By Kim Ross, DCN, CNS, LDN, IFMCP⁺

Cortisol: How It Shapes Occasional Anxiety and Mood

1. Introduction
2. Overview of the HPA Axis
3. Spotlight on Cortisol -The Master Stress Hormone
4. Recognizing Symptoms of High Cortisol
5. Pure Encapsulations Nutrient Solutions
6. Conclusion
7. Resources

Introduction

Stress and occasional anxiousness are increasingly common experiences in today's high-demand world. A poll conducted in 2024 by the American Psychiatric Association revealed that 43% of adults in the United States experience increased feelings of anxiousness, with 53% of those polled attributing this feeling to stress.¹ Although short-term stress responses are adaptive and essential for survival, dysregulated stress responses can significantly impact mood and mental clarity. Central to this physiological stress response is the hormone cortisol.

This blog highlights how cortisol, particularly when levels fluctuate, becomes an underlying driver of changes in mood and emotion. It will also provide targeted, evidence-based interventions that healthcare providers may consider for patients experiencing occasional anxiousness due to stress.

Overview of the Hypothalamus-Pituitary-Adrenal (HPA) Axis

The HPA axis is the body's primary neuroendocrine pathway for responding to stress, governed by a multi-layer negative feedback system. Signaling begins in the hypothalamus, which consolidates internal and external signals to determine the overall "threat" to the body. The hypothalamus releases corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in response to a perceived, physical or emotional stressor.

Next, CRH stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). The pituitary gland comprises the posterior, intermediate and anterior lobes, each responsible for releasing multiple hormones.

Finally, the release of ACTH prompts the adrenal glands to produce cortisol and dehydroepiandrosterone (DHEA) in the adrenal cortex and to release two catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline), from the adrenal medulla.

Once the "threat" (stress) is removed, a negative feedback loop reduces CRH and ACTH production, lowering cortisol levels and returning the system to homeostasis.

While this system is adaptive in the short term, chronic activation of the HPA axis leads to sustained cortisol production, as seen in prolonged stress states. Over time, this can impair receptor sensitivity and disrupt the negative feedback loop, resulting in cortisol fluctuation. Long-term, this fluctuation has been associated with emotional lability, poor resilience, fatigue, cognitive fog, increased cytokine production, changes of glycemic control and circadian rhythm disturbances.^2,3

Spotlight on Cortisol: The Master Stress Hormone

Cortisol is a steroid hormone, specifically a glucocorticoid, synthesized in the zona fasciculata of the adrenal cortex. It exerts its effects by binding to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs), which are widely distributed throughout the central nervous system and peripheral tissues.⁴

Cortisol prepares the body for a "fight or flight" response. It increases blood glucose levels, enhances alertness and temporarily suppresses non-essential processes like digestion and reproduction. DHEA, also produced in the adrenal cortex, is a modulating hormone that buffers the effects of increased cortisol.^3,4

Functions of Cortisol

Cortisol plays a vital role in many physiological processes since most cells in the body have glucocorticoid receptors (GRs).²

Diurnal Cortisol Rhythm

Cortisol follows a distinct circadian rhythm governed by the suprachiasmatic nucleus (SCN) of the hypothalamus. This rhythm includes:^2,4

• A sharp increase within 30 – 45 minutes after waking (the cortisol awakening response, or CAR). A healthy cortisol awakening response can cause a 35-60% rapid increase in cortisol production, followed by a decline within 60 minutes.
• A gradual decline continues throughout the day, reaching its lowest point near midnight.

Of importance, cortisol has an inverse relationship with melatonin, commonly called the sleep hormone.

When Cortisol Fluctuates: Its Impact on Mood

When cortisol regulation changes, either through hypersecretion, receptor desensitization or circadian misalignment, the consequences of mood regulation can be profound.

Elevated cortisol patterns have been linked to³:

• Changes of the HPA axis leads to ongoing elevations in cortisol.
• Disruptions in the production of the inhibitory neurotransmitters GABA and serotonin, which are responsible for creating a sense of calmness.
• Changes in brain structure and function, particularly in the area responsible for mood regulation.
• Hypersensitivity to stressors with increased vigilance and threat perception, leading to increased anxious feelings

The Bi-Directional Relationship Between Cortisol and Occasional Anxiety

Prolonged psychological or physiological stress activates the HPA axis, leading to sustained cortisol secretion. The ongoing elevation of cortisol can cause changes to key brain regions involved in mood and emotional regulation, heightening vigilance, worry and symptoms of anxiousness. This state of occasional anxiousness, in turn, acts as a persistent internal stressor, perpetuating further HPA axis activation and continued cortisol release.

The result is a self-reinforcing feedback loop.

