Childhood Microbial Experience

As communities undergo the transition from traditional rural life to modern urban lifestyles, the prevalence of chronic inflammatory disorders such as allergies, autoimmunity and inflammatory bowel diseases increases dramatically. It now appears that this is at least in part attributable to diminished efficiency of immunoregulation resulting from inadequate exposure to macro- and microorganisms (Old Friends). These Old Friends had to be tolerated, and they evolved methods of manipulating host immune systems, e.g. priming immunoregulatory pathways, sometimes by secreting molecules that directly expand Treg populations. Thus, they were entrusted by co-evolutionary processes with setting up immunoregulatory circuits.

Recently, these ideas have been expanded to include a subset of depressed patients who demonstrate persistently high levels of inflammatory mediators ‘at rest’ and an exaggerated cytokine response to psychosocial stressors. Such observations prompted the suggestion that some depression in rich urbanized societies is a chronic inflammatory disorder attributable to an immunoregulatory deficit. Several lines of evidence converge to support this possibility. First, prolonged administration of inflammatory mediators such as interferon-α causes a depression-like state that is treatable with selective serotonin reuptake inhibitor antidepressants. Second, the cytokine antagonist infliximab demonstrates antidepressant properties, but only in depressed individuals with evidence of increased peripheral inflammation before treatment.

The idea that depression may represent a chronic inflammatory condition in some individuals is increasingly supported by data from developed countries. But we do not yet know whether this association is a universal human attribute or an unintended consequence of modern life. While we do know that chronic inflammatory disorders are less prevalent in traditional rural societies, is this really because contact with the Old Friends has driven efficient regulation of the underlying inflammatory mechanisms? And if so, does this result in less inflammatory response to psychosocial stressors, a lower prevalence of the type of depression that is accompanied by increased biomarkers of inflammation, or both?

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