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Inflammation, Sanitation, and Consternation:  Loss of Contact With Coevolved, Tolerogenic Microorganisms and the Pathophysiology and Treatment of Major Depression

Charles L. Raison, MD; Christopher A. Lowry, PhD; Graham A. W. Rook, BA, MB, BChir, MD, FSB
Arch Gen Psychiatry. 2010;67(12):1211-1224. doi:10.1001/archgenpsychiatry.2010.161.
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Context  Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling.

Objective  To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world.

Data Sources  Relevant studies were identified using PubMed and Ovid MEDLINE.

Study Selection  Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches.

Data Extraction  Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted.

Data Synthesis  Significant data suggest that a variety of microorganisms (frequently referred to as the “old friends”) were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of nonthreatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression.

Conclusion  Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies.

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Figure 1.

Psychosocial stress, inflammation, and immunoregulation in major depressive disorder (MDD). A, Psychosocial stress and factors that contribute to stress, such as social isolation and maladaptive personality, activate brain areas evolved to evaluate and respond to environmental danger. B, These brain areas contribute to activation of stress outflow pathways, including the sympathetic nervous system, with resultant norepinephrine (NE) production, and the hypothalamic-pituitary-adrenal axis, with resultant glucocorticoid (GC) release. In response to psychosocial stress, parasympathetic signaling is also withdrawn, leading to attenuated acetylcholine (ACh) release. C, In general, sympathetic activation promotes innate immune inflammatory processes, whereas parasympathetic signaling and glucocorticoids attenuate inflammation. D, Environmental adversity (whether via α- or β-adrenoreceptor [α/β-AR] stimulation in response to stress or via toll-like receptor [TLR] stimulation in response to infection, tissue trauma, or neoplasm) activates intracellular inflammatory signaling cascades (eg, nuclear factor-κβ [NF-κβ]) within innate immune cells (eg, macrophages and dendritic cells) leading to the production and release of inflammatory cytokines, including interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and IL-6. α7 nAChR indicates α7 nicotinic acetylcholine receptor. E, These cytokines access the brain via leaky regions of the blood-brain barrier or active transport across the blood-brain barrier and can influence brain function via activation of afferent nerve fibers (ie, sensory vagus). Once in the brain, cytokine signals participate in processes known to be involved in the development of MDD, including alterations in monoaminergic neurotransmission, reduction in neurotrophic support, and increased production of excitotoxic/oxidative species that damage neurons and glial cells. F, Environmental adversities that activate inflammation (A and D) also stimulate immunoregulatory mechanisms that constrain inflammatory responses (F), in part via production of anti-inflammatory cytokines, including IL-10 and transforming growth factor β (TGF-β). G, Whereas inflammatory responses to psychosocial adversity are associated with MDD (E), immunoregulatory pathways antagonize these responses and by doing so promote psychosocial resilience, which enhances interpersonal functioning, contributing to euthymia (G). Immunoregulatory processes also likely contribute to euthymia by attenuating background levels of inflammatory activity that have been shown to be elevated in MDD.

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Figure 2.

Loss of contact with the “old friends” and increased inflammatory conditions in the modern world. In populations adequately exposed to old friends, such as many societies in the developing world, priming of regulatory T cells (Treg) is sufficient to maintain an appropriate balance of Treg to effector T cells (Teff), with the result that inappropriate inflammation is generally constrained. When contact with the old friends is disrupted as a result of modern cultural practices (eg, sanitation, water and food treatment, modern medicines), priming of Treg is inadequate, with the result that the ratio of Treg to Teff is low. In this situation, the population as a whole is at risk for a variety of syndromes attributable to inadequate termination of inflammatory responses to any of a range of environmental stimuli. Consistent with this, although the prevalence of serious infections is significantly reduced in the industrialized world, rates of chronic inflammatory conditions (eg, autoimmune diseases, allergies, asthma, and cardiovascular disease) have been shown in many studies to be much higher than in the developing world. Some individuals have a genetic background and/or immunologic history that places them at risk for disorders, such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and type 1 diabetes mellitus (DM), characterized by overactive/uncontrolled helper T cell type 1 (TH1) and/or TH17 activity. In other individuals, TH2 responses are more liable to inadequate control, resulting in asthma and allergic disorders. While not developing gross immune-related pathology, a further group of individuals with inadequate termination of either TH1 or TH2 inflammatory responses is susceptible to central nervous system effects of cytokines, including major depressive disorder. However, conditions associated with TH1/TH17 and TH2 dysregulation are highly comorbid with major depressive disorder. IL-10 indicates interleukin 10; TGF-β, transforming growth factor β.

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Figure 3.

Microorganisms play important roles in shaping immune function in species over evolutionary time, and in individuals across the lifespan, to appropriately respond to a wide range of environmental threats and opportunities. When exposed to an optimal balance of immunostimulatory and immunoregulatory microorganisms during development, the immune system develops a finely honed ability to respond differentially to microorganisms that pose a threat to organismal integrity/survival vs those that are either neutral or may actually benefit the individual. When functioning appropriately, cells of the innate immune system (eg, macrophages, dendritic cells) respond to pathogens with activation of innate immune mechanisms, leading to the production of inflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-a). In addition to having pathogen-killing properties themselves, mediators of the innate immune response aid in the presentation of antigen to effector T cells and activation of cellular immunity. Viruses, bacteria, and protozoal pathogens elicit helper T cell type 1 (TH1) and/or TH17 responses from the cellular immune system, characterized by production of cytokines such as IL-2 and interferon γ (IFN-γ). TH2 responses, mediated by cytokines such as IL-4 and IL-5, appear to be primarily directed toward combating acute helminth infection. These responses, combined with ongoing innate immune activity, lead to intolerance of the invading microorganism and attempts to contain and rid it from the body. This type of immunological intolerance is adaptive in contexts in which the organism in question poses significant danger and can be overcome by immunological mechanisms. However, as a result of reduced immunoregulatory activity in the modern world, due in part to loss of contact with the “old friends,” vulnerable individuals may display inappropriate immune intolerance to an array of nonthreatening or actually beneficial factors in the self or environment, resulting in autoimmune and inflammatory bowel diseases when TH1 and/or TH17 responses are hyperactive and asthma and atopic conditions when TH2 responses are hyperactive. In contrast, contact with old friends favors dendritic and T cells adopting an immunoregulatory profile characterized by production of anti-inflammatory cytokines such as IL-10 and transforming growth factor β (TGF-β). These cytokines suppress TH1/TH17, TH2, and innate immune activity in an ongoing baseline fashion, but also in response to environmental adversities, such as psychosocial stress. These immunoregulatory processes lead to stress resiliency, which enhances psychosocial relationships in a positive feed-forward loop. Combined with reduced background inflammatory tone, these effects protect against autoimmune conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn disease, asthma and atopy, and major depression.

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