Recognizing Symptoms of High Cortisol

Biomarker assessment (e.g., salivary cortisol curve including CAR) may help evaluate diurnal rhythm and identify disruptions. Integrating this data with symptom patterns can help guide personalized nutrition and lifestyle strategies to support healthy HPA axis function.

Pure Encapsulations Nutrient Solutions

Daily Calm combines GABA with clinically backed saffron (affron^®), ashwagandha (KSM-66^®) and l-theanine (Suntheanine^®) to relieve feelings of occasional stress and anxiety. Together, these ingredients address common mental health needs while supporting mood and sleep quality with continued use. Research highlights include a significant reduction in perceived stress after 8 weeks of KSM-66^® and a reduction of occasional anxiousness after 4 weeks of Suntheanine^®.^6,7‡

Suggested Dose: Take 1 capsule two times daily, between meals.

Rapid Calm provides rapid-acting support (<1 hour) for occasional anxiety. It combines vitamin B6 with two clinically researched ingredients, Zembrin^®, a patented extract of Sceletium tortuosum, and Suntheanine^® l-theanine, to help moderate feelings of stress and occasional anxiety. This formula is ideal for as-needed relief from occasional everyday stressors. Research highlights that a single dose of 25 mg Zembrin^® reduced perceived anxiety levels and moderated fear responsivity.^{8,9 ‡}

Suggested Use: Take 1 capsule, as needed, with or between meals.

Cortisol Calm combines vitamin D3, Sensoril^® ashwagandha extract, Rhodiola rosea extract, Magnolia officinalis extract and l-theanine to promote relaxation and a healthy cortisol response. It provides support for occasional stress, calm and emotional well-being. Sensoril^® promotes relaxation and a healthy cortisol response as well as the reduction of perceived stress scale score and plasma cortisol and ACTH levels.^{10,11 ‡}

Suggested Use: As a dietary supplement, take 1 capsule in the morning and 1 capsule in the evening, with meals.

Amino Replete contains a blend of free-form amino acids, provided in the ratios found naturally in high biological value (BV) protein sources, made with high-quality vegetarian ingredients. It enhances healthy neurotransmitter synthesis with amino acid precursors to support cognitive function and positive mood.^‡

Suggested Use: As a dietary supplement, take 1 scoop daily, mixed with 8 ounces of water or juice, between meals, or as directed by a health professional.

Conclusion

Cortisol plays a central role in the body's adaptive response to stress, exerting wide-reaching effects on metabolism, immune function, circadian regulation and mood. For healthcare practitioners, understanding the bi-directional relationship between cortisol and mood and the symptoms of high cortisol is essential for comprehensive assessment and early intervention to interrupt the self-reinforcing cycle of stress and anxiousness.

Resources

For additional resources that include diet and lifestyle recommendations for supporting occasional anxiety, refer to the protocols listed below:

Positive Mood Protocol: Designed by our scientific and medical advisors in collaboration with Dr. James Greenblatt to help you deliver the most effective care and support for your patient's mood and emotional well-being.

For more details on the research on the selected nutrient solutions, download the product information sheets:

• Daily Calm
• Rapid Calm
• Cortisol Calm
• Amino Replete

Drug-Nutrient Interactions Checker: Provides valuable information on potential interactions between your patients' prescriptions, over-the-counter medications and nutritional supplements.

PureInsight^™: Our streamlined platform easily collects patient data and provides valuable recommendations to help achieve their health goals.

Virtual Dispensary: Our Pure Patient Direct program provides account holders FREE access to our virtual dispensary to help simplify patient sales and reduce in-office inventory.

You can also explore Pure Encapsulations^® to find On-Demand Learning, Clinical Protocols and other resources developed with our medical and scientific advisors.

1. American Psychiatric Association. May 1, 2024. Accessed November 11, 2024. https://www.psychiatry.org/news-room/news-releases/annual-poll-adults-express-increasing-anxiousness
2. Jones C, Gwenin C. Physiol Rep. 2021;8(24):e14644. doi:10.14814/phy2.14644
3. Sic A, Cvetkovic K, Manchanda E, Knezevic NN. Diseases. 2024;12(9):220. doi:10.3390/diseases12090220
4. Guilliams T. Principles and Protocols for Healthcare Professionals. Point Institute; 2018.
5. Azmi NASM, Juliana N, Azmani S, et al. Int J Environ Res Public Health. 2021;18(2). doi:10.3390/ijerph18020676
6. Salve J, Pate S, Debnath K, Langade D. Cureus. Published online 2019. doi:10.7759/cureus.6466
7. Hidese S, Ogawa S, Ota M, et al. Nutrients. 2019;11(10). doi:10.3390/nu11102362
8. Reay J, Wetherell MA, Morton E, Lillis J, Badmaev V. Hum Psychopharmacol. 2020;35(6). doi:10.1002/hup.2753
9. Terburg D, Syal S, Rosenberger LA, et al. Neuropsychopharmacology. 2013;38(13). doi:10.1038/npp.2013.183
10. Auddy B, Hazra J, Mitra A, Abedon B, Ghosal S. Journal of the American Nutraceutical Association. 2008;11(1).
11. Pandit S, Srivastav AK, Sur TK, Chaudhuri S, Wang Y, Biswas TK. Nutrients. 2024;16(9):1293. doi:10.3390/nu16091293

⁺Kim Ross is a paid consultant for Pure Encapsulations.

