The gut-brain axis and what it means for the brain health category

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One way to improve one’s quality of life—and, in turn, one’s health—is to reduce the stress in our lives. Stress can have a domino effect, causing one to eat too much or too little, develop bad habits such as tobacco use and excessive alcohol consumption, reduce motivation to be active and to exercise, as well as impact our interpersonal relationship because of irritability and anger.¹

According to Mintel’s Global Consumer Trends for 2023, a survey of 2,000 U.S. internet users above the age of 18 found that 49% of respondents reported experiencing stress in the last year, 38% reported feeling anxiety, 22% reported feeling mental exhaustion, and 20% reported feeling burnt out. In a survey of 1,537 internet users above the age of 18 in the UK that have experienced stress in the past year, 71% reported that managing diet and exercise was important for managing stress.

A proper diet and an active lifestyle can have an immense impact on one’s mental health, but consumers are always looking for an edge: that product that helps them meet their health goals. Dietary supplements that support cognitive health and reduce stress can offer the assistance consumers are looking for, but a novel approach of targeting the gut-brain axis may be the future of stress- and mood-supporting products.

As Nutritional Outlook reported in our January/February 2023 Ingredients to Watch issue, the use of microbiome-supporting products continues to grow. As our understanding of the microbiome becomes more sophisticated, so, too, are the products, which may benefit from taking on a targeted approach—in this case, brain health via the microbiome.²

Formulating products that target the gut-brain axis can be an effective way to not only leverage the desire of consumers to improve their mental health but also the demand for microbiome-supporting products.

The Gut-Brain Axis

The idea that brain health is interconnected with digestive health has been posited for years, and while our understanding of the mechanisms behind these connections is still limited, knowledge on the topic is growing rapidly as researchers strive to solve the puzzle. And it indeed is a puzzle. To put things into perspective, the human gut has the highest cell densities documented for any ecosystem, containing around 10¹³ to 10¹⁴ bacteria, with a diversity of at least 1,000 species.³

The gut-brain axis is defined as the interaction between the enteric nervous system (ENS) that exists within the gastrointestinal (GI) tract, and the central nervous system. The ENS is even referred to as the second brain because it contains as many nerves as the spinal cord, is involved in the regulation of basic gut functions, and has similar neurotransmitters and signaling molecules as the brain.³

A crucial neural pathway for the bidirectional communication between the gut and the brain is the vagus nerve, which has an influence on the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is responsible for our adaptive stress response.³ Another pathway through which the gut and the brain communicate involves direct or indirect signaling via chemical transmitters such as microbial metabolites, and hormones or neurotransmitters which are directly synthesized or modulated by gut microbiota.⁴

Metabolites such as short-chain fatty acids (SCFAs) are very important for GI health by maintaining intestinal barrier integrity, mucus production, and controlling inflammation, but they also play a role in the gut-brain axis. For example, SCFAs control the production of peptides by enteroendocrine cells that stimulate the synthesis of serotonin derived the from the gut.⁴ GI bacteria, such as Lactobacillus spp., Bifidobacterium spp., Bacillus spp., Escherichia spp., and Saccharomyces spp., also play a role in the production of neurotransmitters that control our cognitive functions. Namely, these bacteria are involved in the production of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, dopamine, and serotonin.⁴

Connecting the Gut Microbiome to Mental Health

We’re all familiar with the “butterflies in our stomach” cliché and have experienced GI symptoms in times of high stress. The idea of our guts and minds being linked is therefore somewhat intuitive. However, understanding these connections is more complicated, especially when they’re linked to serious diseases.

Researchers have found a correlation between our gut microbiome and neurological disorders.

