The gut-brain axis is the bidirectional link between the central nervous system (CNS) and the enteric nervous system (ENS). Also known as the body’s “second brain,” the enteric nervous system is the extensive network of 100 million nerve cells that line the full length of the gastrointestinal tract. Although the main role of the ENS is digestion, the messages that travel back and forth between it and the CNS also affect the immune system, cognition, and mood.
The cross-talk between the brain and the gut is profoundly influenced by the gut microbiome, the vast community of bacteria that colonizes the gastrointestinal tract and is most abundant in the colon. The bacteria produce neurotransmitters and metabolites that influence the gut-brain axis through several complex pathways.
The sympathetic and parasympathetic arms of the autonomic nervous system, for example, carry messages along the vagus nerve in both directions. About 80 percent of the information is along the afferent pathway; because digestion occurs autonomically, far less information needs to travel along the efferent pathway. Information about changes in the gut microbiome is sent to the CNS; signals from the CNS influence the gut’s autonomic functions. Similarly, bacterial metabolites stimulate enterochromaffin cells (ECCs) to produce 95 percent of the body’s serotonin in the gut. Gut serotonin is involved with motility and GI secretions, but it is linked to cognition and regulating mood in the brain.
Another good example is gamma-aminobutyric acid (GABA) production by many species of common gut bacteria. GABA is the brain’s primary inhibitory neurotransmitter. A diverse gut microbiome that produces serotonin, GABA, and other neuroactive metabolites may play an important role in maintaining a stable mood.
When the gut microbiome is balanced, and digestion is proceeding normally, both the ENS and the CNS are balanced as well. When the gut microbiome is unbalanced (dysbiosis), bacterial metabolites’ normal production is thrown off. The result can be brain fog, memory issues, and mood disorders such as depression and anxiety. In the other direction, stress hormones such as cortisol can cause dysbiosis and intestinal disorders such as irritable bowel syndrome.
Leaky gut syndrome (increased intestinal permeability) occurs when the small intestine wall is damaged through dysbiosis, poor diet, antibiotics, stress, and other factors. The tight junctions between the epithelial cells open too widely and allow large particles of undigested food to slip through and enter the circulation. The result is inflammation that affects the entire body, including the brain. Leaky gut can be a contributing factor to autoimmune disease and neurodegeneration. When the gut is leaky, intestinal bacteria and lipopolysaccharide (LPS) from bacterial cell membranes can enter the circulation. LPS is a potent activator of the immune system. It causes systemic inflammation and the release of proinflammatory cytokines that impact the brain by affecting the vagus nerve and passing through the blood-brain barrier.
Modulating the Axis
Restoring a disrupted gut-brain axis quickly is key to resolving immediate health issues and preventing longer-term cognitive impairment. Dietary and lifestyle changes to address dysbiosis and leaky gut syndrome are essential. Patients should be encouraged to modify their diet to remove gluten, dairy, processed foods, and alcohol and to add fiber-rich vegetables and fruits. Also, patients should aim for at least 30 to 45 minutes of aerobic physical activity daily. These changes are necessary to make a significant improvement in gut-brain function.
Supplements that modulate the gut-brain axis by tightening loose intestinal junctions, reducing systemic and brain inflammation, and speeding gut-healing should be recommended in conjunction with dietary and lifestyle changes. The supplements complement the changes and speed healing. They can help relieve gut symptoms such as bloating, gas, and diarrhea and help with brain symptoms such as memory problems and fogginess. The combined effects can help patients feel better faster and encourage them to comply with dietary changes and lifestyle improvements.
What affects the gut affects the brain and vice versa. Bearing this in mind at all times is important when choosing supplements for patients with gut-brain issues. The supplements discussed below all have positive effects on both ends of the axis.
Five Supplements to Support the Gut
A plethora of supplements relieves gut symptoms and support gut healing. In my experience, these five supplements are helpful for almost all patients and are the basic starting point for treating gut issues. They have all been shown to improve gut function while also having a positive effect on the brain.