By Kim Ross, DCN, CNS, LDN, IFMCP⁺

Fueling Focus: Optimizing Acetylcholine for Sharper Attention and Cognitive Performance

1. Introduction
2. Acetylcholine and the Cholinergic System
3. Optimizing Acetylcholine Through Diet and Lifestyle
4. Nutrient Solutions to Optimize Acetylcholine
5. Pure Encapsulations Nutrient Solutions
6. Conclusion
7. Resources

Introduction

Did you know?

• 1 in 25 adults have difficulty maintaining attention and focus.¹
• Nearly half of individuals feel their attention span isn't what it used to be.²

Attention and cognitive performance are fundamental to daily functioning, influencing productivity, learning and decision-making. Unfortunately, focus-related difficulties are increasingly prevalent, affecting individuals across all age groups leading to an upward trend in adults seeking support to improve their focus and concentration. The growing prevalence of digital distractions, stress and inadequate nutrition exacerbates attention-related challenges.

This blog highlights the role of the cholinergic system and acetylcholine optimization in enhancing cognitive performance and sustaining mental clarity through integrative strategies, including nutrition, lifestyle factors and targeted nutrient support. 

Acetylcholine and the Cholinergic System

The cholinergic system is a complex system involved in various peripheral and central nervous functions. Its most significant roles include:^3,4

1)    The transmission of signals across nerve cells for muscle activation, memory, learning, neuronal signaling, synaptic plasticity and sensory processing. 

2)    The synthesis and release of the neurotransmitter acetylcholine (ACh).

Acetylcholine is a primary neurotransmitter that, as the name implies, is synthesized from acetyl-coenzyme A (acetyl CoA) and choline. This neurotransmitter is essential for memory formation, learning and sustained attention. It acts at both nicotinic and muscarinic receptors throughout the brain, particularly in the prefrontal cortex and hippocampus, which are critical for executive function and memory recall.⁴  ACh is broken down into acetate and choline. Choline can then be recycled for use by nerves or can be converted back to phosphatidylcholine, a major component of cellular membranes.^3,4   

Studies show that individuals with higher acetylcholine activity demonstrate superior cognitive flexibility, faster reaction times and enhanced working memory. ^5–7 Conversely, acetylcholine depletion is associated with reduced attention span, slower cognitive processing and impaired recall ability.⁸

Nutrition and Lifestyle Interventions for Acetylcholine Optimization

Several factors can influence acetylcholine levels, including poor dietary intake of choline, lack of physical activity and chronic stress. Given acetylcholine's role in cognitive performance, strategic interventions aimed at preserving and enhancing cholinergic function should be a focus of clinical care.

Consuming foods high in choline is crucial since this nutrient is needed to synthesize acetylcholine. 

Key dietary sources include:

• Egg yolks (one of the highest sources of dietary choline)
• Beef and chicken liver
• Fish (rich in both choline and omega-3s)
• Soybeans and legumes
• Wheat germ and bran
• Vegetables (though smaller amounts compared to animal sources) 

Additionally, a Mediterranean-style diet, abundant in healthy fats, polyphenols, and antioxidant-rich foods, has been linked to improved cognitive performance, memory and executive function.⁹

Regular aerobic and strength exercise supports acetylcholine production by:

1. Increasing brain-derived neurotrophic factor (BDNF), which is directly involved in acetylcholine release and synapse maintenance.¹⁰
2. Increasing the release of nitric oxide (NO), which works synergistically with acetylcholine to enhance vasodilation.¹¹

Clinical Pearl: In older adults, low choline intake is associated with reduced gains in strength and muscle quality during resistance training, suggesting that adequate choline is important for muscle function and possibly acetylcholine-related neuromuscular activities.¹²

Mind-body practices can help promote increased focus, attention and cognitive performance; however, there isn't evidence to suggest a direct impact on acetylcholine production. 