Recently, the largest analysis to date investigating the association between the gut microbiome and depression was published in Nature Communications.⁵ The study investigated the relationship between fecal microbiome diversity and composition with depressive symptoms across 2593 individuals. Researchers identified 13 microbial taxa associated with depressive symptoms that included 12 genera and one microbial family, namely: Sellimonas, Eggerthella, Ruminococcaceae (UCG002, UCG003, UCG005), Lachnoclostridium, Hungatella, Coprococcus, Lachnospiraceae UCG001, Ruminococcus gauvreauii group, Eubacterium ventriosum, Subdoligranulum, and family Ruminococcaceae.

Researchers found that Sellimonas, Eggerthella, Lachnoclostridium, and Hungatella were more abundant in subjects with higher depressive symptoms, while all other taxa were depleted in those with higher depressive symptoms. These results are consistent with previous research. Bacteria such as Subdoligranulum and Coprococcus, which were depleted in subjects with higher depressive symptoms, are known to be involved with butyrate production (a SCFA), and Subdoligranulum has been found to be more abundant in those with an omega-3–rich diet.⁵ Omega-3s are also known to have a beneficial effect on cognitive health.

New findings from the study include the associations with genera Sellimonas, Lachnoclostridium, Hungatella, Eubacterium ventriosum, Lachnospiraceae UCG001, and Ruminococcus gauvreauii group. Sellimonas, for example, was positively associated with depressive symptoms. This is significant because it belongs to the family Lachnospiraceae and phylum Firmicutes, and species belonging to Sellimonas are increased in those with inflammatory diseases. Higher abundance of Sellimonas has also been observed after dysbiosis—the imbalance in the gut microbiome in which the gut is colonized with more harmful bacteria. Eubacterium ventriosum, for its part, was found to be depleted with increased depressive symptoms, and previous animal studies showed it to be depleted in mice after traumatic brain injury.⁵ This is consistent because depression is known to be a symptom of traumatic brain injury.

Most of the microbiota identified in the study have an involvement with the synthesis of glutamate and butyrate. The researchers explain that glutamate is widely distributed in the brain and acts as a major excitatory synaptic neurotransmitter known to be involved with the regulation of neuroplasticity, learning, and memory. Low levels of glutamate have been associated in previous research with mood and psychotic disorders, and increasing glutamate levels is becoming a novel therapeutic target for treating depressive disorders.⁵

Butyrate is a SCFA that modulates biological responses of host gastrointestinal health and can affect the gut-brain axis by enhancing “cholinergic neurons via epigenetic mechanisms” while also being able to cross the blood-brain barrier and activate the vagus nerve and hypothalamus, explain the researchers.⁵

Other research has found associations between alterations in gut microbiome with neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).³ For example, Alzheimer’s disease patients, when compared to age- and gender-matched controls not suffering from the disease, were found to have decreased levels of bacteria known to be butyrate producers. Similarly, patients with Parkinson’s disease were also found to have a lower abundance of butyrate-producing bacteria and lower SCFAs overall compared to age-matched controls.

Modulating the Microbiome

While consumers should not turn to dietary supplements to treat serious neurological conditions, this research demonstrates the relationship between our brains and microbiomes, and therefore offers a possible solution for consumers experiencing stress in their daily lives. Consumers are already looking for ways to reduce stress through dietary intervention, and dietary supplements can be a useful tool to this end.

Naturally, consumers looking for brain health solutions via the gut will turn to probiotics. Some probiotic manufacturers have already begun marketing strains for brain health and have clinical validation. IFF (New York City), for example, offers its Howaru Lacticaseibacillus paracasei Lpc-37 ingredient for stress support. One study found that 120 subjects given the probiotic for five weeks experienced significant reductions in perceived exhaustion, fatigue, and stress compared to those taking placebo. The reduction was particularly pronounced among women, whom the researchers noted had higher stress and sleep disruption compared to the men in the study.⁶

