Excerpts from episode 30 (“Food for Thought: Mental Health and the Gut”) of my podcast, The Perfect Stool: Understanding and Healing the Gut Microbiome, edited for readability.
Relationship between Brain Activity and Gut Inflammation
One example of gut-brain dysfunction can begin with decreased brain activity. This could come from a brain injury, concussion or stress. Decreased activity can lead to a decrease in the activation of the vagus nerve, which is the main component of the parasympathetic nervous system (which is one arm of the enteric nervous system, or the two thin layers of more than 100 million nerve cells lining the gastrointestinal tract from the esophagus to the rectum, the other branch being the sympathetic nervous system, which controls the fight or flight response to a stressor). The parasympathetic nervous system oversees many crucial bodily functions, like digestion, control of mood, immune response and heart rate, specifically undoing the work of the sympathetic nervous system after a stressful situation and bringing your body into the rest and digest mode by decreasing respiration and heart rate and increasing digestion when you’re resting, relaxing or eating.
Returning to the vagus nerve – the vagus nerve connects the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via fibers. Decreased activation of the vagus nerve then suppresses the intestinal immune system and decreases intestinal blood flow. This slows digestion and can cause increased growth in pathogenic yeast and bacteria, which then cause intestinal permeability or leaky gut. Leaky gut causes a state of chronic low grade inflammation. And then the inflammatory cytokines or chemical messengers produced in the gut travel through the blood and cross the blood-brain barrier, which activates the microglial cells, which are the immune cells of the brain, and the brain gets inflamed. That inflammation creates a leaky blood-brain barrier, also known as leaky brain. The blood-brain barrier is a single-layered lattice of cells joined by tight junctions that regulates which substances are allowed into the brain, not dissimilar to the way that the intestinal epithelial cells regulate what’s let in and out of the intestines. Generally, it keeps out toxins like heavy metals, pesticides and damaging proteins, while allowing in oxygen, hormones and nutrients. So this brain inflammation decreases nerve conductance, which in turn can cause depression and reduced activity of the vagus nerve, which controls mood, and we’re back where we began: caught in a vicious cycle, in which reduced activity in the brain causes gut inflammation, which inflames the brain, which leads to reduced brain activity.
It’s important to recognize that when gut symptoms persist even in the context of a healthy diet and lifestyle, this could be an indication of a gut-brain axis problem.
And likewise, the problem can also originate in the gut, with a poor diet lacking in fiber and high in sugar, simple carbohydrates, gluten, dairy or other common food allergens creating intestinal permeability, which then sets off the same series of events terminating in mental health issues.
Depression and the Microbiota
In a study published in the journal Nature Microbiology in 2019, researchers in Belgium sequenced the gut microbiome in 1,054 individuals, correlating their findings with measurements of both quality of life indicators and depression status of the participants. They found that those with lower levels of Bacteriodes enterotype 2 displayed lower measurements of quality of life and a higher prevalence of depression while those with higher quality of life indicators were consistently correlated with higher levels of Faecalibacterium and Coprococcus, which produce the short-chain fatty acid butyrate, which feeds gut epithelial cells and helps maintain a healthy gut barrier. They also found that a lack of Dialister and Coprococcus species also correlated with higher levels of depression. The researchers also looked at the genetics of these particular organisms and their role in manufacturing the neurotransmitters dopamine and GABA, which led to the suspicion that this may be another role that the microbiome is playing in mental illness. So overall, while we can’t say that precisely those organisms cause depression, what we do know for sure is that a healthy gut microbiome decreases inflammation, and the inverse, an unhealthy one increases it, and this has an impact on depression, which is at its core an inflammatory disorder.
Another study, which was a systematic review of studies on major depressive disorder and the gut microbiome, found that nine genera were higher in major depressive disorder (Anaerostipes, Blautia, Clostridium, Klebsiella, Lachnospiraceae incertae sedis, Parabacteroides, Parasutterella, Phascolarctobacterium and Streptococcus), six were lower (Bifidobacterium, Dialister, Escherichia/Shigella, Faecalibacterium and Ruminococcus), and six were divergent, meaning different results in different studies. What they suggested is that studying microbial functioning, or the function that any genera of microbes may play, may be more productive than a purely taxonomic approach, or singling out specific families, genera, phyla, etc. of bacteria to understanding the gut microbiome in depression.