1. Controlled breathing exercises, such as pranayama or diaphragmatic breathing, may help regulate cholinergic signaling, vagal tone and enhance parasympathetic nervous system activity, supporting cognitive clarity.¹³
2. Mindfulness meditation has been shown to enhance attention processing and emotional regulation through improved brain connectivity and neuroplasticity.^14,15
3. Time in nature ("green therapy") may support acetylcholine balance by reducing stress hormones.¹⁶

Clinical Pearl: Engage in physical activity in nature for an extra win!

In the digital age, one of the most pervasive disruptors of focus and cognitive efficiency is the constant influx of notifications, multitasking and screen time. Research indicates that frequent digital interruptions can lead to attention fragmentation, reducing the brain's ability to engage in sustained, deep work.¹⁷

To mitigate these effects, healthcare professionals can recommend structured digital detox strategies, such as: 

• Establishing technology-free blocks during the day
• Turning off notifications
• Using "do not disturb" settings during cognitively demanding tasks
• Implementing screen-free morning and evening routines
• Encouraging periods of boredom, creative play and real-world sensory engagement, such as connecting with others in real life, walking in nature or journaling. 

Nutrient Solutions to Optimize Acetylcholine

Targeted nutrient supplementation offers an evidence-based approach to supporting acetylcholine levels and cognitive function. 

Choline is a direct precursor to acetylcholine, which is involved in attention and cognitive performance. Supplemental and dietary intake is associated with healthy memory, attention and learning. Not all forms of choline may provide the same benefits.^18‡ Research suggests GPC and CDP-choline (citicoline) are bioavailable forms that efficiently cross the blood-brain barrier and support acetylcholine synthesis.¹⁸ Cognizin^®, a patented citicoline, increases choline and phospholipid composition in the brain.¹⁹ Studies in children, middle-aged adults and elderly adults indicate that it supports healthy cognition across a wide age range. In two studies, one involving adolescent boys and another involving middle-aged women, 250-500 mg Cognizin^® citicoline offered statistically significant support for daily mental task performance.^20,21

Acetyl-L-Carnitine (ALC) is an ester of the trimethylated amino acid L-carnitine. It plays a dual role in supporting cognitive function: it facilitates acetyl-CoA uptake to enhance acetylcholine production and supports mitochondrial energy production in neurons. Clinical trials suggest that ALC supplementation promotes mental clarity, reduces brain fog and supports focus in individuals with cognitive fatigue.²²

American Ginseng (Panax quinquefolius) has been shown to modulate acetylcholine release and thereby promote learning and working memory.²³ Its active components, known as ginsenosides, also possess protective properties that moderate oxidative stress-induced changes to cholinergic signaling.²⁴

Phosphatidylcholine: choline is a precursor to phosphatidylcholine, a key phospholipid found in cell membranes and serves as a reservoir for choline needed for acetylcholine synthesis.²⁵ 

Phosphatidylserine is a phospholipid critical for synaptic function and neuronal membrane integrity. Multiple studies indicate that supplementation helps support mental acuity, behavioral and cognitive parameters.^26–28

Omega-3 Fatty Acids: The long-chain omega-3 fatty acids EPA and DHA promote healthy cognition, support the release of neurotransmitters and help protect against oxidative stress. One systematic review concluded that omega-3 fatty acid intake (1-2 grams daily) promoted executive function, word and memory recall and cognitive performance.²⁹ 

Pure Encapsulations Nutrient Solutions

Pure Encapsulations^® provides uniquely formulated products made with high-quality, pure ingredients backed by verifiable science to complement your plan of care and support the health of  your patients.^‡

Rapid Mental Energy is a non-stimulant formula that combines two clinically studied extracts, Alpinia galagna(enXtra) and American ginseng (Cereboost^®), to support alertness and sharpen working memory, without interfering with sleep.^{23,30–33‡}

Suggested Use: Take 1 capsule, as needed, with or between meals. It can be used in combination with caffeine.

Phosphatidylcholine (sunflower) is a phospholipid-bound choline that supports cellular function, cognitive function and liver health. It acts as a precursor for phospholipids and acetylcholine, the neurotransmitter involved in attention, memory and neuromuscular function.^‡

Suggested Use: Take 2 capsules daily, with a meal

CogniPhos contains a blend of clinically researched Cognizin^® citicoline, acetyl-L-carnitine, SharpPS^® phosphatidylserine and cofactors to promote daily cognitive performance and mental sharpness while supporting cellular energy and optimal neuronal function. ^21,27‡

Suggested Use: Take 2 capsules, 1-2 times daily, with meals or as directed by a healthcare professional

O.N.E™ Omega provides 1,000 mg of triglyceride-form EPA/DHA produced through a unique solvent-free, supercritical, CO₂-based extraction method to support a healthy inflammatory response.^‡

Suggested Use: Take 1 capsule daily, with a meal

Conclusion

Acetylcholine is a key neurotransmitter involved in attention regulation, memory formation and cognitive flexibility. Clinicians can provide integrative solutions to support acetylcholine production, including a choline-rich diet, regular physical activity, stress management techniques and key nutrients such as choline, phosphatidylcholine, acetyl-L-carnitine and omega-3 fatty acids to support sharper focus and cognitive performance in their patients. 

