The Gut Microbiome: Your Mood’s Micromanager?

by Dr Filomena Trindade, MD, MPH, and Megan Murphy, CAP

All disease begins in the gut.

– Hippocrates

In today’s world we are hyperconnected yet ironically lonelier, more disconnected, and unhappier than ever. Mood disorders are at unprecedented highs (Qureshi & Al-Bedah 2013). Depression haunts 18.8 million Americans, most of whom are women. Every day, the relentless plague of anxiety torments 19 million adults in the US. This means that about 1 in every 10 people is afflicted with depression and/or anxiety. Depression will affect 1 in 4 women in their 40s or 50s and is now the leading cause of disability worldwide (Perlmutter 2015). In spite of the alarming prevalence of mood disorders, they are still socially stigmatized. The societal expectation to “hold it together” has left many cases of clinical depression untreated due to shame, embarrassment or denial of symptoms. For the US economy, these cases of depression are a serious concern because they carry a hefty price tag of over $50 billion spent annually. These numbers are much higher than the costs for treatment of complicated, life-threatening illness such as heart disease or AIDS. Depression and anxiety are clearly no small matters of concern and are well deserving of our keen and earnest consideration.

Depression and anxiety can’t be identified and diagnosed on the basis of a single laboratory exam alone. Depression, for example, doesn’t lend itself exclusively to any one particular biomarker. Therefore, clinicians typically use laboratory testing to rule out other serious conditions that can sometimes mimic the symptoms of depression. Then, if laboratory values appear in the normal range and the symptoms are persistent, the diagnosis matching the patient’s qualitative experience becomes “major depressive disorder” (MDD), also known as clinical depression, major depression, or unipolar depression. MDD is a mental illness characterized by episodes of all-encompassing low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities.

Treatment and Prognosis of Mood Disorders

No matter how mild or severe the case of depression or anxiety, standard-of-care treatment is consistently prescription medication. The tools that doctors use to handle cases of mood disorders are most commonly selective serotonin reuptake inhibitors (SSRIs) such as Prozac, followed by serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants, and in recalcitrant cases, monoamine oxidase inhibitors (MAOIs). Strong benzodiazepines such as Xanax are used for persistent anxiety, and in many cases, practitioners prescribe additional, adjunct anti-inflammatory, antiulcerant, cholesterol-reducing and antihypertensive drugs in conjunction with these potent anxiolytics and antidepressants in an effort to manage or suppress symptoms. Doctors are hard pressed to suppress symptoms and control physiology.

If patients do not respond to any of the aforementioned interventions within eight weeks, then they wind up with a diagnosis of treatment resistant depression (TRD). About one-fourth to one-third of patients with MDD do not respond adequately to two or more prescribed antidepressants (US Department of Health and Human Services 2012).TRD is associated with an overall worse prognosis and higher medical costs. To manage this type of resistant depression, the American Family Physician recommends an algorithm of consecutively rotating different classes of antidepressants (Little 2009). The problem is that this model fundamentally dismisses the root causes of MDD and/or TRD. It aims to suppress symptoms with progressively stronger psychoactive drugs or steadily higher doses of the same drug. Unfortunately, this strategy often leaves patients overly medicated and uncomfortable from the myriad of side effects stemming from their complicated psychotropic cocktail. The presence of mood disorders such as depression and anxiety does not mean that there is an inherent deficiency in Prozac or lack of adequate Xanax in a person. Quite the opposite; it means that there is a hidden, underlying physiological mechanism causing the patient’s neurochemistry to go awry. This invariably makes interventions such as psychopharmaceuticals nothing more than a Band-Aid, and it brings into question the effectiveness of our standard of care.

‘Uprooting’ Mood Disorders: A Functional Medicine Approach

If we want to truly alleviate the suffering of those with serious depression and anxiety, we can’t keep looking at masking or suppressing the symptoms alone. As clinicians, we have to start asking ourselves, why? We need to find the root cause(s) of the symptoms if we want to provide our patients with lasting relief. Any good gardener knows that if you want to get rid of weeds, you have to take them up by their roots; trimming down the stalks will only strengthen their hold in the ground. The same is true with the body. If we don’t address the root cause(s) of dysfunction, then improvement in symptoms will be superficial and fleeting at best.

