Psychobiotics – Emerging Next-Generation Probiotics for the Wellness of Mind & Gut

Over the past several years, several studies have provided convincing evidence of the influence of gut health on mental health and cognition. Researchers refer to the gut and brain link as the ‘microbiome-gut-brain axis,’ which is perceived to be bi-directional. It allows microbial molecules in the gut to communicate with the brain. Conversely, the brain is interacting with the gut and the microbiome.

A few research studies indicate the influences of the gut microbiome on several psychiatric and neurological illnesses – autism, schizophrenia, attention deficit hyperactivity syndrome, Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis.

The term “Psychobiotics” was coined by Psychiatrist Dr. Ted Dinan and neuroscientist Dr. John F. Cryan. Psychobiotics are a segment of probiotics that exert a positive influence on the psychological status of the host. Psychobiotics are live bacteria with beneficial effects on mental health.

Psychobiotics containing strains from Lactobacillus and Bifidobacterium species can improve mood, reduce anxiety, and enhance cognitive functions.

Psychobiotics exert anxiolytic and anti-depressant effects by changes in emotional, cognitive, and neural indices. Hence, it is reasonable to infer that the state of our gut affects our state of mind.

A healthy gut microbiota lowers the risk of infection by defending against pathogen colonization and protects against bacterial penetration by embattling the intestinal epithelium barrier. Prebiotics are included in the definition of psychobiotics as some of the compounds examined for their neural effects are fructans and oligosaccharides.

Pathways that link the microbiome-gut-brain axis

More than 30,000 different bacterial strains are present in the lower gastrointestinal tract. The microbes release numerous signaling molecules that can influence brain and behavior through immunological, endocrinological, and neural mechanisms.

Researchers have proposed multiple pathways to indicate the interaction of gut microbiota with the Gut-Brain Axis-

• Release of neurotransmitters like gamma-aminobutyric acid (GABA) and serotonin by Lactobacillus, Bifidobacterium, Candida, Escherichia, and Enterococcus
• An increase in pro-inflammatory cytokines can trigger depression and other psychiatric conditions in humans. Microbiome composition can restore the balance of pro and anti-inflammatory cytokines
• Vagus nerve modulates gastrointestinal motility and conveys information from the gut to the brain. Stimulating vagus seems to be anti-inflammatory, and its modulation might be a common pathway for actions of anti-depressants, anxiolytics, and psychobiotics
• Psychobiotics act on the brain by exerting effects on the body’s stress response system, which involves the brain and adrenal glands, a system known as the hypothalamic-pituitary-adrenal (HPA) axis, becomes dysfunctional, which disrupts the production of stress-related hormones
• Neuroendocrine (gut hormone) signaling – Bacterial products can stimulate several neuroendocrine cells (EECs), which releases neuropeptides – peptide YY, neuropeptide Y (NPY), cholecystokinin, glucagon-like peptide-1 and -2, and substance P. These neuropeptides enter the bloodstream and influence the enteric nervous system or can directly affect the nervous system

Proteins like brain-derived neurotrophic factor (BDNF) play a crucial role in the development of memory and learning processes, including spatial learning, extinction of conditioned fear, and object recognition is reduced in anxiety and depression, which is reversible through anti-depressants.

Research studies on Psychobiotics

In one of the Whitepapers published by FutureBridge titled “Probiotics – Can it solve the problem of malnutrition?” future research trends depicted the exploration by researchers to understand the impact of the probiotic on the human body and how they can help in the enhancement of brain/behavior / energy. The Whitepaper also illustrated a plausible mechanism of action of probiotics (Exhibit 2) on the gut-brain axis that is beneficial for gut, immune, and brain health, which is still under research.

In the same context, there are a few pre-clinical and clinical studies that have been mentioned in Exhibit 3.

Psychobiotics in rodent models

Psychobiotic research on rodent models makes use of rodent stress inductions and rodent behavioral tests to assess motivation, anxiety, and depression. Some mice models studied are presented in Exhibit 3.

Psychobiotics clinical trials on human models

Multiple findings have identified the microbiome to be a potential target in the treatment of psychiatric illness. The influence of bacteria on behavior has been explored in clinical studies. Dietary interventions are also needed to study the impact on Psychobiotics.

Some of the intestinal microbes, such as Lactobacillus casei, Bifidobacterium infantis, Bifidobacterium bifidum, Escherichia, Bacillus, Saccharomyces, Candida, Streptococcus, and Enterococcus can produce neurotransmitters including serotonin, norepinephrine and gamma-aminobutyric acid.

Nutrition and Psychobiotics

Prebiotics for Psychobiotics

Research studies have been conducted to explore and validate the beneficial role of prebiotics on brain health development. Prebiotics, such as oligosaccharides, dietary fibers, etc., help the growth of probiotics and, therefore, are perceived to impact the health.

Fermentation of common dietary polyphenols results in biotransformation phytochemicals that are beneficial for the shift in growth and stimulation of good microbial population in the gut. Isomaltooligosaccharides, for example, found in traditional foods (honey, sake, miso and soy sauce), fermented cabbage (kimchi), fermented fish oil, and fiber-rich components of conventional diets (soy germ, wheat germ, rice bran or bread) have shown to have a beneficial effect in promoting the growth of Bifidobacteria and Lactobacillus spp.

Nutrition Products

European firm Bened Biomedical is an exclusive distributor of the psychobiotic probiotic strain PS128 under an agreement with Serbia, Kosova, Bosnia, Montenegro, Macedonia, Croatia, Slovenia, and Albania.