Resources

Cognitive Performance Protocol: Designed by our scientific and medical advisors to help you deliver the most effective care and support for your patient.

Drug-Nutrient Interaction Checker:  Provides valuable information on potential interactions between your patients' prescriptions, over-the-counter medications and nutritional supplements.

PureInsight^™: Our streamlined platform easily collects patient data and provides valuable recommendations to help achieve their health goals.

Virtual Dispensary: Our Pure Patient Direct program provides account holders FREE access to our virtual dispensary to help simplify patient sales and reduce in-office inventory.

You can also explore Pure Encapsulations^® to find On-Demand Learning, Clinical Protocols and other resources developed with our medical and scientific advisors.

1. National Institute of Mental Health. National Institute of Mental Health. Accessed March 26, 2025. https://www.nimh.nih.gov/health/statistics
2. Duffy B, Thain M. The Policy Institute. Published online February 2022.
3. Tizabi Y, Getachew B, Tsytsarev V, et al. In: Acetylcholine - Recent Advances and New Perspectives; 2023. doi:10.5772/intechopen.112447
4. Bekdash RA.Int J Mol Sci. 2021;22(3). doi:10.3390/ijms22031273
5. Newman EL, Gupta K, Climer JR, et al. Front Behav Neurosci. 2012;(JUNE). doi:10.3389/fnbeh.2012.00024
6. Dautan D, Huerta-Ocampo I, Gut NK, et al. Nat Commun. 2020;11(1). doi:10.1038/s41467-020-15514-3
7. Ballinger EC, Ananth M, Talmage DA, Role LW. Neuron. 2016;91(6). doi:10.1016/j.neuron.2016.09.006
8. Decker AL, Duncan K. Curr Opin Behav Sci. 2020;32. doi:10.1016/j.cobeha.2020.01.013
9. Fu J, Tan LJ, Lee JE, Shin S. Front Nutr. 2022;9. doi:10.3389/fnut.2022.946361
10. Wang Q, Cui C, Zhang N, et al. J Orthop Translat. 2024;46:91-102. doi:10.1016/j.jot.2024.03.007
11. Kingwell BA. The FASEB Journal. 2000;14(12). doi:10.1096/fj.99-0896rev
12. Lee CW, Lee T V., Galvan E, et al. Nutrients. 2023;15(18). doi:10.3390/nu15183874
13. Herhaus B. Psychoneuroendocrinology. 2024;160. doi:10.1016/j.psyneuen.2023.106751
14. Calderone A, Latella D, Impellizzeri F, et al. Biomedicines. 2024;12(11):2613. doi:10.3390/biomedicines12112613
15. Prakash RS. Archives of Clinical Neuropsychology. 2021;36(7). doi:10.1093/arclin/acab053
16. Shuda Q, Bougoulias ME, Kass R. Complement Ther Med. 2020;53. doi:10.1016/j.ctim.2020.102514
17. Duke É, Montag C. Addictive Behaviors Reports. 2017;6. doi:10.1016/j.abrep.2017.07.002
18. Kansakar U, Trimarco V, Mone P, et al. Front Endocrinol (Lausanne). 2023;14. doi:10.3389/fendo.2023.1148166
19. Silveri MM, Dikan J, Ross AJ, et al. NMR Biomed. 2008;21(10). doi:10.1002/nbm.1281
20. McGlade E, Locatelli A, Hardy J, et al. Food Nutr Sci. 2012;03(06). doi:10.4236/fns.2012.36103
21. McGlade E, Agoston AM, DiMuzio J, et al. J Atten Disord. 2019;23(2). doi:10.1177/1087054715593633
22. Pennisi M, Lanza G, Cantone M, et al. Nutrients. 2020;12(5). doi:10.3390/nu12051389
23. Scholey A, Ossoukhova A, Owen L, et al. Psychopharmacology (Berl). 2010;212(3). doi:10.1007/s00213-010-1964-y
24. Zhu Y, Wang Z, Yu S, et al. Molecules. 2022;27(22):7824. doi:10.3390/molecules27227824
25. Tan W, Zhang Q, Dong Z, et al. J Agric Food Chem. 2020 Dec 16;68(50):14884-14895. doi: 10.1021/acs.jafc.0c06383.
26. Hirayama S, Terasawa K, Rabeler R, et al. Journal of Human Nutrition and Dietetics. 2014;27(SUPPL2). doi:10.1111/jhn.12090
27. Kato-Kataoka A, Sakai M, Ebina R, et al. J Clin Biochem Nutr. 2010;47(3). doi:10.3164/jcbn.10-62
28. Richter Y, Herzog Y, Lifshitz Y, et al. Clin Interv Aging. 2013;8. doi:10.2147/CIA.S40348
29. Dighriri IM, Alsubaie AM, Hakami FM, et al. Cureus. Published online 2022. doi:10.7759/cureus.30091
30. Shin K, Guo H, Cha Y, et al. Regulatory Toxicology and Pharmacology. 2016;78. doi:10.1016/j.yrtph.2016.04.006
31. Bell L, Whyte A, Duysburgh C, et al. Eur J Nutr. 2022;61(1). doi:10.1007/s00394-021-02654-5
32. Ossoukhova A, Owen L, Savage K, et al. Hum Psychopharmacol. 2015;30(2). doi:10.1002/hup.2463
33. Srivastava S, Mennemeier M, Pimple S. J Am Coll Nutr. 2017;36(8). doi:10.1080/07315724.2017.1342576