Figuring out the root cause of mood disorders often means doing some heavy-duty detective work. We have to find the common thread that links all of the patient’s seemingly unrelated symptoms. We might ask ourselves, what could peripheral symptoms such as constipation or bloating have to do with my patient’s chief complaint of anxiety or depression? When we’re looking at the whole of the patient’s symptomatology and not just at isolated components of their physical or mental health, we begin to “connect the dots,” so to speak. Often there is a keystone problem within one bodily system, such as the gastrointestinal (GI) tract for instance, which can catalyze imbalances in other areas of the body, such as the central nervous system. This is the kind of systemwide domino effect that we have to keep our eyes out for.

Every system in the body exists in functional relationship with one another. That is why we have to critically consider the entirety of the patient’s health in every respect, until we can confidentially identify the impetus for their depression. This means using all of our tools – a detailed physical examination along side with a thorough investigation of the patient’s history. Following the identification and elimination of the root cause(s) of the mood disorder, we find that the patient’s symptoms miraculously diminish and their condition is no longer “resistant.” In actuality, it is entirely receptive to treatment, needing only for the root cause(s) to be removed. The reason for this lies in the fact that the origin of mood disorders rests in a disruption of the functional integrity of one or more physiological processes. Hence, once that integrity is restored, symptoms are alleviated and finally we see lasting results.

Mood Disorders and Stress

As we begin to probe deeper into the question of what could be causing the disturbances in brain chemistry that are characteristic of mood disorders, we may first want to consider the ubiquitous presence of stress in our modern lifestyle. One of the most powerful contributors to depression and anxiety is simply everyday chronic stress. While the acute stress response can be an asset for raising performance levels during critical events, if stress becomes persistent and low-level, all parts of the body’s stress apparatus (the brain, heart, lungs, vessels, and muscles) become chronically over- or underactivated. This may produce physical or psychological damage over time. In fact, almost all illness is caused by stress, aggravated by stress, or in itself stress-inducing. Stress is implicated in up to 95% of all primary care visits in the US (NIOSH 2006).That’s because as stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, it causes deleterious effects in numerous organ systems. These changes in themselves can directly incite mood disorders when prolonged over time. Anxiety and depression can also be spawned indirectly by the downstream effects of stress. For example, cortisol-induced intestinal barrier dysfunction can trigger a local inflammatory response characterized by the production cytokines, which travel to the brain and create detrimental changes in mood (Loftis et al. 2010; Söderholm & Perdue 2001). Therefore, clinically, it is crucial to consider the possibility that stress could indeed be at the root of many cases of the mood disorders that we see today.

Mood Disorders as Multifactorial

Every patient has a unique and complex history which catalyzes the progression of their symptoms into a mood disorder. Although the presentation of depression or anxiety could be identical between two different patients, the pathogenesis of their symptoms may be entirely different. There are a myriad of possible offenders in the development of mood disorders, each of which is worthy of its own review depending upon the particular case. Additionally, each potential contending cause may not single-handedly induce anxiety or depression by its own accord. Often we see that there are a multiple of confounding factors in the development and progression of mood disorders. Therefore, it is of the utmost importance that the clinician take responsibility to retrieve the patient’s full history, untangle the web of causality, and connect the dots so that they can determine the root cause(s). Table 1 is a small list of some of the most common physiological factors predisposing a person to mood disorders.

© 2012 Filomena Trindade, MD

As you can see, anxiety and depression are not “just in the head.” Most often, they are symptoms of a greater, systemic, physiological imbalance. The dysfunction of any number of organ systems in the body may provoke neurochemical imbalances which then have the capacity to induce mood disorders. In this article we will focus on one particular area of interest in the body that has recently garnered a substantial amount of emerging research: the gut–brain axis (GBA). Specifically, we will investigate the relationship between the microbiome in the gastrointestinal tract, its relationship with the central nervous system, and the resulting impact on mood.

