Gut brain axis
The gut-brain axis refers to the lines of communication that connect the intestinal tract with the brain. We have long known that the vagus nerve (cranial nerve X) extends from the brainstem to the gastrointestinal tract to modulate digestive function. We also know the vagus nerve allows for bidirectional communication—with motor fibers extending from the brain to the gut, and sensory fibers extending from the gut back to the brain.
But recent research is beginning to unveil a system of much greater complexity connecting the gut and the brain. We now know that communication is not limited to the confines of a single autonomic nerve, but instead involves a web of neurotransmitters, hormones, peptides, cytokines, and chemokines.
The gut-brain axis involves not only the digestive system (the gut) and the nervous system (the brain), but also the immune and endocrine systems. What’s more, the commensal organisms of the intestinal tract—the microbiota—interface with the gut-brain axis, on both the sending and receiving ends of the line.
And if these gastro-neuro-immuno-endocrine-microbiota connections are not enough to make your head spin and your stomach churn, there’s more. The communication networks of the gut-brain axis integrate directly with cognitive and emotional centers of the brain. That’s right—the physical function of the gut is inextricably linked with mental and emotional states of mind.
Let’s take a deeper look at the systems and cells, the molecules and mechanisms, the clinical realities, and the nutrients that support the gut-brain axis.
System and Cells
We’ll begin with a cellular-level examination of the four systems that participate in the gut-brain axis.
Nervous system. There are two critical nervous-system components involved in the gut-brain axis: the autonomic nervous system (sympathetic and parasympathetic) and the limbic system.
The vagus nerve provides parasympathetic input to the gastrointestinal tract, and also communicates messages back to the limbic areas of the brain that process emotion, including the amygdala, hippocampus, and limbic cortex.
Digestive system. Embedded within the wall of the intestinal tract is an intrinsic system of nerves that control digestive motility and secretions. Known as the enteric nervous system, this neuronal web can function on its own, but can also be influenced by nerves extending from the central nervous system.
In addition to the enteric nerves, other participants at the intestinal level of the gut-brain axis include epithelial cells, smooth muscle cells, immune cells, interstitial cells of Cajal (pacemaker cells that regulate motility), and enterochromaffin cells (neuroendocrine cells that release neurotransmitters).
Intestinal microbiota communicate with all of these cells. Due to their receptors that bind to human-produced neurotransmitters, along with their ability to influence immune function, the microbes inhabiting the intestines are thought to be central players in the gut-brain axis.
Endocrine system. The hypothalamic-pituitary-adrenal (HPA) axis participates directly in the gut-brain axis. Stress activates the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which triggers the release of adrenocorticotropic hormone (ACTH) from the pituitary, and then cortisol from the adrenal glands.
The HPA axis influences gut motility, intestinal secretions, composition of the microbiota, and intestinal permeability—connecting the emotional experience of stress to the physical function of the gastrointestinal tract.
Immune system. Components of the immune system that participate in the gut-brain axis include a wide range of cytokines, chemokines, and other chemical messengers.
Imbalances in the intestinal microbiota, production of endotoxins, and intestinal inflammation can spur the immune system to produce pro-inflammatory cytokines and chemokines that adversely affect emotion and mood.
Molecules and Mechanisms: Brain’Gut
Emotional balance and emotional stress have opposite effects on the physiology of the gut. Via parasympathetic, sympathetic, hormonal, and immune signals, the emotions directly trigger lines of communication from the brain to the gut.
Parasympathetic activity. The vagus nerve delivers parasympathetic input to modulate gut motility, regulate the secretion of acid and bicarbonate, and support the health of the mucosal layer. When a person experiences emotional stress, sympathetic outputs of the autonomic nervous system predominate over parasympathetic, compromising all of the above actions.
Sympathetic activity. Studies in mice have shown that the stress of surgery leads to the production of norepinephrine by the sympathetic nervous system, which in turn allows for proliferation and overgrowth of Pseudomonas aeruginosa, Campylobacter jejuni, Escherichia coli 0157:H7:3, or other pathogenic microbes.
