Inflammation, Sanitation, and Consternation

Abstract

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 co-evolved 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.

Depression as sickness behavior? A test of the host defense hypothesis in a high pathogen population

“…As uniquely predicted by the host defense hypothesis, depression among Tsimane is associated with greater baseline immune activation (P1), particularly TNF-α, IL-6, and CRP. The association between depression and greater immune activation is therefore not unique to Western populations, as has been suggested previously (33, 34, 65). This finding challenges the immune dysregulation hypothesis, which posits that pre-adult priming of the immune system weakens linkages between depression in adulthood and inflammation.…”

“…Depression is often associated with immune dysregulation such as delayed mucosal wound healing (31) and reduced cellular immunity (32). The “immune dysregulation hypothesis” posits that reduced infectious microbial exposure during development in Western populations contributes to insufficient anti-inflammatory signaling, which increases baseline levels of depressogenic cytokines, promotes hyper-inflammatory responses to psychosocial or other stressors, and induces depression (33). In the Philippines, where infections are more common than in Western populations, depression is not associated with IL-6 or CRP among younger or older adults (34).…”

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health

“…The hygiene or “Old Friends” hypothesis proposes that this epidemic is due at least in part to reduced exposure to environmental microorganisms that normally prime immunoregulatory circuits and suppress inappropriate inflammation [20]. We and others have proposed that reduced exposure to these old friends in modern urban societies may increase vulnerability to neurodevelopmental disorders (including autism spectrum disorder (ASD), schizophrenia), and stress-related psychiatric disorders such as anxiety and mood disorders [21-38]. Exaggerated inflammation is emerging as an important risk factor in all of these disorders [21-38].…”

“…We and others have proposed that reduced exposure to these old friends in modern urban societies may increase vulnerability to neurodevelopmental disorders (including autism spectrum disorder (ASD), schizophrenia), and stress-related psychiatric disorders such as anxiety and mood disorders [21-38]. Exaggerated inflammation is emerging as an important risk factor in all of these disorders [21-38]. Immunoregulation, measured as a balanced expansion of effector T cell (also called helper T (Th) cell) populations and regulatory T cells (Treg), is known to be driven by microbial signals.…”

Perinatal depression—The fourth inflammatory morbidity of pregnancy?

“…Recent reviews and pooled analyses have found general immune dysregulation (Miller et al 2009) and/or positive associations between depression and various cytokines (IL-1, IL-6, and C-reactive protein (CRP) in Howren et al 2009, TNF-α and IL-6 in Dowlati et al 2010). Some researchers have speculated that the association may exist only for certain subsets of depressed people, those who have a particular sensitivity to pro-inflammatory signals (Raison et al 2010). …”