⁺Kim Ross is a paid consultant for Pure Encapsulations.

Mental Health Care: Exploring the Microbiota-Gut-Brain Connection

By: Kim Ross, DCN, CNS, LDN, IFMCP

1. Introduction
2. What is the Microbiota-Gut-Brain Axis?
3. The Microbiota's Influence on the Gut-Brain Axis
4. The Microbiota-Gut-Brain Axis and Mood
5. Nutrition and Lifestyle Interventions to Support the Microbiota-Gut-Brain Axis
6. Nutrient Solutions to Support the Microbiota-Gut-Brain Axis
7. Pure Encapsulations Nutrient Solutions
8. Conclusion
9. Resources

Introduction

Mental health concerns are a growing global issue, with recent data indicating that nearly 1 in 8 individuals worldwide experience some form of emotional distress, including anxious feelings and mood fluctuations.¹ Evidence suggests that disruptions in gut microbiota composition, often influenced by modern diets, stress and environmental exposures, may play a role in these rising mental health concerns.²

By leveraging dietary strategies, stress management techniques and targeted nutrient support, clinicians can provide natural, sustainable solutions that optimize the microbiota-gut-brain axis to address mental health and emotional resilience.

This blog explores the underlying mechanisms of the microbiota-gut-brain axis, its role in mood regulation and evidence-based strategies, including dietary interventions, stress management techniques and targeted nutrients such as probiotics, prebiotics, ashwagandha and L-theanine to support a balanced and resilient gut-brain connection.^‡

What is the Microbiota-Gut-Brain Axis?

The microbiota-gut-brain axis is a bidirectional communication network between the gut microbiome, the central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS) and the hypothalamus-pituitary-adrenal (HPA) axis.^3,4 This intricate system regulates cognitive function, mood and overall mental well-being. The gut microbiome, composed of trillions of microorganisms, influences neurotransmitter production, immune modulation and hormonal balance, all affecting neurological function and mental & emotional health.⁴

The Microbiota's Influence on the Gut-Brain Axis

The microbiota-gut-brain axis functions through several key pathways facilitating communication between the gut microbiota and the brain. These include neural, immune and endocrine pathways, each playing a distinct role in supporting mental health.

Neural Pathway

The vagus nerve is a primary conduit between the gut and brain, transmitting signals directly from the gut microbiota to the central nervous system.³ Sometimes called the “sixth sense,” the vagus nerve can sense the microbiota and transfer the information to the nervous system, where it integrates and responds appropriately.⁵ Additionally, the enteric nervous system, often called the "second brain," contains millions of neurons that interact with gut microbes to regulate neurotransmitter production and brain activity.

Immune Pathway

The gut microbiome plays a critical role in immune system regulation, influencing cytokine regulation.³ Beneficial microbes promote the release of anti-inflammatory cytokines, such as interleukin-10 (IL-10). Non-beneficial microorganisms can trigger the production of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which have been implicated in neuro-immune responses and mood disturbances.⁶

Endocrine Pathway

The endocrine pathway is more commonly referred to as the neuroendocrine system. The gut microbiota modulates gut hormones and neurotransmitters made in the gut and activates the hypothalamus-pituitary-adrenal (HPA) axis. The HPA axis governs the body's stress response and is involved in mood and immune function.³ Gut bacteria produce neurotransmitters such as serotonin, dopamine and GABA, which are essential for maintaining emotional stability.⁷

The Microbiota-Gut-Brain Axis and Mood

Studies suggest that gut microbiota imbalances are linked to mood fluctuations through altered neurotransmitter production, increased intestinal permeability, HPA dysregulation and heightened cytokine production. Specific bacterial strains, such as Bifidobacterium longum and Lactobacillus helveticus, have been shown to exert anxiolytic and mood-stabilizing effects by modulating gamma-aminobutyric acid (GABA), serotonin, dopamine, tryptophan, cortisol and cytokines.⁷

Nutrition and Lifestyle Interventions to Support the Microbiota-Gut-Brain Axis

Optimizing gut health through targeted nutrition and lifestyle interventions can strengthen the microbiota-gut-brain axis and improve mood regulation.

