Did you know that some of the first antidepressants were actually antibiotics?
Or that some of our current antidepressants actually have strong effects on your gut microbiota?
The link between your gut and your mind is not a new one, but new research is helping us to understand this link better every year.
This article will help you answer:
What are the key factors in the gut’s influence on depressive symptoms?
How do these factors contribute to depressive symptoms?
How do you assess these factors in the research lab or clinic?
What “gut” treatments also affect depressive symptoms?
What “antidepressant” treatments also impact the gut?
Key Players in Your Gut’s Influence on Depressive Symptoms
The gut, in a way, is considered to be outside the body, because the things you ingest come from outside your body and do not really enter the body until they are absorbed in the gut. Nourishing your body is something you do (hopefully) on a regular basis and with this interaction between you and your environment you have a lot of power to affect the way you think, feel and perform. Nutrition is a big topic all on its own, and it is not a focus for this article (it deserves its own!).
For now, let’s start with the intestinal microbiome. Your intestinal microbiome modulates the HPA axis (think stress response), plays a role in tryptophan metabolism (think serotonin and melatonin), produces neuroactive compounds (such as short chain fatty acids and neurotransmitters), produces B and K vitamins, and influences the production and expression of neurotransmitter receptors in the central nervous system, amongst other functions. [1,2] A fairly old but illuminating study in mice suggests the microbiome is also a powerful force in elimination of heavy metals like mercury, which may in turn play a role in depressive and other symptoms.  In addition, these helpful flora protect you from invaders by producing antimicrobial peptides (essentially their own form of antibiotics) and help maintain the intestine. [1,2] That’s a fairly long to-do list! Those are some specifics, but you probably already had a general idea about the importance of these little creatures.
One thing your microbiome does for you that you may not have been aware of is that it helps you produce your own “benzodiazepines”. Benzodiazepines are a type of medication that helps with anxiety. Anxiety very commonly occurs along with depression and realizing the impact that your gastrointestinal health can have on both depression and anxiety is important. What’s curious in the you-produce-benzodiazepines story is that you have these compounds in your body but you don’t actually have the enzymes that would allow you to make them.
Naturally, researchers wondered what was going on! What they discovered was that you have multiple types of microbes in your gut that helps make these “endozepines” for you.  This is a wonderful discovery. The benzodiazepines that you can take as medication are only supposed to be used on a short-term basis, and then carefully discontinued under supervision. But based on this research, working on gastrointestinal health could provide more long-term relief.
Another lesser known function of those gut microbes of yours is the production of “vitamin Q” or queuine. This is a compound only your microbes can produce, and that can be obtained in very limited amounts from diet, but that you must have. Why do you need it so badly? Because there is a certain cofactor you need to make neurotransmitters and vitamin Q helps keep this cofactor in top working condition. A lack of the cofactor in its useful state is associated with a wide range of abnormalities and has been suggested as one way in which some psychiatric symptoms can occur. 
The Intestinal Barrier
What about the intestinal barrier? The intestinal barrier between you and your environment consists of one layer of enterocytes connected by “tight junctions” in addition to a mucosal layer and your microbiome. The mucosal layer provides a layer of separation of the microorganisms from the epithelial cells and gives these microorganisms a place to stay that prevents them from being pushed out of the gastrointestinal tract with peristalsis (contractions that move food through your gut).  Immune cells, such as lymphocytes and dendritic cells, are also involved in the intestinal barrier and not only keep tabs on potential pathogens but affect your tolerance for different foods.  Glial cells function to protect the intestinal nervous system and also impact permeability. 
Interestingly, your intestinal barrier may not be all that different from your blood-brain-barrier which serves to protect your brain from unwanted chemicals and pathogens. As the name implies, the barrier in the brain is made up of blood vessels which carefully regulate what can and cannot pass into the brain. These work closely with astrocytes, a type of glial cell whose role in the blood brain barrier is recognized but not fully understood.  Unlike blood cells in other areas of the body, these blood cells protecting the brain are connected by tight junctions, similar to the connections between epithelial cells in the gut.  Also similar to the intestinal barrier, the blood brain barrier is associated with immune cells, in this case mainly microglia. 
It is normal for certain things to pass from your gut to your body (it’s not “leaky” but purposeful). After all, what’s the use of eating if you don’t absorb any nutrients. However, your intestinal barrier must allow the right things in and keep the wrong things out. What could cause the intestinal barrier to face a breach of security? One major factor is stress. This includes psychological stress, but it also includes inflammation, infections, oxidative stress, heat stress, prolonged strenuous exercise, alcohol, food additives and certain medications like NSAIDs.  Hormones can also play a role. Did you know that progesterone levels are also correlated with increased intestinal permeability during the late luteal phase of the cycle? This in turn is associated with severity of premenstrual symptoms such as anxiety, fatigue, breast swelling and food cravings. 
