Evolving Concepts
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Major Depressive Disorder, Immunoregulation, Inflammation and Our Changing Microbial Environment

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Major Depressive Disorder, Immunoregulation, Inflammation
Major Depressive Disorder – Immunoregulation

Urbanized societies are suffering an epidemic of chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel disease. This is at least partly due to elimination from the hygienic modern concrete and tarmac environment of microorganisms and helminths with which man co-evolved. These organisms needed to be tolerated, and so were “entrusted” by evolution with crucial roles in driving immunoregulatory pathways which become defective in their absence, leading to reduced control of inflammation. But persistently raised (or therapeutically introduced) proinflammatory mediators can drive depression. Thus we argue here that when studying the causes of depression we need to consider not only the psychosocial environment, but also the microbiological environment. Moreover the immunoregulatory roles of these organisms from our evolutionary past are being tested in exciting clinical trials in many chronic inflammatory disorders. There is huge potential for extending these trials into those cases of major depressive disorder that present evidence of persistently raised inflammatory mediators.

Inflammation and depression

The association between inflammation and depressed mood is well established (some dissenting voices are discussed later). Numerous factors that increase peripheral markers of inflammation are also associated with increased risk of depression. These include psychosocial stress, social isolation, obesity, smoking, sedentary life-style and female sex. Thus, as can be anticipated, peripheral markers of inflammation such as proinflammatory cytokines and C-reactive protein (CRP) are often found to be raised in depression even when no other illness is detected [reviewed and referenced in 1].

Recent meta-analyses have confirmed that there is a dose-response relationship between depression and the inflammatory markers CRP, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha [2, 3]. In contrast, levels of the major regulatory mediators, IL-10 and TGF-beta are usually reduced relative to the proinflammatory ones, while treatments that reduce depressive symptoms reverse this imbalance [reviewed and referenced in 1]. Interestingly, stressors, which promote depression, tend to downregulate the correlates of immunoregulation such as CD25+ Treg, IL-10 and Foxp3 [4, 5].

Moreover, the excess of proinflammatory mediators seen in depression could play a direct role in driving the disorder because administration of IL-2 or interferon (IFN)-alpha, which are used as treatments for hepatitis or some cancers, induces states strikingly similar to naturally occurring depression that are treatable with antidepressant drugs [6, 7]. Even acute immune stimuli have been shown to produce short term increases in depression, anxiety and cognitive dysfunction when administered to humans, and these behavioural effects can be reversed by pretreatment with an antidepressant [8-11].

Mild immune stimuli – typhoid vaccination in this case – also produce powerful feelings of social disconnection and these feelings play an important role in generating depressive emotions [12]. Consistent with known relationships between central nervous system (CNS) functioning and behavior, both acute and chronic inflammatory stimuli have been shown to induce changes in brain activity that are similar to those observed in the context of depression. For example, typhoid vaccine has been reported to acutely increase activity in the subgenual region of the anterior cortex (sACC) and impair functional connectivity between many mood-relevant brain areas (e.g. sACC, amygdala, medial prefrontal cortex and nucleus accumbens) [8].

Short-term depressive symptoms induced by typhoid vaccine were also associated with changes in activity in the ventral striatum in response to hedonic stimuli [10]. Chronic inflammatory exposure resulting from treatment with IFN-alpha has been shown to similarly affect functional activity in the ACC and basal ganglia, both areas of central relevance to depression [13, 14].

Depression and chronic inflammatory disorders

Another major link with inflammatory states is the greatly increased incidence of depression in individuals suffering from chronic inflammatory disorders. This is not merely due to the inherently depressing nature of chronic illness, because the risk of depression, as we have discussed elsewhere, is related to the levels of proinflammatory cytokines rather than to the symptoms of the disease [discussed and referenced in 15].

It is this link between depression and chronic inflammatory disorders that led two of us to propose in 2008 that a subset of cases of depression might be due to an environmentally-induced immunoregulatory problem (the Hygiene Hypothesis) that was already being explored in relation to the chronic inflammatory disorders, rather than to a psychological or psychosocial one [15]. In this conceptualization, some individuals’ depression might be the only apparent symptom of an immunoregulatory deficit.