The Gut–Brain Connection

In recent years, the gut has earned the affectionate title of “second brain.” It warrants this kind of headline in part because of its ability to manufacture a physical reaction from an emotional stimulus. We are all familiar with the feeling of being “sick to our stomach” when we hear bad news or getting “butterflies” when thinking about kissing a lover. These are examples of how the gut becomes the physical expression of our mental-emotional state; and, as we will soon come to see, it is also the mental-emotional expression of our physical state. Moreover, the so called “second brain” is an actual physical, anatomical structure. It is a large plexus of nerves called the enteric nervous system (ENS) which indeed operates much like a second brain. It can function entirely independently from the central nervous system (CNS) and rivals none other than the spinal cord in pure quantity of nervous tissue. The ENS is a subconsciously driven mechanism that not only regulates entire digestive process but also, as it turns out, asserts its own form of communication with the CNS.

We’ve known for a long time that the CNS communicates with the gut. For instance, in the face of stress, the brain and spinal cord make the executive decision to shut off digestive function and shunt resources to more vital, survival physiological processes such as increasing heart and respiration rates. However, recent research published in multiple journals has made it strikingly clear that the reverse is true as well. The gut also talks to the brain.

The communication between the gut and the brain is bidirectional – a two-way street with equal amounts of traffic heading in both directions. If we pay attention, our clinical experience often confirms this. Namely, “Psychiatric comorbidity, including depression and anxiety, occurs frequently in up to 60% of all patients with a functional gastrointestinal disorder” (Park et al. 2013). One study even showed that patients with irritable bowel syndrome (IBS) had stark physical changes that occurred in the brain – alterations in the cingulate gyrus, cortical thinning, and enhanced glutamate signaling (Labus et al. 2014); and, what’s more, visceral hypersensitivity accompanied these changes in neuroanatomy and physiology. Moreover, given the nature of this poignant relationship between the gut and the brain, it should be no surprise that the induction of chronic depression alters motor activity and the microbial profile in the colon (Park et al. 2013). And it doesn’t stop there. The feedback between the gut and the brain goes full circle. Under the influence of a neuropsychiatric condition, indicators from the GI tract travel to the brain to impact its functioning and subsequently, the changes in brain function feed back to the gut to alter the motility, secretion, and immunological response of the intestines (Fichna & Storr 2012). To close the loop, these changes in the gut link back up to the brain, and symptomatically we see the perpetuation of the already disordered mood.

As you can see, the circular feedback between the gut and the brain is so intimate that their roles in regulating the stability of mood blur into one another. The functioning of the gut and the brain seem to work more as a singular continuum rather than two discrete organ systems. In fact, clinically, it is often difficult to delineate which factor – the gut or the brain – first initiated pathogenesis. We’re faced a causal dilemma, as in which came first, the chicken or the egg? Regardless of the instigator, however, it is imperative that treatment for mood disorders factor in both sides of this intricate GBA.

Gut–brain axis is the term used to refer to the two-way communication between the gut and the CNS. Fichna and Storr, in their July 2012 article in Frontiers in Pharmacology, detail the major players in the GBA as the ENS, the gut wall in the periphery (including the microbiota), the CNS, and the hypothalamic-pituitary-adrenal (HPA) axis. All these constituents of the GBA work to pass messages back and forth between the gut and the brain by using various signaling molecules. These messengers travel along neural, endocrine, and neuroimmune pathways. Holzer and his team did an amazing job of simplifying this concept in their article in Neuropeptides 2012. They explained that the gut talks to the brain via four different information carriers: (1) sensory neurons – both vagal and spinal afferent neurons, (2) cytokines, (3) gut hormones, and (4) gut microbiota-derived signaling molecules. These molecules manage to transmit information from deep within the gut and disseminate it all the way to the brain. Then, the other way around, the brain talks to the gut via autonomic neurons and neuroendocrine factors. These brain-to-gut communication vehicles carry outputs stemming from the CNS and going to the intestines. Therefore, the term gut–brain axis encompasses all of these bidirectional signaling molecules that travel endlessly between these two seemingly unrelated parts of the body.

Stress, Leaky Gut, and the GBA

A range of factors, all of which seem to be associated with systemic inflammation, appear to increase the risk for developing depression. Possible precipitating factors include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental caries, as well as a deficiency in sleep and vitamin D. In this article however, we will focus on the distinct role of intestinal permeability as a source for inflammation and as a causative factor underlying the dysfunction of the GBA and the consequent effect on mood.