Here are more detailed examples of these breaches for those who are extra curious:
Psychological stress is implicated in gastrointestinal permeability through mucosal nerve-stimulated release of corticoliberin (CRH) and possibly acetylcholine and their effects on mast cells. 
Proinflammatory cytokines (messengers of the immune system) such as IL-1B and TNF-alpha increase intestinal tight junction permeability. [7–10] Curiously, IL-1B and TNF-alpha are also responsible for increasing permeability of the blood-brain-barrier. [11–14] If your intestinal tract is letting things leak in, it really doesn’t seem like optimal timing to also have your blood-brain-barrier compromised!
Infectious agents can trigger inflammation by allowing the immune system to mount an attack on problematic microbes. Cells in your gut detect when microbes cross from the inside of your gut to the inside of your body and this sets off an alarm for neutrophils, monocytes and cells of the adaptive immune system to cross into the problem area and eliminate the microbes.  These attacks leave behind collateral damage in the form of inflammation and tissue damage.  Microbes themselves also have several sneaky ways of getting past the immune system and infecting their host. These methods include disruption of tight junction proteins, receptor-mediated endocytosis and hiding out in phagocytic cells amongst other methods. 
Prolonged strenuous exercise. Research suggests the gastrointestinal system may be the first to take a hit during exercise-heat stress.  The effects of exercise-heat stress include disruption of the intestinal barrier, allowing for elevated levels of plasma LPS.  Dehydration (through its reduction in blood flow) or the use of NSAIDS in these situations further exacerbates the problem of intestinal barrier compromise. 
Once the intestinal barrier has been compromised, your body is faced with a couple of challenges.
One of these is that LPS from intestinal bacteria and other microbial antigens are free to wander and wreak havoc. LPS is a glycolipid complex found in the outer membrane of Gram-negative bacteria. Patients with depression have been found to have high levels of antibodies to resident Gram-negative bacteria. These levels were especially high in patients with chronic depression. The pattern of antibody elevation was such that it indicated the bacteria had spread beyond the gut.  The LPS in bacteria like these has been shown to:
Produce sickness behaviours in healthy humans, including increased body temperature, malaise, anxiety, depressed mood, and decreased memory 
Activate TLR4 , a receptor for recognizing pathogens
Induce IDO , an enzyme in the kynurenine pathway
Induce monocyte (a type of white blood cell) activation and movement into the central nervous system 
And trigger production of inflammatory compounds/mediators 
When bacteria “escape” from the gut like this, a resulting inflammatory response can reach the brain in several ways: the vagus nerve can transmit signals that activate microglia, the bacteria or toxins can trigger inflammation that alters the blood brain barrier (and this neuroinflammation may last months), or existing inflammation can interact with gut permeability to encourage the bacterial translocation in the first place, which then compounds the existing inflammation.  To be clear, in this context I’m not talking about bacteria dancing through your body’s bloodstream – that would be sepsis, and that is a very serious medical condition. This is more a matter of the bacteria slipping out of the gut and into the lamina propria and mesenteric lymph nodes, where the bacteria interacts with the immune system outside the gut. Typically, the bacteria can be handled right there, without creating a big fuss, and this is not really considered a pathological event. However, sometimes the load of LPS is too high and other immune cells are recruited which leads to an inflammatory response. 
As you are probably familiar with, not only can the gut affect the brain but the brain can also affect the gut in this case. For example, it has also been suggested that psychological stress amplifies these responses to bacterial translocation because of its effect on macrophages and on the immune response to LPS. 
The end result is a lot of inflammation. But the trouble isn’t over yet.
The second issue with an injured intestinal barrier is food-derived antigens. In this scenario, your immune system sees certain foods as foreign invaders and will attack them if recognized. We call those recognizable pieces “antigens” and you can think of them as wearing a name tag that your immune system can identify. (There’s actually a few different responses that can occur, for example Celiac disease is an autoimmune reaction – not an allergy, but we’ll stick with this analogy for now for the sake of simplicity.)
Commonly problematic antigens include gliadin and glutenin from gluten proteins and casein and whey from bovine milk proteins. Certain ones of these particular antigens are sometimes referred to as “exorphins” because they act like morphine by binding to opioid receptors. [as described in 1] This may help explain why people can be so attached to wheat and dairy products.