The “Hygiene” or “Old Friends” hypothesis

The hygiene hypothesis, or as we prefer to call it, the “Old Friends” hypothesis, suggests that one reason for the increasing incidence of chronic inflammatory disorders such as allergies, inflammatory bowel disease (IBD) and autoimmunity (e.g. Type 1 diabetes; multiple sclerosis) [16], in developed countries since the mid-19th Century is the depletion from the urban environment of immunoregulation-inducing organisms that accompanied mammalian evolution.

The organisms involved are associated with feces (e.g. intestinal microbiota, helminths and fecal-oral transmission of infections/carrier states), animals (farm or pet) and mud [17-22].  Humans were continuously exposed to these organisms from early in evolution, right through the Neolithic age with the introduction of agriculture and husbandry, and were not deprived of contact with them until the 2nd Epidemiological Transition (urbanization), starting in the early 19th Century in Europe and USA.

Multiple aspects of the modern environment have contributed to the elimination of many organisms transmitted by the fecal-oral route, and have also profoundly altered the gut microbiota [17]. These include the spread of the concrete and tarmac environment, and increases in hygiene, public health education and modern medical interventions. Further details are reviewed elsewhere [16]. Across evolutionary time, it was necessary for these organisms to be tolerated for a number of reasons. Some, for example were ubiquitous or unavoidable (saprophytes, and neonatal infections). Some were an essential part of mammalian physiology (microbiota). Some could not be eliminated, and attempts to do so merely drove pointless immunopathology (helminths).

Therefore co-evolutionary forces ensured that they took over essential roles in the optimal functioning of immunoregulatory pathways [16]. Mammals can thus be seen as being in a state of evolved dependence on such organisms, which have been “entrusted” with genes that are essential to our immune system. Many of these organisms cause dendritic cells to drive Treg (regulatory T lymphocytes), or even secrete molecules that directly expand Treg populations [22-26]. Overwhelming data show that a failure of immunoregulatory mechanisms reliably leads to simultaneous increases in the diverse types of immunopathology observed with increasing frequency in the modern world (Th2-mediated allergies, and Th1/Th17-mediated autoimmunity and IBD).

For example, genetic defects of Foxp3 (a transcription factor important to immunoregulation) leads to the X-linked autoimmunity–allergic dysregulation syndrome (XLAAD), which simultaneously manifests aspects of allergy, autoimmunity and enteropathy [27]. The suggestion we made in 2008 was that in some individuals, chronically raised circulating proinflammatory mediators due to weakened immunoregulation might increase vulnerability to depression or cause depression [15].

Depending on the history and genetics of the individual, this depression might or might not be accompanied by a detectable Th2- or Th1/Th17-mediated disease (allergy, IBD or autoimmunity). This concept was then developed and amplified in 2010 [1]. If this is correct, rates of depression should be increasing, particularly in urban environments.

Rates of depression and the environment

While there is no universal agreement, there is evidence that rates of MDD are increasing in developed countries, as expected if there is an association with chronic inflammatory disorders, stress and obesity [discussed and referenced in 1]. Moreover, moving from the developing world to the U.S. increases the risk for MDD. For example, Mexican immigrants to the U.S. have rates of depression similar to those seen in Mexico. However, individuals of Mexican descent born in the U.S. have higher rates of MDD that are equivalent to the U.S. population at large, suggesting that it is American life itself—and not acculturation shock—that accounts for the increase [28].

Interestingly there is a significantly higher risk of mood and anxiety disorders in urban populations, compared to rural ones [29], which is compatible with a mechanism involving the “Old Friends” hypothesis. A recent functional magnetic resonance imaging (fMRI) study compared the effects of social stress on individuals brought up in urban versus rural environments [30].

