Inflammation as the Common Pathophysiology Linking Stress, Mental Illness, Autoimmunity and Chronic Disease: Implications for Public Health Policy

Genetics, epigenetics, infection, stress and trauma predispose individuals to systemic chronic inflammation that contributes to mental illness, autoimmune conditions, and chronic disease. This paper explores the interplay of these issues and their serious health consequences. While modern medicine has made significant advances in disease care, it appears that lifestyle intervention, early childhood intervention, and socioeconomic investment and have the potential to make an even greater impact on the mental and physical well-being of the population.

PNI: Psycho Neuro Immunology; SNS: Sympathetic Nervous System; HPA: Hypothalamic-Pituitary-Adrenal; PNEI: Psycho-Neuro-Endocrine-Immunology; NF-κB: Nuclear Factor-Kappa B; IL: Interleukin; TNF: Tumor Necrosis Factor; GCs: Glucocorticoids; PGE2: Prostaglandin E2; CRP: C Reactive Protein; NMDA: N-Methyl-D-Aspartate; PANDAS: Pediatric Autoimmune Neuropsychiatric Disease Associated with Streptococcal Infection; PANS: Pediatric Acute-onset Neuropsychiatric Syndrome; OCD: Obsessive Compulsive Disorder; PTSD: Post-Traumatic Stress Disorder; ACE: Adult Childhood Experiences; CDC: Centers for Disease Control And Prevention; SLE: Systemic Lupus Erythematous; IBD: Inflammatory Bowel Disease; RA: Rheumatoid Arthritis; AD: Alzheimer’s Disease; Aβ: b-Amyloid; APA: American Psychological Association

1975, Robert Ader and Nicholas Cohen at the University of Rochester demonstrated a Pavlovian response in rats initially fed saccharin-flavored water and the drug cyclophosphamide, which suppressed antibody production. When the conditioned rats were subsequently fed saccharin-flavored water without cyclophosphamide, they again exhibited immune suppression. The investigators referred to this observed connection between the brain and immune system as Psycho Neuro Immunology (PNI) [1].

Ader and Cohen’s vivid demonstration of the mind-body connection refuted the mind-body dualism proposed by René Descartes, who in the 17th century contended that mental phenomena are non-physical, and therefore the mind and body are separate and distinct [2]. Since Ader and Cohen’s work in 1975, there has been a wealth of data further demonstrating the relationship of thoughts, emotions and physiology.

The connection between mind and body has been elaborated in studies exploring the cross-talk connectivity of the nervous, immune and endocrine systems. For example, stress responses leading to activation of the Sympathetic Nervous System (SNS) and Hypothalamic-Pituitary-Adrenal (HPA) axis resulting in the release of catecholamines and the fight or flight response has been shown to lead to the release of glucocorticoids that suppress immune function and pro-inflammatory cytokines which lead to inflammation [3,4]. In 2011, Pittman described this multidirectional cross-talk as “A neuro-endocrine-immune symphony [5]. This concept, that psychological stress is inextricably linked to neuroendocrine and immune responses, is the basis of the scientific field of Psycho-Neuro-Endocrine-Immunology (PNEI) [6].

The negative impact of chronic stress on the physical body has been appreciated for decades, particularly in patients with hypertension, cardiovascular disease, musculoskeletal pain syndromes, digestive issues, headaches and even cancer [7]. The common pathophysiologic pathway of these chronic conditions is the capacity of stress to cause inflammation.7 However, less attention has been given to the impact of physiological factors associated with physical illness on mental health. As previously illustrated, dysregulation of the immune system is invariably associated with disruption of homeostasis in nervous and endocrine function. This review will focus on the immunological aberrations associated with increasing “allostatic load,” a term which refers to the long-term dysregulation of the processes involved in the stress response, or “the cumulative burden of chronic stress” [8]. In particular, it will highlight the role of inflammation in the interplay of psychological stress and dysfunction, susceptibility to autoimmune disorders, and chronic illness. See figure 1 for a schematic of these connections.

A systematic literature search was conducted on PubMed employing a combination of the term “inflammation” and the controlled vocabulary terms "genetics," "epigenetics," "adverse childhood experiences," "stress," "trauma," "post-traumatic stress disorder," "mental illness," "autoimmune illness," and "chronic disease." Human studies and those published within the last 10 years were prioritized. Relevant articles were further assessed through full-text analysis, and additional relevant studies identified through manual searches of the references cited in selected articles. An additional Google search was conducted for the conclusion section utilizing the vocabulary terms “socioeconomic issues” and “early childhood intervention” linked with “mental and physical health outcomes,” which was then filtered to include relevant scholarly articles.

Stress, inflammation and mental health disorders

Emotional and mental stress contributing to anxiety and depression have traditionally been considered psychological issues, and viewed as distinct from maladaptive physiological responses. However, accumulating medical research has documented the role of neuroinflammation in the pathogenesis of these syndromes.