There has been a lot of discussion over the years on the clinical relevance of food-derived antigens and on the accuracy of various tests that investigate these antigens. Gluten has had its fair share of the limelight in this arena and we are learning more each day as new research is published. It’s nefarious role in mental illness cannot be ignored, but it is a large topic and merits its own article.
How Do You Assess Gastrointestinal Health?
What labs do researchers and health professionals use to evaluate the gastrointestinal tract’s contribution to mental health? They use a combination of labs to evaluate:
Such as lactulose/mannitol ratios, anti-Saccharomyces cerevisiae antibodies (ASCA), fecal calprotectin, intestinal fatty acid binding protein and zonulin
Microbes and microbial antigens (including viruses, bacteria, parasites, etc)
Such as soluble CD14 and LPS binding protein
Antibodies to LPS (IgM/IgA)
Antibodies to microbes like the T. gondii parasite, measles virus and various bacteria
Comprehensive stool analysis
Through antibody levels to antigens like gluten, gliadin, casein, tissue transglutaminase, and endomysium
Through antibody levels to a number of different components in your body like the NMDA receptor and the cerebellum. These may vary depending on the psychiatric symptoms. For example, some may have a known connection with psychosis while others may be more relevant in an autism spectrum disorder.
This is not a comprehensive evaluation of all the autoimmune reactions stemming from the gut, and it is important to remember that autoimmune reactions based in other areas of the body can be implicated in conditions such as depression as well.
Note that some of these have more relevance in a research setting than in a clinical setting, so don’t be surprised if your healthcare provider doesn’t run the whole list. In addition, there may be other labs a practitioner runs based on a patient’s specific concerns.
To put these into context, consider that people with recent suicide attempts have higher levels of
anti-Saccharomyces cerevisiae antibodies (an indicator of intestinal permeability), 
intestinal fatty acid binding protein (an indicator of damage to gut cells) 
anti-LPS antibodies (an indicator of bacterial antigens) 
anti-gliadin antibodies (an indicator of gluten sensitivity) 
than people from a healthy control population. This highlights the complexity of factors involved in your mental health. Even within the gut, it’s not just one process, but many!
It’s clear that those 300 square metres of interaction between your outside and inside environment are critical real estate to your mental health, but how exactly does the impact of intestinal barrier function get all the way up to your brain?
Here is a simplified version:
The intestinal barrier is compromised
Microbial and food antigens spark inflammation and immune responses.
The blood brain barrier is compromised in a similar manner to the intestinal barrier. Altered blood brain barrier function has been reported in autism, psychosis and affective disorders like depression. 
This compromised blood brain barrier allows for the entry of inflammatory and immune processes that were triggered in the gut (and elsewhere in the body). 
The inflammatory and immune processes that started in the gut cause problems in other areas of the body, including autoimmune processes. This encourages the inflammatory and immune processes to keep going, and with the blood brain barrier not able to do its job to the best of its ability, will continue to affect the central nervous system. 
However, there is another way that your gut affects your brain, and that is through the vagus nerve. The vagus nerve is a part of the parasympathetic nervous system and is the basis for the enteric (gastrointestinal) nervous system. Your vagus nerve communicates with your enteric nervous system and your brain and is able to activate the hypothalamic-pituitary axis in response to stress. It is also able to exert an anti-inflammatory effect through inhibition of cytokine release and via a cholinergic anti-inflammatory pathway. When a pathogen appears in the gut, these pathways allow the vagus nerve to limit the inflammatory response from occurring in the rest of the body. 
Treating the “Gut”
Based on these factors, there are several ways treatments can target gut-related contributions to depressive symptoms. Each of these will also depend on the person and require consult with a healthcare provider.
Improvement of the intestinal barrier by reducing stress, decreasing inflammation, taking care of infections, evaluating medications that contribute to a compromised intestinal barrier, and removing alcohol.
You are likely familiar with the relationship between non-steroidal anti-inflammatory medications such as aspirin, ibuprofen and indomethacin and peptic ulcer disease. However, these medications have also been demonstrated to affect intestinal permeability and inflammation. In a small study of healthy volunteers, this effect has been shown to occur shortly after ingestion, with aspirin having the lowest effect and indomethacin having the greatest effect on intestinal permeability. 
A 3-week alcohol detox results in improvements in intestinal permeability. Systemic inflammation markers also decreased somewhat during withdrawal and this was correlated to depressive symptoms and alcohol craving. [as mentioned in 1]
Note that there are no FDA-approved medications at the present moment that can magically restore this barrier function. Treatment focus is on addressing the underlying cause (inflammation, for example).
Reduction of food-derived antigens.