Going into a bit more detail on the role of specific gut bacteria in creating neurotransmitters, studies have shown that Lactobacillus and Bifidobacterium, typically genera in multistrain probiotics, synthesize GABA from monosodium glutamate which is notable because it’s hypothesized that depression may be caused by a deficit in GABA. Escherichia coli (aka E. coli), Bacillus and Saccharomyces produce norepinephrine (which you may know also as noradrenaline), whose general function is to mobilize the brain and body for action. Candida (a yeast, not a bacteria), Streptococcus, Escherichia and Enterococcus produce serotonin, which is the key hormone that stabilizes our mood, feelings of well-being and happiness and helps with sleeping, eating and digestion. And Bacillus and Serratia produce dopamine, which plays a role in how we feel pleasure. This is leading to research on a new class of drugs called “psychomicrobiotics” for the treatment of psychiatric disorders.
Another study that sheds some light on the mechanism by which the gut microbiome can cause depression was a controlled clinical trial on patients with major depressive disorders that helped validated the existence of an immune response to LPS or lipopolysaccharide, which is a component of the cell walls of gram negative bacteria. LPS is believed to also play a role in depression, along with inflammatory cytokines. The study looked at concentrations of the immune cells IgM and IgA against the LPS of 6 gram negative bacteria from the family Enterobacteria, which would indicate an immune response in the blood to bacteria. They found that the prevalence and median values for serum IgM and IgA against LPS of enterobacteria are significantly greater in patients with major depressive disorder than in normal volunteers, which led them to conclude that “. . . the results show that intestinal mucosal dysfunction characterized by an increased translocation of gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.” That means that the blood-based immune response indicates that this LPS is escaping the intestines and creating this immune response. They go on to suggest that patients with major depressive disorder should be checked for leaky gut by means of the IgM and IgA panel used in the study and be treated for it if found.
The Gut-Brain Axis and Anxiety
If you’ve ever had an experience that made you “feel nauseous” or had “butterflies” in your stomach before a public speaking event, you are probably clued into how your gut responds to anxiety-producing situations. Conversely, conditions in your gut can trigger various emotional responses in your brain, like anxiety, which studies have shown may affect up to a third of people at some point in their life. The enteric nervous system doesn’t just send messages to regulate the digestive system, it also receives information from the digestive system, creating thoughts in your brain. For a long time, researchers and clinicians thought that anxiety and depression contributed to conditions like IBS and other problems like constipation, diarrhea, bloating, pain and upset stomach. However, new research suggests the reverse is true too: that people suffering from IBS and other functional bowl problems are at much higher risk of developing depression and anxiety. As a result, you may find your gastroenterologist suggesting antidepressants to treat your IBS, not because they think the problem is in your head, but because these medications can calm symptoms by acting on nerve cells in the gut, as can cognitive brain training or other psychotherapies.
Looking at the research evidence on gut-based interventions for anxiety, a systematic review of 21 studies with 1503 people from 2019, examined the evidence from observational studies to support improvement of anxiety symptoms by regulating the intestinal microbiota. Of the 21 studies, 14 had probiotics as interventions to regulate the microbiota and 7 had non-probiotic interventions, like diet adjustments. Overall, 11 of the 21 studies showed a positive effect on anxiety symptoms by regulating gut microbes. Of the 14 studies that used probiotics, more than a third found them to be helpful in reducing anxiety symptoms, while 6 out of the 7 remaining studies that used others means found those to be effective. The researchers concluded that more studies are needed to clarify the conclusion that non-probiotic interventions are more effective that probiotic interventions in reducing anxiety, but overall, they did affirm that regulating intestinal flora is effective in alleviating anxiety symptoms.