Evolutionary Aspects of Diverse Microbial Exposures and Mental Health: Focus on "Old Friends" and Stress Resilience

Abstract

The prevalence of inflammatory disease conditions, including allergies, asthma, and autoimmune disorders, increased during the latter half of the twentieth century, as societies transitioned from rural to urban lifestyles. A number of hypotheses have been put forward to explain the increasing prevalence of inflammatory disease in modern urban societies, including the hygiene hypothesis and the "Old Friends" hypothesis. In 2008, Rook and Lowry proposed, based on the evidence that increased inflammation was a risk factor for stress-related psychiatric disorders, that the hygiene hypothesis or "Old Friends" hypothesis may be relevant to psychiatric disorders. Since then, it has become more clear that chronic low-grade inflammation is a risk factor for stress-related psychiatric disorders, including anxiety disorders, mood disorders, and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD). Evidence now indicates that persons raised in modern urban environments without daily contact with pets, relative to persons raised in rural environments in proximity to farm animals, respond with greater systemic inflammation to psychosocial stress. Here we consider the possibility that increased inflammation in persons living in modern urban environments is due to a failure of immunoregulation, i.e., a balanced expression of regulatory and effector T cells, which is known to be dependent on microbial signals. We highlight evidence that microbial signals that can drive immunoregulation arise from phylogenetically diverse taxa but are strain specific. Finally, we highlight Mycobacterium vaccae NCTC 11659, a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, as a case study of how single strains of bacteria might be used in a psychoneuroimmunologic approach for prevention and treatment of stress-related psychiatric disorders.

Keywords: Anxiety; Darwinian medicine; Depression; Gut-brain axis; Hygiene hypothesis; Microbiome; Microbiota; Microbiota-gut-brain axis; Old friends; Posttraumatic stress disorder.

Fig. 1

Risk factors for stress-related psychiatric disorders include: (1) genetic predisposition; and (2) environmental influences, including adverse childhood experiences (ACEs), and exposures to diverse microbial inputs. Microbial inputs can be either proinflammatory or anti-inflammatory/immunoregulatory (i.e., resulting in a balanced expression of regulatory T cells (Treg) and effector T cells). A failure of immunoregulation can lead to chronic low-grade inflammation and increased risk of stress-related psychiatric disorders. Figure created with biorender.com

Fig. 2

Potential sources of the three categories of “Old Friends” and how they interact with the immune system to induce anti-inflammatory and immunoregulatory effects. The three categories of “Old Friends” are: (1) harmless environmental microorganisms found in mud, untreated water, and fermenting vegetable material that have been depleted during the transition from a rural to an urban lifestyle; (2) organisms that form part of the co-evolved human microbiota (including commensal microorganisms); and (3) “Old Infections,” i.e., infections present in early man that usually do not sterilize or kill the host and that have also been depleted since urbanization. (A) The soil in this diagram depicts a diverse set of microorganisms that live within it, an environment that is rare to find in an urban environment compared to a rural one, thus depicting the first category of “Old Friends.” Here, a person harvesting lettuce they have grown is agitating the soil enough to form soil particulates that they eventually breathe in, exposing themselves to “Old Friends.” (B) One broad subset of soil microbes, Actinobacteria, are commonly found in the upper airway, depicted by mycobacteria from the genus Mycobacterium being inhaled into the nasal cavity (Macovei et al. 2015; Kim et al. 2022). Dendritic cells “sample” the contents of the nasal lumen by extending pseudopods that allow the cell to phagocytize a bacterium. The dendritic cell will then digest it and CD103⁺, CCR7⁺ dendritic cells migrate to a nearby lymph node via a lymphatic vessel to present processed antigens of the bacterium to lymphocytes. (C) Dendritic cell sampling is a common theme of the innate immune system – in the lumen of the small intestine, home to part of the gut microbiome, dendritic cells undergo a similar process of phagocytizing microorganisms in the lumen, digesting them, and ultimately presenting the processed antigens to lymphocytes. Unlike in the upper airway, dendritic cells in the small intestine mostly sample microorganisms that form part of the co-evolved human microbiota – the second category of “Old Friends.” The commensal microbes in the small intestine are especially influenced by whether a person was raised in an urban/rural environment as well as diet. (D) Animals that humans are in close contact with, such as dogs, can also influence the composition of the human microbiota. Commensal microbes from a dog’s skin microbiome can be transferred to a person’s skin, where they can colonize to form part of the person’s skin microbiome (Song et al. 2013); further, dogs can expose their owners to “Old Friends” by bringing microbes found in mud and untreated water into the house. (E) The last category of “Old Friends” is depicted by Helicobacter pylori infecting the epithelial cells of the stomach. Unlike a regular infection that produces a robust inflammatory response, if H. pylori is tolerated by the dendritic cells and lymphocytes of the immune system, then an anti-inflammatory and immunoregulatory response (i.e., characterized by a balanced expression of regulatory and effector T cells) arises instead (Arnold et al. 2012; Lundgren et al. 2005). Abbreviations: DC, dendritic cell; IL, interleukin; TGF-β, transforming growth factor beta; Treg, regulatory T cell. Not to scale. Figure created with biorender.com

Fig. 3

A dendritic cell transports a phagocytized “Old Friend” to a lymph node and presents it to naïve T cells, resulting in differentiation of naïve T cells into regulatory T cells. (A) A mature CD103⁺, CCR7⁺ dendritic cell migrates to a lymph node via an afferent lymph vessel. An “Old Friend” is bound to TLR2 and is ultimately phagocytized and bound to MHC II for presentation to a lymphocyte. (B) Activation of a naïve T cell in the presence of IL-10, TGF-β, and IL-18 secreted from a dendritic cell results in differentiation of the naïve T cell to a FoxP3⁺ regulatory T cell. (C) A FoxP3⁺ regulatory T cell migrates from the lymph node to tissue via an efferent lymph vessel. Abbreviations: CCR, C-C chemokine receptor; CD, cluster of differentiation; IL, interleukin; MHC, major histocompatibility complex; TCR, T cell receptor; TGF-β, transforming growth factor beta; TLR, toll-like receptor; Treg, regulatory T cell. Not to scale. Figure created with biorender.com