Sometimes the goal is to remove these foods long enough for the intestinal barrier to heal and sometimes the goal is to remove these foods for longer, or permanently. This will depend on the person.
Improvement of defenses by improving the microbiome.
Antibiotics: Kill off problematic infections
Probiotics: Supplement with beneficial microbes
Fecal microbiota transplant: Considered an investigational drug in the US and Canada, but offered in various places around the world. While fascinating, there are serious safety concerns that have yet to be addressed, including the ability to screen for prions and other infectious agents.
For more on this topic, check out the article “Do probiotics improve your mental health?” which explores this in greater detail.
Use of antidepressant medications
Surprisingly, antidepressant medications do have effects on your gut.
Some antidepressants have effects on gut bacteria, for example by making them more resistant to antibiotics or by acting like antibiotics. [23,24]
Other antidepressants can have the opposite effect of increasing susceptibility to certain kinds of antibiotics. For example, it was recently discovered that the tricyclic amines antidepressants can cause methicillin-resistant Staphylococcus aureus to regain sensitivity to Beta-lactam antibiotics. 
In animal models of depression, the antidepressant fluoxetine demonstrates an ability to reverse LPS-induced changes in behaviour. 
Stimulation of the vagus nerve
Vagus nerve stimulation decreases feelings of stress and improves feelings of relaxation. Stimulating the vagus nerve has been used in both the treatment of epilepsy and treatment-resistant depression. 
These last two points merit further discussion, as they have not been elaborated on earlier.
Antidepressant medications and gut health
You may be familiar with the fact that the improper use or overuse of antibiotic drugs can lead to the development of resistant infections. Bacteria, for example, can become resistant to a drug when exposed to that drug over time. When the dose isn’t quite high enough to kill the bacteria, it is able to replicate and develop ways to protect itself from the drug. What’s interesting is that this resistance development can happen even with certain drugs that were not developed with the intention of having antibiotic properties.
As recent research has revealed, the drugs that can do this include antidepressants. When researchers treat bacteria with different doses of the antidepressant fluoxetine (also known as Prozac), the bacteria increase the number of mutations they make.  These mutations give the bacteria protective mechanisms that can be used to help the bacteria survive against antibiotics like amoxicillin, chloramphenicol, tetracycline, fluoroquinolones, and aminoglycosides.  This investigation has yet to be continued in human participants, but it is important to realize that antidepressants do have an effect on bacteria because bacteria are an important part of our gastrointestinal health. It is possible that some antidepressants may have a detrimental effect by contributing to antibiotic resistance, but it is also possible that some may actually exert their beneficial antidepressant effects partly through their effects on the microbiome. It is also possible for them to re-sensitize bacteria to antibiotics they had previously been resistant to. 
Antidepressants that have antimicrobial effects include monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors and even ketamine.  These do act in ways aside from their effects on your microbes, but it is plausible that part of their effect does relate to this antimicrobial activity. Funny enough, one of the first drugs used as an antidepressant was actually a drug for tuberculosis!  If antidepressants have antimicrobial effects and a drug for tuberculosis was used for its antidepressant effects, could some other antibiotics also be used as antidepressants?
There actually is one antibiotic that has been studied for treatment of depression. This antibiotic is minocycline, a tetracycline, and it appears to have a statistically significant antidepressant effect compared to placebo.  However, tetracyclines are not without their adverse effects and this is not necessarily a helpful approach to take. For example, tetracyclines have an association with thyroid dysfunction  and this itself can lead to a number of physical and mental health concerns. In addition, using medications with the effect of both acting as antidepressant and antibiotic could pose other problems in cases where both effects are not actually needed. Not all cases of depression require an antibiotic, just like not all cases of infection require an antidepressant.
Stimulation of the vagus nerve and depressive symptoms
Now for a lesser known therapeutic: vagus nerve stimulation. Stimulation of the vagus nerve can be accomplished through surgical implantation of a pulse generator or through ear clips containing a stimulator which gives an electrical impulse to a branch of the vagus nerve located around the ear.  This is a therapy that was initially used in epilepsy, but vagus nerve stimulation has since made its way into the repertoire of options for patients with treatment-resistant depression, after it was noticed that patients with epilepsy also had an improvement in depressive symptoms.