Diet and Its Influence on the Microbiome

Diet is described as one of the most influential and rapid contributors to microbial changes.^3,4 A symbiotic relationship between fiber, polyphenols, prebiotics and fermented foods in the diet supports microbial diversity and enhances gut-brain communication.

• Fiber is a food source for beneficial bacteria and promotes short-chain fatty acid (SCFA) production. Among its benefits, SCFAs support the GI barrier, promote the production of serotonin and GABA, modulate the immune system and influence the gut-brain connection through the vagus nerve.⁸ Fruits, vegetables, legumes and whole grains are rich sources of dietary fiber.
• Polyphenol-rich foods like berries, apples, green tea, olive oil and dark chocolate may act as prebiotics.³ They have been shown to modulate the gut microbiome by increasing beneficial bacteria (i.e., Bifidobacterium, Firmicutes, Lactobacillus) and reducing harmful bacteria (i.e., Clostridium) while also supporting the body’s natural inflammatory processes and providing antioxidant and neuroprotective properties.⁹ Many polyphenol-rich foods are also a good source of fiber.
• Prebiotics found in foods like garlic, onions, leeks, bananas, apples, honey, chicory root, flaxseed and asparagus fuel the growth of beneficial bacteria. By default, many prebiotic foods are also a source of fiber and polyphenols.
• Fermented foods, including yogurt, kefir, kimchi, miso, cheese, vinegar and sauerkraut, provide beneficial probiotics that enhance gut microbiota composition and are a readily available source of SCFAs. Homemade fermented foods will provide the most probiotic diversity, and the fermentation process increases the polyphenol bioavailability.¹⁰

In contrast, a diet high in processed foods, refined sugars and artificial additives can disrupt the gut microbiome, contributing to mood fluctuations and an altered cytokine response.⁴

Stress, Physical Activity and Sleep: Their Influence on the Microbiome

Stress negatively impacts gut microbiota composition and vagal tone, increasing intestinal permeability and cytokine response.⁵ Conversely, gut microbiota diversity may influence how one handles stress, partially due to the influence on the production of GABA and serotonin.¹¹ Stress management techniques like meditation, deep breathing and cognitive behavior therapy can help restore microbial balance, reduce HPA overactivity and support emotional resilience.⁵

Physical activity, particularly aerobic exercise, fosters microbial diversity and enhances the production of beneficial short-chain fatty acids (SCFAs), improving HPA axis control and positive moods.¹²

Sleep and the microbiome have a complementary relationship. Sleep is essential for maintaining a healthy microbiome, and a diverse microbiome has been positively correlated with increased sleep efficiency and total sleep time. Sleep deprivation has been linked to shifts in microbial composition and increased cortisol levels.¹³

Nutrient Solutions to Support the Microbiota-Gut-Brain Axis

Targeted supplementation with specific nutrients and bioactive compounds can further enhance the gut-brain connection and promote positive mental health.^‡

Probiotics & Prebiotics

Probiotic supplementation has been extensively studied for its effects on gut health and mood regulation. More specifically, in 2013, the term 'psychobiotics' was coined, describing the beneficial bacteria that produce health benefits for mental health.⁷ Multiple probiotic strains have been shown to enhance GABA and serotonin receptor expression in the brain, reduce cortisol levels and reduce cytokine activation. (Table 1)^‡

The most extensive and compelling evidence to support emotional and mental health exists for Lactobacillus helveticus Rosell-52 (RO052) and Bifidobacterium longum Rosell-175 (RO175).⁷ In a randomized, double-blind, placebo-controlled trial, supplementation with this combination maintained healthy urinary cortisol levels, indicating the potential to lessen occasional stress.¹⁴ In a separate analysis, supplemented subjects reported positive mood, relaxation and enhanced cognitive function.¹⁵ Further, multiple human studies have reported positive mood effects with this specific combination of probiotic strains.⁷

Prebiotics works synergistically with probiotics. The various types of prebiotics include fructans, galactooligosaccharides, xylo-oligosaccharides, chitooligosaccharides, lactulose, resistant starch and polyphenols. Prebiotics modulate and support the growth of the gut microbiota, specifically Bifidobacteria and Lactobacilli, increase SFCA production, improve gut barrier function, modulate the immune system and positively influence mood.^16‡