The mucosal membrane of the intestines is made up of epithelial cells that function to digest and absorb nutrients, regulate immune response, and mount a barrier that separates the internal lumen of the gut from the external environment. Under normal circumstances, this wall of cells is sown together by tight junctions which are selectively permeable to only a relatively few molecules. However, because the intestinal mucosa is sensitive to neurohormonal signals emitted from the CNS, it is subject to the tyranny of stress. In fact, “various types of psychological and physical stress induce dysfunction of the intestinal barrier, resulting in enhanced uptake of potentially noxious material (e.g., antigens, toxins, and other pro-inflammatory molecules) from the gut lumen” (Söderholm & Perdue 2001). It appears that when the body is inundated with a stressor, autonomic nervous stimulation causes the release of corticotrophin-releasing hormone (CRH) and/or acetylcholine (Ach) at nerve fibers adjacent to the intestinal barrier. These neurotransmitters then go on to activate nearby mast cells that are speculated to release the bioactive constituents ultimately responsible for inducing epithelial permeability (Söderholm & Perdue 2011). In other words, following a stressor, neuroendocrine factors such as Ach (acetylcholine) and CRH could be the instigators for the breakdown of tight junctions between intestinal epithelial cells. Given the onset of stress, the functional integrity of the intestinal barrier is substantially compromised and we see an increase in gut permeability.

We often think of stress as purely psychological; however, it can be physical as well. If a patient has a hypersensitivity to foods containing the protein gluten for instance, they will produce IgG antibodies in response to the gliadin. This is a physical stressor because the IgG reaction triggers the overproduction of zonulin, which then loosens the tight junction barrier and increases the permeability of the gut wall (Karakuła-Juchnowicz et al. 2014). The immune system has to then respond to the presence of unmetabolized molecules seeping from the gut lumen out into the blood stream. The risk of this “leaky gut” is that there is an increased load of antigens passing through the gut mucosa. This inevitably incites an inordinate level of immune stimulation and in the end leads to inflammation. Inflammation is a “pathway to both risk and neuroprogression in depression” (Berk et al. 2013).

Inflammation/Cytokine Theory of Depression

The question remains, how exactly does intestinal permeability and its resulting immune-inflammatory response affect the brain and precipitate a mood disorder? According to one theory, the answer is cytokines. Cytokines mediate between the immune system and the CNS. For instance, during the inflammatory response following an incident of gut barrier permeability, the brain intercepts these immunomodulatory signaling molecules known as cytokines. Cytokines switch “on” or “off” immune-regulating proteins such as interferons (IFN) and interleukins (IL). In their circulation, these pro-inflammatory, immune-stimulating cytokines exert their influence on the brain in four main ways: (1) via the vagal nerve, (2) by seeping through a weak and porous blood–brain barrier, (3) through active transport across the blood brain barrier, and (4) in binding to endothelial brain cells (Loftis et al. 2010). Once they’ve accessed the brain, cytokines intercede in synaptic transmissions and can alter both the anatomical structure of neurons as well as their physiological functioning. In fact, chronic exposure to an excessive number of these molecules can even deteriorate neuroplasticity which is essential to healthy cognition, mood, and behavior (Loftis et al. 2010).

While it is postulated that cytokines are the intermediaries between an inflamed leaky gut and mood disorders, other studies have also shown that they may also be behind the link between stress and depression. That’s because cytokines ignite sympathetic arousal and HPA axis activation (Fichna & Storr 2012). Even as long ago as the mid 1990s, scientists correlated the presence of cytokines, levels of stress, and the severity of depression. Now, over the course of a decade more of research, the idea of a neuroimmune, potentially stress-related, cytokine-induced depression is central to our biological understanding of the disorder.

The Role of the Microbiota

At the same time that cytokines relay messages to the brain in the presence of inflammation in the gut, there is another highly influential mediator that must be considered in gut–brain communication: the gut microbiota (GM). A central player in the GBA, the GM consists of some 100 trillion bacteria with over 1000 different species, outnumbering human cells 10 to 100 times (Zhou & Foster 2015). As with any ecosystem, diversity in the GM is prized, and maintaining this well-balanced ratio of distinctive species may very well be our ticket to both physical and mental well-being (Park et al. 2013; Zhou and Foster 2015).