It is not known precisely how vagal nerve stimulation exerts its antidepressant effects, although studies have demonstrated changes in activity of several brain regions implicated in depression as well as changes in levels of monoamines such as dopamine, norepinephrine and serotonin. [21,29] Increased activity in the ventral tegmental area of the brain responsible for producing dopamine, increased firing in the raphe nuclei (serotonin production) and increased firing in the locus ceruleus (norepinephrine production) suggest the vagus nerve stimulation acts differently from other antidepressant therapies by increasing baseline firing of neurons without desensitizing serotonergic and noradrenergic receptors.29 Changes in monoamines occur acutely but acute versus long-term therapy results in different activation and deactivation patterns in the brain and may help explain why it takes several months before vagus nerve stimulation results in clinical improvements.  Decreases in proinflammatory cytokines, (including the inhibition of TNF-alpha), increased neurogenesis and modulation of CRH secretion have also been suggested as mechanisms by which vagus nerve stimulation may act as an antidepressant. [21,29]
Early studies on implanted devices are not without flaws, but considering further follow-up studies and the severity of the study populations the results are worth a second look. When improvements in depressive symptoms are seen, they are seen to occur over months rather than weeks and shorter studies may miss seeing any significant progress. It is also important to recognize that the patients in these studies had tried multiple courses of antidepressant medication or other therapies such as electroconvulsive therapy.  This level of treatment resistance is a significant clinical challenge.
Studies on implanted vagus nerve stimulation demonstrate that patients had higher response rates and fewer completed suicides with vagus nerve stimulation compared to treatment as usual.  A five year observational study found a response rate of 67.6% and a remission rate of 43.3% for the vagus nerve stimulation group compared to response and remission rates of 40.9% and 25.7% respectively for the treatment as usual group.  An interesting subanalysis revealed that the response rate remained higher in the vagus nerve stimulation group than the treatment as usual group even for patients who had previously received electroconvulsive therapy (typically considered a last resort therapy for very severe depression). 
An additional consideration is the potential for cognitive improvement with vagus nerve stimulation in patients with depression. This was studied in one small trial with promising results over a two year period.  Although it needs to be repeated on a larger scale, it is relevant considering the significant cognitive impairment in depression and the lack of therapeutics that address this specific aspect.
The use of vagus nerve stimulation in thousands of patients for treatment-resistant depression and epilepsy has created a large database from which to gather safety information.  One possible side effect of implanted devices is hoarseness and voice alteration, as the signal can sometimes affect the recurrent laryngeal nerve as well.  Serious adverse events are not common.  Transcutaneous devices are available, and may provide an alternative without these potential adverse events. For example, a version that clips to the ear has also been found to reduce depressive symptoms but larger randomized, controlled studies are needed. 
There are reports of manic symptom emergence with vagus nerve stimulation. One report describes the occurrence of manic symptoms in two patients with a history of unipolar depression who had never demonstrated manic symptoms on any previous antidepressant therapy.  The authors of this report point out that this is important because it provides additional support to the idea that vagus nerve stimulation has a mechanism of action that is unique from other antidepressant therapies.  These two patients were able to remain on the vagus nerve stimulation without any additional manic episodes for up to five years after the initial incident. 
The idea of stimulating the vagus nerve or influencing mood via the ear is not a new one. The auricular branch of the vagus nerve is the only peripheral branch of the vagus nerve, and it innervates the area just outside the auditory meatus. Auricular acupuncture is a traditional therapy that has been used for hundreds of years for a variety of health concerns and research indicates that it does have some effect on the vagus nerve. 
In rats, auricular manual acupuncture or electroacupuncture in a variety of locations on the ear produce autonomic effects, including decreased heart rate, decreased blood pressure and gastric contraction.  The greatest changes however, were seen with points in a region innervated by the auricular branch of the vagus nerve: the inferior concha.  Auricular acupuncture, however, has not been studied in humans in the context of alleviating severe depression.
Curiously, some forms of meditation and yoga breath work have also been demonstrated to influence the vagus nerve and exert a therapeutic effect.  But we can also go back and consider the very basics, and the influence your gut microbiome has on the vagus nerve. Antibiotics and other medications with antibiotic-like side effects, probiotics and your diet all have an impact on your gut flora. Those gut flora in turn communicate with the vagus nerve, which passes messages along to your brain.  Perhaps the most powerful demonstration of the therapeutic potential of vagus nerve stimulation comes from a study just released a couple months ago, demonstrating benefits in an animal model of sepsis. 
Everything in this article could, of course, be explored in more and more detail. We are, after all, very complex creatures. Yet it always comes down to the realization that we cannot isolate condition x, y, or z to one system of the body. Depression belongs not to the gastrointestinal system alone, nor does it belong solely to the brain or the mind. It doesn’t even belong to the two in a kind of joint guardianship. Instead, its symptoms and their roots are intricately woven through multiple systems and when each is given respectful consideration there is greater opportunity to illuminate root causes and achieve wellbeing.
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