Butyrate

Butyrate is one of the three most abundant short chain fatty acids (SCFAs) produced by anaerobic bacterial fermentation of polysaccharides/fiber in the colon, where it serves as an energy source for epithelial cells.¹⁷ Considered a functionally versatile molecule, butyrate provides support for maintaining gastrointestinal health and regulating the neuro-endocrine-immune pathways, in part due to its ability to cross the blood-brain barrier.^17,18‡

Ashwagandha

Ashwagandha (Withania somnifera) is an adaptogenic herb that modulates the HPA axis and maintains healthy cortisol levels. In a double-blind trial, 60 participants with high perceived stress scores were randomized to receive KSM-66 Ashwagandha^® extract (125 mg or 300 mg) or placebo twice daily for 8 weeks. A significant reduction in perceived stress scale (PSS) scores was observed with both doses of ashwagandha compared to the placebo group. Mean cortisol response decreased by 17% and 33% in the groups receiving 125 mg and 300 mg twice daily, respectively, after 8 weeks. Subjects receiving ashwagandha also exhibited significant improvements in sleep quality.^19‡

L-Theanine

L-theanine an amino acid found in green tea, may be most recognized for its ability to exert anxiolytic effects by modulating GABA activity and for its role in regulating the stress response. In a double-blind crossover trial, 30 healthy adults received l-theanine (200 mg Suntheanine^®/day) or placebo for 4 weeks. L-theanine significantly improved stress-related symptoms, including low-mood symptoms and occasional anxiety per validated questionnaires and sleep (Pittsburgh Sleep Quality Index; PSQI)^‡

Newer research also suggests that l-theanine influences the gut-brain connection by increasing beneficial bacteria, such as Lactobacillus, while also decreasing non-beneficial bacteria, such as Closterium.²¹

Pure Encapsulations^® Nutrient Solutions

Pure Encapsulations provides uniquely formulated products made with high-quality, pure ingredients backed by verifiable science to complement your plan of care and support microbiota-gut-brain axis in your patients.^‡

ProbioMood is a clinically researched combination of probiotic strains that promotes emotional well-being and relaxation. This formula contains the well-researched strains Lactobacillus helveticus Rosell-52 and Bifidobacterium longum Rosell-175. It was developed using an innovative, patented microencapsulation process designed to protect the probiotic strains from harsh conditions, including gastric acidity.^‡

Suggested Use: Take one (1) capsule daily, with or between meals

Poly-Prebiotic is a shelf-stable prebiotic formula that includes 1.5 g of clinically researched PreticX^™ XOS (xylo-oligosaccharides) that enhances the growth of Bifidobacteria. In contrast to FOS and other common prebiotics, studies on XOS report very low incidence of gas and bloating.^20,21

Suggested Use: Take three (3) capsules, 1-2 times daily, with or between meals

SunButyrate^™-TG liquid is a unique butyrate-rich triglyceride oil that allows for direct delivery of 875 mg of butyric acid (per serving) to the intestines. Benefits include supporting gut cell and barrier function and promoting cytokine balance.^‡

Suggested Use: As a dietary supplement, take 1 teaspoon, 1-3 times daily, with meals.

Daily Calm combines GABA with clinically backed saffron (affron^®), ashwagandha (KSM-66^®) and l-theanine (Suntheanine^®) to relieve feelings of occasional stress and anxiety. Together, these ingredients address common mental health needs while supporting mood and sleep quality with continued use.^‡

Suggested Use: Take one (1) capsule, two times daily between meals

Conclusion

The microbiota-gut-brain axis plays a pivotal role in supporting mental health. The gut microbiota communicates with the brain through neural, immune and endocrine pathways, influencing neurotransmitter production, stress response and cytokine regulation. Healthcare professionals can support gut health and enhance mental well-being by utilizing targeted nutrients such as probiotics, prebiotics, ashwagandha and l-theanine, in combination with diet and lifestyle strategies.

Resources

Microbiota-Gut-Brain Axis Protocol: Designed by our scientific and medical advisors to help you deliver the most effective care and support for your patient's intestinal health.

Drug-Nutrient Interaction Checker:  Provides valuable information on potential interactions between your patients' prescriptions, over-the-counter medications and nutritional supplements.

PureInsight^™: Our streamlined platform easily collects patient data and provides valuable recommendations to help achieve their health goals.

Virtual Dispensary: Our Pure Patient Direct program provides account holders FREE access to our virtual dispensary to help simplify patient sales and reduce in-office inventory.

You can also explore Pure Encapsulations^® to find On-Demand Learning, Clinical Protocols and other resources developed with our medical and scientific advisors.

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