Another probiotic strain, from Lallemand Health Solutions (Mirabel, QC, Canada)—Lacticaseibacillus rhamnosus HA-114—was found in a recent study to significantly impact eating behaviors and mood-related factors, compared to placebo.⁷ In the study, 152 adults were given a dietary intervention with the addition of either placebo or the probiotic strain. Both groups experienced reductions in their weight from the dietary intervention, but only the probiotic group experienced decreases in binge-eating tendencies, disinhibition, and food cravings. Lallemand has also recently announced that its Rosell Institute for Microbiome and Probiotics received a $1.6 million research grant from the Weston Family to study this same probiotic strain for its impact on ALS.⁸

A probiotic blend from AB-Biotics (Barcelona, Spain), consisting of Pediococcus acidilactici KABP 021 (CECT 7483), Lactiplantibacillus plantarum KABP 022 (CECT 7484), and L. plantarum KABP 023 (CECT 7485), was found to help subjects with stress-induced gastric distress.⁹ While the study was small, results showed that subjects taking the probiotic blend experienced improvements in mental health scores and saw significant improvements in diarrhea-related problems that led to better overall work habits, including less missed work and improved productivity. The researchers observed that improvements in gastric issues coincided with increased abundance of Faecalibacterium, a butyric acid–producing bacterium.

Based on these studies, modulating the gut microbiome with probiotics can have real-world impacts on people’s mental health, potentially improving their health in numerous other ways. Weight management, for example, can be a controversial category, but offering a product that bolsters a healthy diet and exercise by reducing disinhibited eating can be a real game changer, especially when you consider how many people use food as comfort during stressful situations. Similarly, stress-induced gastrointestinal issues can have real negative impacts on our personal and professional lives, compounding the stress one experiences. If probiotics can help alleviate stress and related issues, that, too, can have an immense positive impact on consumers.

Prebiotics, a well-known complement to probiotics, may help support the gut-brain axis as well. Defined as carbohydrates that are selectively fermented by gut microbiota, thus modulating the composition of the microbiome, prebiotics may help in the production of SCFAs like butyrate, which we’ve established confer numerous benefits, including potential brain-health benefits.³ SCFAs produced by microbes may also influence the expression of brain-derived neurotrophic factor (BDNF), which in turn supports the growth of new neurons and the survival of existing neurons.³ A recent preclinical study found that supplementation with a proprietary galactooligosaccharide (GOS) ingredient from Clasado Biosciences (Reading, UK) may reduce unfavorable metabolites while increasing healthy metabolites such as the SCFA butyrate.¹⁰ There may not yet be enough research to directly link prebiotics to the gut-brain axis, but the potential is there to elucidate their relationship with our brain.

Benefits to the gut-brain axis may not be isolated to pre- and probiotics either. Herbs known to support brain health may in fact have gut-modulating mechanisms. For example, Bacopa monnieri and ashwagandha have been shown, in vitro, to increase butyrate-producing bacteria and significantly alter the composition of gut microbiota.³ Once again, more research is necessary to understand this relationship, but in the future, the gut-brain axis may be another way to communicate the benefits of brain health–supporting herbs.

Concepts like the gut-brain axis provide a framework for understanding the interconnectedness of our bodies’ systems, which can be attractive to consumers who seek a more holistic approach to their health. Stress is also a universal experience that we all seek to avoid or minimize in our daily lives, and unfortunately, the ways people seek to alleviate stress are not always healthy and productive. Dietary supplements can offer a safer way to improve people’s quality of life.

The fact that microbiome-supporting products like pre- and probiotics are likely to be a part of consumers’ existing supplement regimen makes supporting the gut-brain axis a relatively easy sell. Researchers are still working out the details of the gut-brain relationship, but there is a growing acceptance of the concept, and study results are making their way to mainstream audiences. For example, the results of the Nature study were featured in The Washington Post.¹¹ The gut-brain axis may not be mainstream quite yet, but now may be the time to start developing products that target the gut-brain axis, gaining a foothold in the category while boosting awareness and educating consumers.

