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From the Townsend Letter
October 2015

The Gut Microbiome: Your Mood's Micromanager?
by Filomena Trindade, MD, MPH, and Megan Murphy, CAP
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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 & 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.

Table 2: Functions of the Microbiome
Modulation of host nutrition and energy harvest
Digestion of carbohydrates and proteins
Fermentation and breakdown of food components indigestible by the host for nutrient harvest
Affect signaling pathways influencing lipid and glucose metabolism
Development of host immune system and immune modulation
Protection against pathogens
Drug metabolism
Bile acids metabolism
Influence of intestinal epithelial homeostasis
Produce and secrete neurotransmitters
Production of vitamins
Absorption of minerals
Influences learning and memory
© 2015 Filomena Trindade, MD

The role of the GM is many-sided and mutually interdependent with other bodily functions. Scientists speculate that the reason 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 make 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 appears 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 & Foster 2015), as well as an abnormally developed HPA axis, among other things (Tillisch 2014). The functional consequences of these structural 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 & 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-Juchnowicze al. 2014). As we have noted ad nauseam, the GM responds 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 effects 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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