Interestingly enough, this vast internal ecosystem never looks exactly the same between any two people. As with fingerprints, we all have microbiomes that are uniquely characteristic (Zhou & Foster 2015). Even identical twins have variability in the constitution of their GMs (Simões et al. 2013). In a large part, the GM is a reflection of the environment to which we have been exposed since birth. The colonization and diversity of microbes in our gut are influenced by our mother’s method of delivery (vaginal or C-section); whether we were breast fed; our first solid foods; if we grew up with siblings; what kind of diet and lifestyle we’ve had to date; whether we travel frequently or have used many antibiotics in the past; as well as our genetics, sex, and age (Tillisch 2014, Zhou & Foster 2015).The GM unmistakably interfaces with our environment and adapts accordingly. It coevolves alongside us in dynamic participation with the multitude of changes that we encounter throughout our lives.

Research suggests that we host this array of commensal bacteria because we have a symbiotic, mutually beneficial relationship with them. They play an integral role in a variety of physiological processes that are critical to maintaining homeostasis. In return, we grant them free access to “room and board,” giving them three square meals a day to enjoy in our perfectly warm, ideally anaerobic gastrointestinal (GI) tract. We are most obliged to house these little bugs because they happily take on a number of critical responsibilities important to the maintenance of our everyday health. Table 2 below enumerates the functions of the GM identified to date; although we know full well that this list will surely grow as more research is done and additional undertakings of the GM are discovered.

© 2015 Filomena Trindade, MD

The role of the GM is many-sided and mutually interdependent with other bodily functions. Scientists speculate that the reason being is that over the course of millions of years, the microbiome has coevolved in a give-and-take rapport with other systems such as the CNS, immune system, and endocrine system (Montiel-Castro et al.). If this is indeed true, we would find that an inadequate microbiome might be indicated in numerous pathologies, and in fact, it is. Subpar condition of the microbiota is associated with “neuropsychological disorders including depression and autism spectrum disorder, metabolic disorders such as obesity and gastrointestinal disorders including inflammatory bowel disease and irritable bowel syndrome” (Zhou & Foster 2015). We are only beginning to understand the breadth of influence that these microflora have in our bodies. What we do know, however, is that they appear to have an unexpected, profound, and far-reaching effect on the brain.

Introducing the Gut–Brain Axis

The GM may in fact be the single most influential component of the GBA. The two-way relationship between the microbiota and the CNS means that when there is a disruption in the constitution of microbes, brain chemistry and behavior can change (Mayer et al. 2015; Tillisch 2014). Vice versa, the proceedings of the brain can stimulate changes in the microbial constitution of the gut thereby effecting GI function such as motility and secretion (Park et al. 2013). The GM has a profound influence on the brain and can actually alter both its development and functioning, through the use of substances such as neurotransmitters, neuropeptides, cytokines, hormones, bacterial metabolites, and growth factors as well as the enteric neurons, vagal afferent nerves, and finally, immune and HPA axis modulation (Tillisch 2014; Fichna & Storr 2012; Zhou & Foster 2015). In the spirit of reciprocity, the CNS also uses some of the same routes of communication –the vagal nerve and HPA axis – to talk to the gut.

The vagus nerve is of particular interest in this discussion as it is the cranial nerve which innervates the GI tract and processes the bulk of autonomic parasympathetic stimuli. In fact, the “… bidirectional signaling between the gastrointestinal tract and the brain, mainly through the vagus nerve, the so called ‘ microbiota-gut-vagus-brain axis’ is vital for maintaining homeostasis and it may be also involved in the etiology of several metabolic and mental dysfunctions/disorders” (Fichna & Storr 2012). Namely, the GM uses the vagal nerve to administer its remarkable influence on the CNS and the body at large, in part through the direct activation of neurons embedded in the gut lining.

The influence of the GM on this gut–brain feedback loop lies in its ability to mediate neuronal function of ENS neurons (Zhou & Foster 2015). It appears that the microflora actually depend on the ENS and vagal nerve to administer their effect through the GBA. Put another way, the GM itself may be able to activate neuronal pathways that then go on to influence the functioning of the CNS and, hence, the state of our mood. This particular pathway of the GBA was confirmed in a study done by Bravo et al. in 2011 in which the probiotic Lactobacillus rhamnosus was given to rats with both subdiphragmatic vagotomies and intact vagus nerves. After the microbial manipulation, the mice without the vagus nerve had no change in mood or behavior, whereas rats who maintained an intact vagal nerve had “reduced anxiety and depressive-like behaviors and long-term changes in gamma-aminobutyric acid receptor expression in the CNS” (Zhou & Foster 2015), specifically in the hippocampus, amygdala, and locus coeruleus (Tillisch 2014). In a similar manner, Bercik et al. (2010 and 2011) demonstrated that probiotic treatment can minimize anxiety induced by gut inflammation. These anxiolytic effects were associated with changes in brain-derived neurotrophic factor and were dependent on the vagus nerve.