Stress hormones. Emotional stress triggers the HPA axis, resulting in the production of cortisol, which further compromises gut motility, secretions, and the integrity of cellular tight junctions. And when the natural mucosal habitat becomes compromised by stress, imbalances of microflora (called dysbiosis) and increased intestinal permeability can occur.
Inflammatory mediators. The domino effect of stress on the intestinal tract doesn’t end with neural and hormonal input. Stress-induced dysbiosis and intestinal permeability can activate an immune response, resulting in higher levels of pro-inflammatory chemical mediators. Studies in mice have shown that stress adversely affects the composition of the microbiota in ways that correlate with increased levels of pro-inflammatory cytokines.
Molecules and Mechanisms: Gut’Brain
The messages sent back to the brain from the gut depend on several components of the intestinal terrain—not the least of which is the microbiota and its molecules. The intestinal microbiota initiate communication signals from the gut to the brain by influencing levels of neurotransmitters, short-chain fatty acids, tryptophan, and endotoxins.
Neurotransmitters. The intestinal microbiota is capable of producing molecules that act as local neurotransmitters in the gut lumen. Lactobacillus and Bifidobacterium species produce gamma-aminobutyric acid (GABA), while other species generate serotonin, dopamine, melatonin, histamine, or acetylcholine.
By supplying these neurotransmitters, gut microbiota can directly activate the vagus nerve to communicate with the brain and influence mood. For example, animal studies show that Bifidobacterium longum has an anxiolytic effect—but only when the vagus nerve is intact.
The messages transmitted back to the brain via the vagus nerve influence neurotransmission, neurogenesis, and neuroinflammation in the brain. One animal study showed that administration of the probiotic Lactobacillus rhamnosus resulted in higher brain levels of GABA mRNA. Considering that GABA is one of the most calming neurotransmitters, this could be a mechanism by which the intestinal microbiota influences mood.
Short-chain fatty acids. Some of the microbes in the intestine produce short-chain fatty acids (SCFAs) such as butyric acid, propionic acid, and acetic acid.
SCFAs stimulate the enterochromaffin cells to release mucosal serotonin, which can cross into the plasma. Higher plasma serotonin is linked with psychiatric disorders. But fluoxetine (a selective serotonin reuptake inhibitor to treat mood disorders) blocks transport of gut-derived serotonin into the plasma.
Tryptophan. Gut-derived serotonin that circulates in the plasma can’t cross the blood-brain barrier, so the brain relies on a steady supply of tryptophan to serve as a serotonin precursor. Tryptophan is absorbed from the gut, crosses the blood-brain barrier, and is then synthesized into brain serotonin.
Interestingly, by influencing immune function and the balance of pro-inflammatory or anti-inflammatory cytokines in the gut, the intestinal microbiota can also influence tryptophan availability to the brain. For instance, if conditions in the gut are more inflammatory, tryptophan can be shunted down the hepatic kynurenine pathway to produce quinolinic acid.
Endotoxins. A final way that the intestinal microbiota can influence communication from the gut to the brain is by activating an immune response and influencing the production of cytokines and chemokines.
Gram-negative bacteria produce an endotoxin called lipopolysaccharide (LPS), which circulates through the body and triggers an immune response. Elevated LPS is associated with elevated inflammatory biomarkers and symptoms of depression.
Clinical Realities
Humans have long recognized the connection between digestive and emotional health—at first anecdotally and now through scientific studies. The side effects of antibiotics, the symptoms of irritable bowel syndrome (IBS), and the physiology of depression provide three real-life examples of the connection between the gut and emotions.
Antibiotics. Antibiotics disrupt the intestinal microbiota, contributing to dysbiosis and potential overgrowth of pathogenic bacteria or yeast. Since the introduction of antibiotics in the 1930s, reported side effects have included not only digestive distress but also psychiatric effects ranging from anxiety to depression to psychosis.
Researchers in the United Kingdom conducted an extensive study from 1995 to 2013 to evaluate whether antibiotic use increases the risk for anxiety or depression. The study found that a single use of antibiotics boosted the risk for both anxiety or depression, and recurrent use increased the risk to an even greater extent.