Social stress induced quite different fMRI responses in the two groups. The authors attributed this to putatively different levels of childhood exposure to social stressors during urban versus rural upbringing. But would social stressors in children differ significantly in the two environments in a wealthy European country (Germany)? It is equally likely that the findings were due to the “Old Friends” mechanism, leading to diminished regulation of proinflammatory mediators in those subjects who had an urban upbringing. Indeed the protective effects of the

German farming environment against allergies and early onset inflammatory bowel disease require that the child be exposed to the farming environment during the first 2.5 years of life…a rural upbringing [20]. The authors of the fMRI study did not measure levels of circulating proinflammatory cytokines in the two populations [30]. The “Old Friends” view of the data would postulate higher levels in the subjects who had urban upbringings.

Alternative views

There are few dissenting voices to the view that inflammation can be linked to depression. There are claims that proinflammatory brain-recognizing lymphocytes can protect mice and rats from behavioral changes triggered by stressors [31, 32]. We analyzed these and other data in detail and concluded that the findings were due to secondary entry into the CNS of another cell type with regulatory functions [33]. More recent work by some members of the same group has implicated IL-4-positive T cells that drive alternative macrophage activation in the meninges, leading secondarily to regulatory pathways including increased IL-10 and decreased TNF-alpha [34, 35].

Thus the issue might now be resolved, with agreement that protecting both structural and functional aspects of neuronal function requires regulatory pathways, perhaps particularly IL-10.
A more bizarre claim appeared recently in PNAS [36]. The authors used a dataset from the “sequenced treatment alternatives to relieve depression” (STAR*D) study to investigate retrospectively the effect of simultaneous administration of non-steroidal anti-inflammatory drugs (NSAID) or analgesics on the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant depression. The authors concluded that the patients who took NSAID were less likely to go into remission, and suggested that blocking inflammation inhibited the effects of treatment.

However two issues undermine this conclusion. First, the same decrease in remission rates was noted in patients taking non-anti-inflammatory analgesics (such as acetaminophen), so clearly inflammation was not the issue. Secondly, the data were not controlled for pain. Pain strongly predicts a failure to respond to antidepressants and the patients taking these analgesics were presumably doing so because of pain [37].

Interestingly, in the absence of pain, trials of cycloxygenase-2 inhibitors as add-on treatments for depression show significant beneficial effects [38]. Some confusion has also arisen from the fact that acute transient inflammatory stimuli can lead to activation of a specific subset of serotonergic neurons in the interfascicular part of the dorsal raphe nucleus (DRI) of mice [39]. This effect is associated with transient reductions in immobility in the forced swim test, which is a standard test for antidepressant activity [39].  But this antidepressant-like behavioral effect of inflammation is extremely short-lived. The neurochemical and behavioral effects observed 6-12 hrs after injection of the inflammation-inducing agent then waned rapidly. This finding in no way argues against the overwhelming evidence that persistent inflammatory states drive depression.

Conclusions

There is overwhelming evidence relating some forms of depression to chronic inflammation and to sustained increases in circulating proinflammatory cytokines. But we know that one reason for the increasing burden of chronic inflammatory states in modern urban societies is the loss of co-evolved immunoregulation-inducing “Old Friends”. Exciting clinical trials have been performed, or are in progress, testing the ability of the “Old Friends” to treat these chronic inflammatory diseases (helminths for multiple sclerosis, or IBD, or allergies for example) [discussed and referenced in 16].  It will be important to start monitoring mood in such trials, and also to devise studies aimed specifically at depression. A few preliminary studies have tested probiotic formulations [40, 41], but the Old Friends hypothesis suggests that there are many other important possibilities.

Author(s) Affiliation

Graham A.W. Rook – University College London (UCL), Centre for Clinical Microbiology, Royal Free Campus, London NW3 2PF, UK

Charles L. Raison – Department of Psychiatry, University of Arizona School of Medicine, John & Doris Norton School of Family and Consumer Sciences, University of Arizona, Tucson AZ, USA

Christopher A. Lowry – Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder CO, 80309-0354, USA

Cover Image, Credit: Adrian Cousins, Depression – artist’s interpretation. Wellcome Images.
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