The Lactobacillus plantarum PS128 strain available in the sachet format, wherein each sachet contains 30bn colony forming units (CFU). It modulates the microbiota-gut-brain axis by increasing the serotonin and dopamine concentration in crucial brain areas such as the hippocampus and frontal cortex, which in turn improves mental well-being by reducing symptoms such as stress, anxiety, and insomnia.

DuPont is looking at probiotics to improve cognitive health, specifically, stress relief with its HOWARU Calm. Reports on the U.S. brain/mood new supplement product market suggests its expansion at a compounded annual growth rate (CAGR) of 6.5% from 2013 to 2018.

Immunity and digestive health products are still the core focus for probiotic supplements, around 5% of all new launches (in supplements) included brain/mood health claims. More research, such as the ability to identify and confirm new specific strain which directly impacts mood, is one of the driving factors in the growth of this category.

Future of Psychobiotics

Emerging Research Focus

Several ongoing research studies are assessing the therapeutic potential of Psychobiotics. It has been suggested that bacterial strains provide a type of resilience against mood disorders. Dr. J.A. Foster, Psychiatry and Behavioral Neuroscience of the McMaster University suggest promising future with psychobiotics as we evolve our understanding of mental health.

However, according to a systematic review of the psychiatric benefits of probiotics in humans, there is weak evidence indicating positive results. Some have stated that it would be unable to provide the actual translational value of psychobiotics without rigorous elucidation of mechanisms. Numerous studies have been published that record the subject’s psycho-physiological variables, but only with a few published effects.

This probiotic segment is slowly emerging in terms of research and requires statistical power expertise to add more resolution and record the clinical evidence. Explorations in technical and conceptual aspects are also needed, which will pave the way for the emergence of efficient psychobiotics. A knowledge gap assessment for the future development of psychobiotics is shown in Exhibit 4.

Besides, antibiotic mixtures like neomycin, bacitracin, and pimaricin demonstrated neurochemical and behavioral changes through microbiome impact.

Consumption of anti-psychotic drugs has shown a directly proportional increase in the abundance of gut microbiome and weight gain among the patients. Both anti-biotics and anti-psychotics may be classified in the category of psychobiotics. The importance of considering the side effects assessments to understand the impact of probiotics consumption is illustrated through the use of these two drug categories, which is still missing from the current research focus.

To confer the most benefit from psychobiotics, continuous evaluation of the impact of gut microbiota and its mechanism of action on the gut as well as the brain is of utmost importance.

Researchers have predicted the potential necessity of personalized psychobiotics in the future. They have suggested that, even though identical bacterial species colonize the human gut, an individual’s gut-microbiome composition varies due to:

• Genetics
• Lifestyle
• Diet pattern
• Local experiences
• Environmental exposures

Additionally, the gut-microbiome composition is affected by an individual’s physical activity, illness, or stress-related disorders.

All the factors mentioned above alter the best ‘prescribed’ probiotics to address the symptoms of anxiety and depression. However, presently the priority is to focus on generic psychobiotics before the introduction of individualized psychobiotics.

Some Unanswered Questions on Psychobiotics

• What are the associated dose-response functions of psychobiotics?
• What are the mechanisms of action of prebiotics versus probiotics in the gut and on the gut microbiome?
• What is the difference in the functionalities of prebiotics and probiotics on microbiome structure and relative abundance?
• What are these undetected consumer cost benefits of psycho-physiological and psychotic treatments when compare to the consumption of psychobiotics?
• What is the impact of long-term psychobiotic ingestion on gut and brain?
• What is the time course for the emergence of various psychobiotic effects, and how long do they last?
• Why some probiotic strains and prebiotics show effect, while others do not, and are these linked to dosage?
• How do factors such as age, diet, genotype, and sex moderate the effects of psychobiotics?
• Who are the active players in the segment?
• Which strains are the most effective and capable Psychobiotics? Which are the most effective product formats for the consumption of Psychobiotics?

Possible Opportunities in Psychobiotics

Dr. Gerard Clarke from APC microbiome Institute at University College Cork, discussed the therapeutic potential of psychobiotics. Following are the key highlights:

• enlisting the challenges faced by the researchers in the development of safe and biologically-stable compounds that able to cross the blood-brain barrier (biologics and pharma)
• opportunity for psychobiotics, which can release molecules that can easily cross the blood-brain barrier

These highlights can be one of the future research fields for the microbiome-gut-brain mechanism. Clinical trials performed on a larger scale involving psychobiotics are a necessity to validate health claims.

Dr. Emeran Mayer, a gastroenterologist, University of California, who is also the author of “Mind-Gut Connection,” believes rigorously tested and FDA-approved psychobiotics will be available within the next 5 to 10 years. He also stated that “the concept of adding psychobiotics in the future is exciting.”

References

1. Psychobiotics
   – A new approach for treating mental illness
2. Beopanax selected as psychobiotic product distributor
3. The-Next-Wave-of-Probiotics-are-Not-Just-for-Your-Gut
4. The-simplified-guide-to-the-gut-brain-axis/
5. www.ncbi.nlm.nih.gov – pmc – articles – PMC5131922/
6. pubmed.ncbi.nlm.nih.gov – 30200574
7. Advances-in-human-microbiome-science-gut-brain-interaction/
8. S0166-2236(16)30113-8.pdf