IBS. More than half of patients with IBS also experience anxiety or depression. Antidepressant medications, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), are considered to be useful in the management of IBS.
It appears the association between IBS and mood is bidirectional. Traumatic life events during childhood increase the risk of IBS, and having IBS can also lead to mood issues. A recent study conducted in Australia concluded that functional gastrointestinal disorders precede mood disorders in the majority of individuals (two-thirds), rather than vice versa (one-third).
Depression. Patients who experience depression have been found to have higher circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), and interleukin-6 (IL-6). They have also been found to have higher concentrations of serum antibodies to LPS—the endotoxin released from gram-negative bacteria in the gut.
Researchers have suggested that the pathophysiology of depression may be influenced by intestinal dysbiosis, increased intestinal permeability, translocation of LPS endotoxins, and the resultant immune reactivity and inflammation.
Nutritional Support
For practical purposes, our knowledge of the gut-brain axis informs us that we need to take a holistic and synergistic approach to supporting both digestive and emotional health. When emotional concerns predominate, we need to consider the gut—and vice versa.
This type of approach aims to support a healthy complement of intestinal microflora, along with a healthy mucosal layer, inflammatory response, and response to stress. Dietary supplements to achieve these goals include probiotics; prebiotics; and demulcent, immune-supportive, and adaptogenic herbs.
Probiotics. Probiotics are the healthy bacteria or fungi that make up the intestinal microbiome. Supplementation with probiotics is one way to support microbial diversity, immune function, and balanced mood.
One study of healthy women who drank a probiotic cocktail showed that they experienced changes in brain regions that process emotion. Another human study, which was double-blinded and placebo-controlled, found that 30 days of supplementation with Lactobacillus and Bifidobacterium probiotics supported healthy mood, particularly as it related to depression, anxiety, anger, and hostility.
Prebiotics. Prebiotics are the nondigestible starches that fuel the growth of probiotic microorganisms in the intestinal tract. Fructooligosaccharides (FOS) and galactooligosaccharides (GOS) are two examples. Daily consumption of GOS has been shown in humans to modulate cortisol levels, suggesting that prebiotics may indirectly support a healthy stress response and mood.
Arabinogalactan, another nondigestible starch, serves as a fermentation source for microbes residing in the intestines. Arabinogalactan supports healthy digestive function and modulates immune function.
Demulcent herbs. These herbs are rich in polysaccharides that soothe and nourish mucus membranes. The mucosal layer of the intestinal wall is the natural habitat for intestinal microbiota, so when it’s compromised, so is the microbiota.
Demulcent herbs indirectly support a balanced microbiota, and hence optimal functioning of the gut-brain axis. Examples include Aloe vera leaf, marshmallow root (Althea officinalis), and slippery elm bark (Ulmus rubra).
Immune-supportive herbs. Herbs that support a healthy and balanced immune-inflammatory response can be beneficial in modulating the gut-brain axis—because inflammatory conditions in the gut can lead to elevated pro-inflammatory cytokines in the circulation that influence emotional and mental health.
Immune-supportive herbs include turmeric root (Curcuma longa), ginger root (Zingiber officinale), and Boswellia serrata gum extract.
Adaptogenic herbs. These herbs support a healthy stress response, which can be an important way to support the gut-brain axis because of the adverse effects cortisol can have on digestive health. Adaptogenic herbs also help balance HPA axis function.
Adaptogenic herbs include rhodiola root (Rhodiola rosea), holy basil leaf (Ocimum sanctum), ashwagandh a root (Withania somnifera), Siberian ginseng root (Eleutherococcus senticosus), and Astragalus root (Astragalus membranaceus).
Forging New Pathways
Researchers are only on the cusp of understanding the complexities of the communication pathways within the gut-brain axis. But whereas the relationship between digestive health and mood was once theoretical and anecdotal, there are now established physiological pathways to describe this link.
The intricacies of the gut-brain axis are a humbling reminder that the body cannot be reduced to distinct or independent systems, but instead functions as a comprehensive, mysterious, and awe–inspiring whole.