61 MICROBIAL “OLD FRIENDS”, IMMUNOREGULATION AND PSYCHIATRIC DISORDERS GRAHAM A.W. ROOK 1 , CHARLES L. RAISON 2 , and CHRISTOPHER A. LOWRY 3 1 Centre for Clinical Microbiology, Department of Infection, University College London (UCL), London, UK; 2 Department of Psychiatry, College of Medicine and Norton School of Family and Consumer Sciences, University of Arizona, Tucson, AZ, USA; and 3 Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO, 80309-0354, USA SUMMARY Many diseases are increasing in prevalence in urban communities in devel- oped countries. Immigrants are also at increased disease risk, particularly if they move from a poor to a wealthy country during infancy. Moreover, the prevalence of many of these conditions increases further in second-genera- tion immigrants, suggesting that exposure (or lack of exposure) to critical influences during pregnancy and infancy may play an important role in con- ferring risk for many chronic diseases common in the modern world. The diversity of diseases involved is remarkable. They include chronic inflam- matory disorders (autoimmunity, allergy and inflammatory bowel disease), many cancers, (such as prostate, colorectal and various childhood cancers) and a range of psychiatric disorders including depression, disorders precip- itated by psychosocial stressors or low socioeconomic status, and disorders with a developmental component such as schizophrenia and autism. Here we explore important parallels among the increases in these diverse types of disease. We merge the immunological explanation (hygiene, or “Old Friends” hypothesis) with psychosocial explanations, and suggest that there are underlying mechanisms, many involving the gut microbiota, that are relevant to all these disorders and that transcend the boundaries between traditional medical disciplines. INTRODUCTION Many diseases are increasing in inci- dence in developed countries. These increases tend to be greatest in urban communities. Immigrants are also es- pecially vulnerable to these diseases, particularly if they move from a poor to a wealthy country during infancy, sug- gesting that infancy provides a critical window for the influence of factors that are protective in poor countries, or det- rimental in rich ones. Remarkably, the incidence of many of these conditions increases further in second-generation immigrants, suggesting that exposure (or lack of exposure) to critical influ- ences during pregnancy may play an important role in conferring risk for many diseases common in the modern world. The most remarkable aspect of this problem is the diversity of diseases