Brain-Body Institute team,” said West. “This has developed my understanding of how vagal signals are encoded from gut to brain and fostered a lifelong interest in neuroscience.”

Dr. Christine West was awarded her PhD in January 2021.

Did you know?

Vagus nerve stimulation (VNS) is currently used to help those with treatment-resistant depression. An implanted surgical device delivers an electrical impulse to the vagus nerve, which is similar to how a pacemaker works.

According to John Bienenstock, study co-author and Director of the Brain-Body Institute at St. Joe’s, the discovery of the unique neural firing pattern may lead to a generational leap in technology used for electrical stimulation of the vagus nerve.

Kunze explained that his lab has designed a device to mimic the antidepressant code, and they are preparing to test it on animal models.

“Such a device may not only be useful in humans, but also in agriculture to treat animals that are stressed by transportation or overcrowding,” says Kunze.

Beyond vagus nerve stimulation, the antidepressant code and methodology may prove to be quite useful as a screening tool for novel potential antidepressant drug candidates. This has the potential to speed up drug discovery and commercialization of new pharmacological treatments for depression.

The published findings as they appeared in Nature Scientific Reports.

Scientists at St. Joe’s have also been investigating other physiological phenomena linked to the vagus nerve. For instance, previous novel research by West and Kunze demonstrated that a compound called squalamine can reverse age-related gut motility impairment in mice, reducing instances of constipation. Like humans, mice experience progressively slower gut motility and frequent constipation as they age, which can be comorbid with mood disorders. In that study, squalamine was shown to excite the enteric nervous system, which strongly influences the firing rate of the vagus nerve, improving gut motility to youthful levels.

Both the current and previous studies are proving to have strong implications for our understanding of the vagus nerve and the future of treatment for a variety of disorders linked to the gut-brain axis.

Did you know?

Squalamine is an aminosterol compound that was first discovered in the liver of the dogfish shark in 1993. Since then, a synthetic version has been developed.

This research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC), the Weston Family Foundation, a Clifton W. Sherman Scholarship, and a Queen Elizabeth II Graduate Scholarship in Science & Technology.

Dr. John Bienenstock

Remembering Dr. John Bienenstock

This article is dedicated to the memory of Dr. John Bienenstock, known internationally as a visionary physician, scientist, academic and a leader at McMaster University and St. Joseph’s Healthcare Hamilton.

During his tenure at McMaster, he became renowned world-wide as a pioneer in mucosal immunology, introducing the concept of a common mucosal immune system. He also advanced the knowledge of neuroimmunology and in understanding how the brain and nervous system collaborate. He was chair of the Department of Pathology from 1978 to 1989, and dean and vice-president of the Faculty of Health Sciences at McMaster from 1989 to 1997. He was known for establishing a substantial research infrastructure at the Faculty.

The professor of pathology officially retired in 1998, but he remained active in his research and as director of the McMaster Brain-Body Institute at St. Joseph’s Healthcare Hamilton.

Visit this page to read tributes from Dr. Bienenstock’s friends and colleagues.