Prebiotics. A broad term for soluble dietary fiber that passes through the small intestine largely undigested, prebiotics act as fertilizer for supporting the growth of beneficial bacteria in the colon. Prebiotic fiber is found in plant foods high in inulin and fructans, including artichokes, asparagus, chicory, beans, onions, leeks, apple skins, and barley. Patients should be encouraged to add servings of prebiotic foods to their daily diet. However, during dysbiosis treatment, patients may need more prebiotic fiber than they can comfortably eat, and some patients will never add enough prebiotic foods to their diet to make a difference in their gut health. Prebiotic supplements containing fructooligosaccharides (FOS) or xylooligosaccharides (XOS) are a good alternative. XOS supplements are particularly valuable because they are highly effective in small doses.
Probiotics. When the gut microbiome is healthy, harmful bacteria are massively outnumbered by beneficial bacteria. In dysbiosis, harmful bacteria are present at much higher levels. Fermented foods that contain live bacteria, such as kefir, sauerkraut, and kimchi, can be helpful, and patients should be encouraged to eat them. However, the portions needed to have a positive effect are large, and most patients won’t be willing or able to eat enough. Recolonizing the colon through foods alone is also slow and unpredictable. To restore a good balance of beneficial bacteria, probiotic supplements are a good approach. These supplements contain billions of colony-forming units per capsule. Different probiotic products vary in the species and strains they contain. In general, a high-quality probiotic product contains strains of lactobacilli and bifidobacteria, along with Bacillus subtilis in spore form and a range of other bacterial species.
Glutamine. Well-known as a critical nutrient that fuels the gut’s epithelial cells, glutamine is the most abundant amino acid in the body. It’s key for maintaining the gut mucosal lining integrity and keeping bacteria from escaping out of the gut. When the gut barrier is disrupted and leaky, glutamine is very helpful for healing the damage. Glutamine supplements are a tasteless powder that can easily be mixed with clear liquids such as water or juice or stirred into foods.
Collagen. Collagen is vital for rebuilding the intestinal lining. It contains the amino acids glycine, glutamine, and proline, all of which are beneficial for the stomach lining and the intestinal tract. Bone broth is an excellent dietary source of collagen. Supplements containing Type I, II, and III collagen (the collagen in your gut is 90 percent Type I) are easy to take and are readily absorbed. As a bonus, the collagen’s properties will also improve the appearance of hair, skin, and nails.
Zinc carnosine. The secret ingredient for rebuilding a damaged gut lining is zinc carnosine. In this supplement, zinc (well-known for its wound-healing properties) is chelated with L-carnosine, a peptide combining the amino acids beta-alanine and histidine. The combination has powerful anti-inflammatory and antioxidant qualities. Zinc carnosine is very valuable for restoring the integrity of the gut tight junctions, lessening exercise-induced gut permeability, and restoring the gut mucosal lining’s protective properties. In addition, zinc carnosine has been shown to improve taste disorders—a growing issue for post-COVID-19 patients.
Five Supplements to Support the Brain
Omega-3 fatty acids. Fish oil, the most commonly used dietary supplement for omega-3 fatty acids, is a key supplement for maintaining both brain health and gut health. Omega-3 fatty acids are required for the production of BDNF (brain-derived neurotrophic factor), which supports the survival of existing neurons and encourages the growth of new neurons and synapses. High levels of DHA, a component of fish oil, inhibit neuronal cell death and are an important neuroprotective agent. Omega-3 fatty acids positively affect the gut microbiome, impacting the brain through the gut-brain axis. Conditions such as major depressive disorder, anxiety, and autism spectrum disorder are often associated with systemic inflammation, gut permeability, and dysbiosis. Restoring a better balance in the gut microbiome and reducing gut-associated inflammation can help improve symptoms.
Pro-resolving mediators. Lingering inflammation from leaky gut syndrome or dysbiosis can continue to affect brain function even after the primary cause has been treated. In the central nervous system, inflammation can allow neutrophils and cytokines to infiltrate through the blood-brain barrier. Supplements of pro-resolving mediators (PRMs) can shift the body from an inflammation-driving to inflammation-resolving conditions by repairing the blood-brain barrier. The pro-resolution mechanisms that balance the normal inflammatory response to prevent excess inflammation and bystander tissue damage can sometimes be inadequate. PRMs can help resolve the inflammation and help reduce brain fog and memory problems. PRMs provide the final boost many patients need to overcome inflammation affecting the gut-brain axis.
