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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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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 illnesses 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 confidently 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.

Table 1: Precipitating Factors for Mood Disorders
Gut bugs: Dysbiosis and the gut microbiota
Food allergies/sensitivities
Digestive insufficiencies/excess
Oxidative stress/mitochondrial dysfunction
Stress-psychological or physical or both
Hormone imbalance
Nutrient deficiencies
Prescription medications
Genetic predispositions/SNPs
EMFs and dirty electricity
Trauma – pyschosocial or physical
More than one cause?

© 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 affect 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 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 sewn 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 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 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 bloodstream. 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 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.

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