The Evolution & Medicine Review

By Graham Rook

Chronic inflammatory disorders (allergies, autoimmunity, IBD) have increased dramatically in developed countries. But depression is strongly associated with these disorders and should therefore be increasing in parallel. While there is no universal agreement, there is evidence that rates of depression are indeed increasing (discussed and referenced in Raison et al., 2010). Moreover, moving from the developing world to the U.S. increases the risk. 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 that are equivalent to those of the U.S. population at large, suggesting that it is the American lifestyle rather than acculturation shock that accounts for the increase (Vega et al., 2004). Interestingly there is also a significantly higher risk of mood and anxiety disorders in urban populations, compared to rural ones (Peen et al., 2010).

These findings all imply an environmental trigger that is more prevalent in developed and urban situations than in undeveloped and rural ones. But what is this environmental trigger? Is it, as most workers in the field of psychiatry will assume, the different psychosocial environment, or is it something quite different…..the microbial environment?

The “Old Friends” hypothesis is an update of the hygiene hypothesis, which has been the subject of a previous post to this forum. The Old Friends hypothesis suggests that many micro- and macroorganisms with which mammals co-evolved (helminths, organisms associated with feces, mud and animals, and microbiota) have been “entrusted” with a role as inducers of appropriate levels of background immunoregulation (Rook, 2010). They took on this role because they needed to be tolerated by the immune system. Indeed many of them cause dendritic cells to drive regulatory T cells, while others secrete molecules that directly drive proliferation of regulatory T cells (Atarashi et al., 2011; Geuking et al., 2011; Grainger et al., 2010; Hang et al., 2010; Round et al., 2011). Removal of these organisms from the modern urban environment, together with massive changes to the microbiota secondary to the altered microbial inputs, dietary changes and antibiotics, has led to immunoregulatory defects. These defects lead to increased susceptibility to chronic inflammatory disorders in a genetic subset of individuals, and to persistently raised circulating proinflammatory mediators without apparent inflammatory disorders in another subset. But both of these states will lead to increased susceptibility to depression which is commonly associated with raised levels of these inflammatory mediators, whether an inflammatory disorder is clinically apparent or not. Moreover, depression that can be treated with standard anti-depressant drugs can be caused by the therapeutic administration of IL-2 or IFN-α (discussed and referenced in Raison et al., 2010).

A recent functional magnetic resonance imaging (fMRI) study compared the effects of an experimental social stressor on individuals brought up in urban versus rural environments (Lederbogen et al., 2011). Social stress induced quite different fMRI responses in the two groups. The authors attributed this to 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 (Radon et al., 2007; Riedler et al., 2001). The authors of the fMRI study did not measure levels of circulating proinflammatory cytokines in the two populations (Lederbogen et al., 2011). The “Old Friends” view of the data would postulate higher levels in the subjects who had urban upbringings.

It is inevitable that workers in the field of psychiatry and brain function will tend to assume that only psychosocial factors are relevant, but I suggest that in this case the microbial environment is at least as strong a candidate.


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Geuking, M.B., Cahenzli, J., Lawson, M.A., Ng, D.C., Slack, E., Hapfelmeier, S., McCoy, K.D., Macpherson, A.J., 2011. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794-806.
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Hang, L., Setiawan, T., Blum, A.M., Urban, J., Stoyanoff, K., Arihiro, S., Reinecker, H.C., Weinstock, J.V., 2010. Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. J Immunol 185, 3184-3189.
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Round, J.L., Lee, S.M., Li, J., Tran, G., Jabri, B., Chatila, T.A., Mazmanian, S.K., 2011. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974-977.
Vega, W.A., Sribney, W.M., Aguilar-Gaxiola, S., Kolody, B., 2004. 12-month prevalence of DSM-III-R psychiatric disorders among Mexican Americans: nativity, social assimilation, and age determinants. J Nerv Ment Dis 192, 532-541.