It is the main aim of this clinical project to investigate the cellular, molecular and microbiome-related mechanisms underlying the increased prevalence of stress-associated mental as well as physical disorders in individuals raised in an urban (URBANs) versus rural (RURALs) environment.

Background: Urbanization is on the rise,(1) and stress-associated somatic and mental disorders are more prevalent in urban vs. rural areas.(2-4) Many of these disorders are accompanied by an over-reactive immune system and chronic low-grade inflammation,(5, 6) and prospective human and mechanistic animal studies strengthen the idea that an exaggerated immune (re)activity plays a causal role in their pathogenesis.(5, 7-9) Deficits in immunoregulation are thought to be in part dependent on reduced exposure, especially during early life,(10, 11) to microorganisms with which mammals co-evolved.(12) These “Old Friends” needed to be tolerated, as they were either part of host physiology (human microbiota), harmless but inevitably contaminating air, food and water (environmental microbiota), or causing severe tissue damage when attacked by the host immune system (helminthic parasites).(12) However, contact with these microorganisms that play a crucial role in setting up regulatory immune pathways is slowly but progressively diminishing in high-income countries, particularly in the concrete landscapes of urban areas.(11, 13) Noteworthy, the decline in biodiversity is currently facilitated to unprecedented levels due to dramatic changes in global climate, excessive levels of environmental pollution as well as recent COVID-19-related restrictions. Besides the declining availability of health promoting green space rich in biodiversity,(14, 15) another critical factor contributing to the diminishing contact with “Old Friends”, particularly in urban areas, seems to be the lack of regular contact with animals.(16-19) Supporting this hypothesis, dog ownership has been shown to increase microbial diversity and relative abundances of dog-associated bacterial taxa across multiple locations within the home.(20, 21)

Main findings: In a recent study (Urban vs. Rural Stress Study, URSS) we demonstrated that systemic immune activation in response to a standardized laboratory social stressor, namely the Trier Social Stress Test (TSST), is increased and prolonged in healthy male URBANs raised in the absence of daily contact with pets, relative to healthy male RURALs raised in the presence of farm animals, even though the inflammatory stress response triggering HPA axis and SNS activation were more pronounced in the latter.(22) In detail, in response to the TSST, URBANs raised in the absence of pets showed a more pronounced increase in the number of peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-6 concentrations compared with RURALs raised in the presence of farm animals. Moreover, ex vivo cultured PBMCs from URBANs raised in the presence of pets secreted more IL-6 in response to the T cell-specific mitogen concanavalin A (ConA) than respective PBMCs from RURALs raised in the presence of farm animals. In turn, anti-inflammatory IL-10 secretion was suppressed following TSST in URBANs raised in the absence of pets, suggesting immunoregulatory deficits in urban participants following social stress. Importantly, URBANs reporting absolutely no pet contact differed in their salivary microbiome composition from all other URBANs and RURALs reporting regular or at least occasional contact to farm animals or pets belonging to others households, and displayed a significantly higher TSST-induced immune activation compared to URBANs reporting at least occasional contact to pets belonging to others,(23) suggesting that the complete absence of any pet contact plays a critical role in mediating the negative consequences of urban upbringing. The other way round, having a pet may mitigate some of the decreases in exposures to diverse microbial environments and the associated immunoregulatory deficits in those living in modern urban environments and, therefore, represent a primary prevention strategy for chronic low-grade inflammation and development of any kind of stress-associated disorder linked to an (over)activated immune system. In line with this hypothesis we showed in a follow-up study (Effects of Pets on Social Stress, EPSS) that adult healthy male URBANs raised in the absence (noPETs) vs. presence (PETs) of household pets were characterized by deficits in their immunoregulatory and intestinal barrier function, which under basal conditions did not translate into a chronic low-grade inflammatory state.(24) This was different under acute psychosocial stress conditions. Exposure to the TSST resulted in a facilitated mobilization of particularly neutrophil granulocytes in noPETs vs. PETs, accompanied by an enhanced pro- and compromised anti-inflammatory systemic stress response.(24) Together, the presence of pets during urban upbringing seems to reduce the risk for developing stress-associated disorders later in life (i.e., primary prevention) by facilitating immunoregulatory and barrier functions, in turn preventing an overshooting immune activation in response to acute stressors and chronic low-grade inflammation in response to repeated/chronic stressors.

Main collaborators: Prof. Dr. Christopher Lowry (University of Colorado, Boulder, USA), Prof. Dr. Harald Gündel, Dr. Katja Weimer, Dr. Marc Jarczok, Prof. Dr. Hans Kestler, Dr. Alexander Groß, Prof. Dr. Markus Huber-Lang (Ulm University or Ulm University Medical Center, Ulm, Germany), Prof. Dr, Andreas Meyer-Lindenberg, Prof. Dr. Heike Tost (Central Institute of Mental Health, Mannheim, Germany), Prof. Nicolas Rohleder (Friedrich-Alexander-Universität, Erlangen, Germany), Prof. Dr. Graham Rook (University College London (UCL), London, United Kingdom)