According to Montiel-Castro et al. in their 2013 publication in Frontiers in Integrative Neuroscience, “The microbiota-gut-brain axis has multiple effects on emotions, motivation and other higher and complex cognitive functions … [and] may even influence memory formation, emotional arousal, affective behaviors and decision making processes.” The microbial population in the gut can have this effect in part because of its relationship with the vagus nerve. Microbially stimulated vagal afferents send signals to the brainstem nuclei, as well as cholinergic and noradrenergic projections to the cortex – all of which end up mitigating emotional well-being, behavior and cognition (Tillisch 2014). Numerous studies such as these have substantiated the role of the microbiota in triggering vagal afferents via enteric neurons which then signal the CNS and ultimately produce a change in mood.

Gut Microbiota in the Stress Response

The central nucleus of the amygdala is famous for being the emotional learning center and fear-processing locus of the brain. One fascinating study showed that signals from the amygdala can actually activate the HPA axis (Fichna & Storr 2012). This in turn causes a cascade of neuropeptides such as corticotrophin releasing factor (CRF) and adrenocorticotropic hormone (ACTH) along with glucocorticoids, to be disseminated. The flood of stress hormones spawns anxiety-type behaviors, undesirable changes in bowel habits, and visceral sensitivity (Fichna & Storr 2012). Furthermore, in the presence of a stressor and HPA axis activation, cortisol is released, which “…can alter gut permeability and barrier function, and thus contribute to variations in gut microbiota composition” (Montiel-Castrol et al. 2013). These findings demonstrate the link between emotional fear leading to stress and finally to GI sensitivity. This is important because this chain of events occurs by way of the HPA axis and the ENS – two central players in the GBA.

While a stress response initiated from the brain can disrupt the bowel, the state of the bowel’s microbiota can also disrupt the stress response in the brain. In fact, it appears that the CNS depends on the microbiota to mediate the fear response. For instance, studies conducted on mice without adequate microbiota (germ-free mice) showed a disproportionate, inordinate stress response (Tillisch 2014). In the same way, another study on humans showed that with the addition of beneficial microbes, there were improvements in mood and a decrease in urinary cortisol levels (Tillisch 2014). Lastly, in yet another study, the effects of the commensal flora Bifidobacterium infantis were tested in newborn rats subjected to early life stress by being separated from their mothers and forced to swim. During the swim test, cytokine levels and markers of motivation and brain monoamines were measured. Amazingly, the results indicated that in spite of the stressors, the rats treated with the probiotic had scores similar to rodents that had never experienced any early life stressors. And what’s more, they had a “normalization in brainstem noradrenaline and peripheral cytokines” (Tillisch 2014). In sum, all these studies demonstrate that the stress response can be mediated by beneficial gut microbes that seem to be able to quell the reactivity of the HPA axis. Indubitably, the stability of our stress response and thus our mood depends at least in part on the cross-communication between the trillions of bacteria that inhabit our gut and the CNS.

The Gut Microbiota in the Immune Response

The GM can also affect brain chemistry through immunomodulation. Gut microbes can trigger a local immune response at the level of the intestinal mucosa. This immune signaling often goes hand in hand with intestinal barrier dysfunction, ENS activation, and changes in GI sensory motor function (Tillisch 2014). In fact, it appears as though after the administration of probiotics, positive changes in the GM may “reduce inflammation, restore epithelial barrier function and potentially ameliorate behavioral symptoms associated in children with autism” (Zhou & Foster 2015). In the same vein, cognitive impairment due to diabetes and inflammation significantly improved after probiotic treatment in animal models (Tillisch 2104). In addition, by working through the immune system, the GM (including pre- and probiotic agents) can regulate the production and circulation of pro-inflammatory cytokines (Montiel-Castrol et al. 2013). And, as aforementioned, cytokines have significant effects on neural activity. For example, low-grade inflammation stemming from chronic infections in the GI tract can disrupt gut function and indirectly encourage anxiety and depressionlike behaviors; these changes in mood are likely “… immune-mediated, and involve changes in pro-inflammatory cytokines and altered metabolism of kynurenine/tryptophan pathways” (Borre et al. 2014). Again, we see the bidirectional nature of the GBA, and in this case the role of the gut microbiota in that communication, as a modulator of inflammatory cytokines. Naturally, all of these data makes the human intestinal microbiome a keen area of interest for researchers hoping to discover how to ameliorate the outstanding rates of mood disorders that we see today.

