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Promoting health by managing the four “M’s” of homeostasis

Published: November 15, 2023
By: B. Aldridge / College of Veterinary Medicine and Health Innovation Professor, Carle Illinois College of Medicine, University of Illinois, Urbana-Champaign, IL, USA.
Brian Aldridge (University of Illinois)
Biological health is a complex topic of discussion and is often misunderstood as existing as a binary state in terms of the presence or absence of disease. In many ways, it is useful to explain health at a population or system level as the existence of individuals in 1 of 3 states: those in a healthy condition, those with a prediseased status, and those in a diseased state. At a systems level, it is useful to understand that there is a dynamic, ever-changing flow of individuals and the population as a whole between these 3 states. We would contend that it is actually quite unusual for an individual to move directly between the healthy and diseased state, without some transition through the pre-diseased state. A useful perspective is to view each individual in a population as having a health “phenotype.” The healthy, “normal” state is that in which individuals are highly resilient to perturbation (disruptions to homeostasis). The second or intermediate state is termed the “pre-disease” state, in which individuals are unstable, sensitized to perturbation and existing at the very edge of normal function. We can view this as a reversible state and a great place to intervene to restore normal health. The “disease” state occurs when the unstable pre-disease state undergoes decline, or a downward transition to clinical deterioration. Importantly, individuals in this disease state are also somewhat stable, and can be considered as resilient and robust in their pathological state. As such this state is not readily reversible. So, what might induce or influence the transition of an individual between the healthy and pre-diseased state? We would suggest that to understand this, it is useful to appreciate the biology and dynamics of stress, or system perturbation, on the healthy state. We jokingly tell our students that “Stress is spelled C-H-A-N-G-E,” and that to understand stress we need to appreciate how an individual or population resists or responds to change. In addition, to help us design interventions that can prevent the transition of an individual from the healthy to pre-disease state, or to promote restoration of an individual from the pre-disease to healthy state, we need to understand the nature and operation of the stressors, or the drivers of change, within our systems.
There are 4 main channels of stress to the individual, the 4 “M’s”: mucosal, mental (neuroendocrine), microbial, and metabolic. The mucosal sites, such as the respiratory, gastrointestinal, urogenital, and skin surfaces are where the host directly interacts with its physicochemical and microbiological environment. Neuroendocrine stress works through special senses and is communicated and manifest through the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Metabolic stress is the response of the host to changes in water or nutrient supply, particularly in terms of energy and proteins, but also with respect to electrolytes, acid-base, vitamins, and minerals. Microbial stress involves invasion by a unique, virulent pathogen or, more commonly, emergence of a resident pathogen from perturbations of the mucosal microbiota. Now stressors, or drivers of change, can act at both the local or the systemic level. For instance, mucosal stressors act directly at the specific body surfaces described earlier, whereas neuroendocrine and metabolic stressors are, by definition, systemic. It follows that the impact of stress can be either local or systemic. For instance, physical damage of the nasal mucosa will act as a local stressor. But the involvement of the neuroendocrine and metabolic system means that the response to some stressors can involve every body system. For instance, imagine a prolonged and difficult transport journey. This would invoke neuroendocrinological responses through fear and new social interactions, mucosal responses through dehydration and microbial shifts, cardiovascular responses through dehydration, and metabolic changes through alterations in nutrient demand and availability So while the 4 major avenues of stress are distinct from each other, they are also but inter-related to, each other. Envision a thermoregulatory stressor—either heat or cold stress. This would challenge the health of an individual through all 3 portals: it could cause physicochemical or microbial changes in the respiratory tract, it could put pressure on metabolic resources of the body, and might invoke neuroendocrinological perturbation through changing physical environment. As described, the stressors to health are not only variable in nature and magnitude but are also dynamic and continuous in time. We should recognize that these challenges to health are a normal part of life, and so cannot be avoided completely. The drivers of change are all around us—they are physical, chemical, microbial, climatic, and social, so are often related to the nature and quality of the living environment. Because they are universal in life, the body is actually designed to recognize and counter these common stressors. In the normal state of health, change drivers are resisted, or countered, by normal anatomical-physiochemical processes, and so stress mechanisms and responses should not always be considered as pathological, but should be recognized as normal adaptations to normal events of change and uncertainty. The ability to resist and respond to these many drive changers are innate, but are influenced by both genetics and epigenetics in that they are both inherited and learned or developed. While it is understandable to think of stress as a single and it is important to appreciate that the effects of stress can be cumulative and formative. So, although the transition from health to the predisease state could arise from a sudden and severe incursion of change, it is as likely to develop in an individual that is exposed to repeated, low-grade, non-catastrophic physiological, neuroendocrinological, or metabolic perturbations. For instance, it has been shown that stressors actually determine the trajectory of organ development. Individuals that have experienced earlylife adversity may have long-term, detrimental immune system disturbances. Maternal diets during pregnancy can impact future neurological development and cognitive abilities, and have longterm effects on metabolic progression and inclination.
In view of the importance of change and of the stressors that drive and influence change, and our understanding that stress impacts the biological resilience and disease resistance of a host, it is important to appreciate that stress can and should be measured and influenced at both the level of input (i.e., the stressors themselves), and the level of response (i.e., the capacity of the host to resist or adapt to the stressor). This is especially important in defining our approach to managing and caring for individuals and populations, because, ultimately, resistance and adaptability to stressors determine health outcomes and therefore quality and productivity of life.
Presented at the 11th Symposium on Gut Health in Production of Food Animals in St. Louis, USA.

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Brian Aldridge
University of Illinois
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