References

1. Stress Symptoms: Effects on Your Body and Behavior. The Mayo Clinic. Accessed February 10, 2023. https://www.mayoclinic.org/healthy-lifestyle/stress-management/in-depth/stress-symptoms/art-20050987
2. Krawiec, S. Look Beyond the Gut and Take Advantage of the Growing Microbiome Space: 2023 Ingredient Trends for Food, Drinks, Dietary Supplements, and Natural Products. Nutritional Outlook. January 31, 2023. Accessed February 10, 2023. https://www.nutritionaloutlook.com/view/look-beyond-the-gut-and-take-advantage-of-the-growing-microbiome-space-2023-ingredient-trends-for-food-drinks-dietary-supplements-and-natural-products
3. Peterson, C.T. Dysfunction of the Microbiota-Gut-Brain Axis in Neurodegenerative Disease: The Promise of Therapeutic Modulation With Prebiotics, Medicinal Herbs, Probiotics, and Synbiotics. J Evid Based Integr Med. 2020, 25: 1-19. DOI: 10.1177/2515690X20957225
4. Pferchy-Wenzig, E.M.; Pausan, M.R.; Adjomand-Woelkart, K; Röck, S.; Ammar, R.M.; Kelber, O.; Moisel-Eichinger, C.; Bauer, R. Medicinal Plants and Their Impact on the Gut Microbiome in Mental Health: A Systematic Review. Nutrients. 2022, 14 (10): 2111. DOI: 10.3390/nu14102111
5. Radjabzadeh, D.; Bosch, J.A.; Uitterlinden, A.G.; Zwinderman, A.H.; et al. Gut Microbiome-Wide Association Study of Depressive Symptoms. Nat Commun. 2022, 13: 7128. DOI: 10.1038/s41467-022-34502-3
6. Patterson, E.; Griffin, S.M.; Ibarra, A.; Ellsiepen, E.; Hellhammer, J. Lacticaseibacillus paracasei Lpc-37® Improves Psychological and Physiological Markers of Stress and Anxiety in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled and Parallel Clinical Trial (the Sisu Study). Neurobiol Stress. 2020, 13: 100277. DOI: 10.1016/j.ynstr.2020.100277
7. Choi, B.S-Y.; Brunelle, L.; Pilon, G.; Cautela B.G.; Tompkins, T.A.; Drapeau, V.; Marette, A.; Tremblay, A. Lacticaseibacillus rhamnosus HA-114 Improves Eating Behaviors and Mood-Related Factors in Adults With Overweight During Weight Loss: A Randomized Controlled Trial. Nutr Neurosci. 2022. DOI: 10.1080/1028415X.2022.2081288
8. Grebow, J. Lallemand’s Probiotic to Be Studied for Effects on Lou Gehrig’s Disease. Nutritional Outlook. February 25, 2022. Accessed February 10, 2023. https://www.nutritionaloutlook.com/view/lallemand-s-probiotic-to-be-studied-for-effects-on-lou-gehrig-s-disease
9. Sato, T.; Honda, S.; Tominaga, Y.; Miyakoshi, Y.; Ueda, T.; Sawashita, J. A Probiotic Blend Improves Defecation, Mental Health, and Productivity in Healthy Japanese Volunteers Under Stressful Situations. Heliyon. 2022, 8 (9):e10614, DOI: 10.1016/j.heliyon.2022.e10614
10. Marzorati, M.; Ghyselinck, J.; Van den Abbeele, P.; Maruszak, A.; Harthoorn, L. Galactooligosaccharide (GOS) Reduces Branched Short-Chain Fatty Acids, Ammonium, and pH in a Short-Term Colonic Fermentation Model. Appl. Microbiol. 2023, 3 (1): 90-103. DOI: 10.3390/applmicrobiol3010008
11. Wapner, J. The Link Between Our Food, Gut Microbiome and Depression. The Washington Post. January 31, 2023. Accessed February 7, 2023. https://www.washingtonpost.com/wellness/2023/01/31/gut-microbiome-anxiety-depression/