The Gut Microbiota in Neuropsychology

One of the most fascinating aspects of the microbiome is that certain strains of bacteria can actually manufacture and secrete numerous neuroactive substances. Neurotransmitters such as gamma-aminobutyric acid, serotonin, catecholamines, and histamine can all be bacterially produced (Tillisch 2014; Dinan et al. 2013). These neurohormones can conduct their signals to the CNS with the help of local neuroendocrine cells on the gut epithelia (such as enterochromaffin cells) and/or through enteric nerves (Tillisch 2014 ). At the same time, the microbiota also influence the endocrine system by letting off “metabolites such as short chain fatty acids, biogenic amines, neurotransmitters and neurotransmitter precursors [that can] gain access to the systemic circulation” and later affect mood (Tillisch 2014). We speculate that it is likely that the metabolic byproducts of the microbiota depend in part on their strain and in part on the relative activation of the HPA axis and immune system. Clearly, the presence of the GM is an integral part of the inexorable gut–brain continuum and must therefore be aptly considered in the management of mood.

The Gut Microbiota in Nervous System Development

Along with the faculty of manufacturing neurotransmitters, the GM also appear to be influential in the actual development of the nervous tissue within the CNS and ENS. Studies on germ-free mice with no commensal bacteria show that “the myenteric plexus of the jejunum and ileum … [had] an unorganized lattice-like appearance, with fewer ganglia and thinner nerve fibers” (Zhou and Foster 2015), as well as an abnormally developed HPA axis, among other things (Tillisch 2014). The functional consequences of these structurally abnormalities cannot be underestimated. Germ-free mice experienced less brain-derived neurotrophic factor, an irregular stress response as well as decreased intentional motility, immune function, and cell excitability (Zhou and Foster 2015; Tillisch 2014). Interestingly enough, however, after colonization with standard microbiota, many of these functional abnormalities were considerably rectified. This result demonstrates both the pliability and significance of the GM in the GBA.

The Gut Microbiota and Diet

The GM may be the linking factor between diet and depression. Diet has been shown to affect the composition of the GM (Simões et al. 2013), and in the opposite direction, accumulating evidence indicates that the makeup of GM influences behavior. According to Jørgensen et al. (2014), a diet high in sucrose and poor-quality saturated fat contributes to depressionlike behavior in mice. In their study, mice fed a diet high in fat had adverse changes in both behavior and microbial composition. The underlying mechanism behind this may have been the documented increase in interleukins, cytokines and TNF-alpha – all of which are participants in the inflammatory cytokine model of depression.

Additionally, food sensitivities causing an IgG reaction may affect the permeability of the gut and be another source of covert inflammation leading to depression (Karakuła-Juchnowicz al. 2014). As we have noted ad nauseam, the GM respond to a leaky gut with immune activation, often inciting inflammatory cytokines that ultimately prove to dysregulate mood. Together, this evidence suggests that the mediator between food and mood is indeed the GM.

Reconstituting the Gut Microbiome: A Frontier in Mood Management

There are innumerable factors in our modern diet and lifestyle that sabotage the balance and diversity of the ecosystem in our gut. Anything from infection, stress, antibiotics, and environmental toxins to depression, excess sugars, and poor-quality soil in conventional food sources could weaken the integrity of the GM. In the same vein, while basic hygiene is vitally important, our obsession with sanitization does not help our microbial diversity thrive. Antibacterial sprays and gels kill both the good and the bad bugs. As a result, our immune systems are left without a piece of their inborn GI defense, and we find ourselves getting sicker more often.Whether intentional or not, the aggregate effect of our war on microbes renders our baseline microbiome less than robust. Consequently, we become vulnerable to tenacious, opportunistic gut pathogens such as Candida albicans. In short, any type of intestinal dysbiosis has the potential to stimulate the GBA and lead brain chemistry awry, effectively subjecting us to the pain of anxiety and/or depression (Park et al. 2013).