Magnesium L-threonate. Magnesium is vital for the brain as an essential cofactor to make many of the enzymes involved in brain functions. It’s also crucial for maintaining and growing connections among synapses, tasks that are central to learning and memory. High levels of magnesium in the brain and cerebrospinal fluid are related to a lower incidence of Alzheimer’s disease and brain aging. The supplement magnesium L-threonate passes through the blood-brain barrier more effectively than other magnesium forms and doesn’t cause digestive upsets.
Vitamin D3 with vitamin K2. High serum levels of vitamin D are extremely important for maintaining brain health and reducing the risk of cognitive impairment from Alzheimer’s disease and other neurodegenerative diseases. Vitamin D is also significant for its anti-inflammatory and antioxidant properties. Conversely, low vitamin D can lead to increased calcium in the brain, which is linked to depression and can cause an increase in the amyloid plaques that characterize dementia. Vitamin D works synergistically with vitamin K to regulate calcium and keep it from accumulating in the soft tissues, such as the blood vessels that nourish the brain. Supplements should include vitamin D in the form of cholecalciferol (vitamin D3), the most absorbable form, and vitamin K in the form of menaquinone (vitamin K2). This combination is most effective for preventing the calcification of blood vessels.
Curcumin. The active compound in turmeric root, curcumin, is what gives curry powder its vivid yellow color. Curcumin activates the Nrf2 antioxidant signaling pathway, turning on genes involved in detoxifying and eliminating free radicals. In the brain, curcumin supplements have powerful anti-inflammatory and antioxidant qualities. Curcumin also helps prevent dementia by inhibiting the formation of amyloid proteins. Perhaps most importantly, curcumin supplementation can significantly increase serum levels of BDNF (brain-derived neurotrophic factor). BDNF plays an important role in protecting existing neurons and stimulating the growth of new neurons. High levels can help prevent cognitive impairment and aid in recovery from concussion and brain injury.
Optimal bidirectional communication on the gut-brain axis is the superhighway to health for everyone.
Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017;7:124-136.
Chen Q, Chen O, Martins IM, Hou H, Zhao X, Blumberg JB, Li B. Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions. Food Funct. 2017 Mar 22;8(3):1144-1151. doi: 10.1039/c6fo01347c. PMID: 28174772
Hewlings S, Kalman D. A Review of Zinc-L-Carnosine and Its Positive Effects on Oral Mucositis, Taste Disorders, and Gastrointestinal Disorders. Nutrients. 2020 Feb 29;12(3):665. doi: 10.3390/nu12030665. PMID: 32121367; PMCID: PMC7146259
Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov;24(11):3059-68. doi: 10.1093/cercor/bht163. Epub 2013 Jun 24. PMID: 23796946
Costantini L, Molinari R, Farinon B, Merendino N. Impact of Omega-3 Fatty Acids on the Gut Microbiota. Int J Mol Sci. 2017 Dec 7;18(12):2645. doi: 10.3390/ijms18122645. PMID: 29215589; PMCID: PMC5751248
Serhan, C. N. and Petasis, N. A. (2011) Resolvins and protectins in inflammation resolution. Chem. Rev. 111, 5922– 5943, DOI: 10.1021/cr100396c
Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124
Anjum I, Jaffery SS, Fayyaz M, Samoo Z, Anjum S. The Role of Vitamin D in Brain Health: A Mini Literature Review. Cureus. 2018 Jul 10;10(7):e2960. doi: 10.7759/cureus.2960. PMID: 30214848; PMCID: PMC6132681
Sarraf P, Parohan M, Javanbakht MH, Ranji-Burachaloo S, Djalali M. Short-term curcumin supplementation enhances serum brain-derived neurotrophic factor in adult men and women: a systematic review and dose-response meta-analysis of randomized controlled trials. Nutr Res. 2019 Sep;69:1-8. doi: 10.1016/j.nutres.2019.05.001. Epub 2019 May 9. PMID: 31279955./