While it may be difficult to keep dysbiosis at bay given the circumstances of our modern world, the good news is that, with more awareness, we can actively promote the status of beneficial bacteria in the gut. Researchers are optimistic that future therapeutic strategies for mood disorders may invoke the talents of the GM to harmonize the GBA with the intention of allaying anxiety and depression. With each passing day, the scientific community continues to grow in its understanding of the nature of the GM and its therapeutic potential. On that note, as you may have gathered from the previous discussion, each strain of intestinal bacteria has a different “personality,” if you will. Specific microbes seem to impart certain advantageous or deleterious effects on the GBA, depending on their nature. It is our task, among others, to identify the tendencies and actions of these microbes in the body so that we are better able to harness their potential and target their therapeutic capability in clinical practice .

Until relatively recently, the majority of studies on the affects of probiotics on the microbiome have been done on rodent models. However, more recently one study in humans demonstrated that consumption of a fermented milk product containing a combination of probiotics (Bifidobacterium animalis, Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactococcus lactis) actually modulated brain activity (Tillisch et al. 2013). In this study, social anxiety was measured after 4 weeks of eating this fermented food. What was found was “ … a reduction in brain activity in a network of areas, including sensory, prefrontal, and limbic regions, while processing negative emotional faces” (Hilimire et al. 2015). In other words, the participants had less reactivity to negative social stimuli after regular ingestion of probiotics than they had done before. Furthermore, a control group that ingested a nonfermented milk product showed no such changes in brain activity. This suggests that the probiotics in the fermented milk were responsible for the modulation in brain activity that reduced social anxiety. Hence, probiotics could possibly be used as a low-risk intervention for the treatment of anxiety (Hilimire et al. 2015).

We also have data suggesting that the anxiety often associated with chronic fatigue syndrome can be mediated by the ingestion of probiotics. Measurements on the Beck Anxiety Inventory starkly decreased after regular consumption of Lactobacillus casei. Similarly, in a double-blind, placebo-controlled trial, the effects of L. helveticus and B. longum were measured on healthy participants. At the end of 30 days of consuming these beneficial bugs, participants reported substantially less psychological distress (Zhou & Foster 2015). Another study of the same caliber demonstrated that prebiotics or “trans-galactooligosaccharide[s], which promote the growth of indigenous beneficial gut bacteria such as Lactobacilli, resulted in decreased scores on the anxiety subscale of the Hospital Depression and Anxiety Scale (HADS-A) in patients with irritable bowel syndrome” (Hilimire et al. 2015). Cumulatively, these evidences support the idea that mood is regulated, at least in part, by gut bugs.

It is quite possible that one day, instead of going to the doctor and getting a prescription drug for anxiety or depression, psychiatric patients may very well receive “psychomicrobiotics” instead (Fond et al. 2015). These individually targeted psychotropic microbes would be aimed to work through the GBA to relieve symptoms of a mood disorder. With the use of stool testing, it is indeed possible that a snapshot of an individual’s unique microbiome could be assessed and subsequently assigned the appropriate psychomicrobiotics. Manipulating the microflora to combat microbial dysbiosis in psychiatric patients can be done through the use of probiotic or prebiotic supplementation and/or by fecal microbial transplant. The addition of beneficial bacteria can “influence end-points related to mood state (glycemic control, oxidative status, uremic toxins), brain function (functional magnetic resonance imaging fMRI), and mental outlook (depression, anxiety)” (Bercik et al. 2014).In sum, as the field of gastrobiological psychiatry grows, we see the increasing relevance of the GM as an access point from which to therapeutically direct the proceedings of the GBA and correct a disturbance in mood.

Finally, while this article has focused on the role of the GM in mood disorders, it is important to remember that anxiety and depression are complex, multifaceted issues with numerous possible etiological factors. That being said, given the substantial evidence that the GM works through the GBA to either catalyze or ameliorate mood disorders, it is imperative that clinicians thoroughly investigate this mechanism as a possible contributor to their patients’ disease, as well as a potential pathway to their long-term healing and recovery.

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