Stress has been defined as “a state of threatened homeostasis provoked by a psychological, environmental, or physiological stressor” [7]. Once the threat leading to an acute stress has passed, an individual can return to homeostasis. In an otherwise healthy individual, short-lived stress activates immune function and is anti-inflammatory. However, the same processes that allowed an individual to respond to acute stress can become maladaptive in the face of chronic stress, which erodes resilience [8].

Chronic psychosocial stress has a profound impact on various physiological systems, including suppression of immune function with activation of inflammation. Stress increases the production of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor-Alpha (TNF-α), and activates Nuclear Factor-Kappa B (NF-κB), which is required for maximal transcription of these cytokines [9-13]. While Glucocorticoids (GCs) released during the stress response are normally anti-inflammatory, in the presence of cytokine activation they can become pro-inflammatory owing to a number of factors including increased production of Prostaglandin E2 (PGE2), amplification of inflammasome NLRP3 activity, and decreased GC-receptor levels [7]. In turn, inflammatory mediators impact the activity of neurotransmitters and neuroendocrine hormones as well as brain structures and function, thereby influencing emotional state, behavioral activity and cognitive function [11,12].

The association of depression with inflammation is well documented. Kohler CA, et al. [14] performed a meta-analysis of 82 studies that compared cytokine profiles in 3212 people diagnosed with Major Depressive Disorder (MDD) with 2798 healthy controls. They found elevated levels of IL-6, IL-10, TNF-α and other cytokines in the depressed cohorts relative to controls.

While depression is the most common neuropsychiatric disorder studied in this context, there is abundant documentation that other mental health disorders are also associated with increased inflammation: anxiety disorders (elevated levels of TNF-α, IL-6, IL-1ß, and C-Reactive Protein [CRP]) [15], bipolar disorder (elevated levels of TNF-α, IL-6, and IL-1ß) [16] and psychosis (elevated levels of IL-6, IL-10, and CRP) [17] are all associated with significant inflammation.

While stress is a potent driver of inflammation, the inverse is also true; clinically there are multiple lines of evidence that neuroinflammation is a significant cause of mental health disorders:

• Several studies have documented that high blood CRP levels in people with depression are associated with more severe symptoms and worse response to treatment [18].
• Non-steroidal anti-inflammatory drugs have been beneficial in patients with depression, anxiety, bipolar disorder and schizophrenia [19].
• Patients with autoimmune illnesses can present with treatment-resistant depression that responds to immunosuppressive therapy [20].
• Children and adolescents with Pediatric Autoimmune Neuropsychiatric Disease Associated with Streptococcal Infection/Pediatric Acute-onset Neuropsychiatric Syndrome (PANDAS/PANS) exhibit mood and behavioral changes associated with anti-neuronal antibodies and neuroinflammation; symptoms generated by cross-reactivity to microbial pathogens include Obsessive Compulsive Disorder (OCD), anorexia, anxiety with panic attacks, intrusive thoughts, irritability, rage, behavioral regression, tics, and chorea [21].
• Eating disorders including anorexia nervosa and bulimia have been associated with infections and autoimmunity [22,23].
• A nationwide study in Denmark found a strong association in children and adolescents who had been treated for infections with the subsequent incidence of mental health disorders [24]. Bransfield, et al. [25] have published an extensive list of microbes associated with mental illness.
• Patients with neuroborreliosis can manifest a wide spectrum of neuropsychiatric disorders caused by autoimmune reactivity to microbes outside the central nervous system [26].
• N-Methyl-D-Aspartate (NMDA)-receptor encephalitis is a condition in which antibody-mediated brain inflammation can generate mental health issues, including psychosis [27].

The physiology of Post-Traumatic Stress Disorder (PTSD) iconically demonstrates the maladaptive stress response leading to a complex disruption of the PNEI system, resulting in chronic inflammation and severe neuropsychiatric symptoms. PTSD is a disorder that “can occur in people who have experienced or witnessed traumatic events or threatened with death, sexual violence, or serious injury” [28]. In patients with PTSD, psychological trauma leads to increased neural connectivity during emotional processing, particularly involving enhanced communication between the amygdala (which detects threats), insula (which perceives awareness of the physical body and emotions), and hippocampus (which stores memory) [29]. Neuroendocrine changes associated with PTSD include activation of the SNS and HPA axis with consequent dysregulation of catecholamines, cortisol, and neurotransmitters including serotonin and dopamine [28,30,31].

Significantly, PTSD is associated with serious immune system dysregulation. Patients with PTSD exhibit an increase in pro-inflammatory cytokines with elevations in IL-1β, IL-6, IL-17, TNF-α, and CRP, and a decrease in anti-inflammatory cytokines including IL-4 and IL-10 [28,30,31]. Neuroinflammation is theorized as likely to be a key factor in the ongoing cycle of PTSD symptoms.

It is noteworthy that inflammation may be a risk factor for the development of PTSD. For example, a marine resiliency study found that baseline plasma CRP levels were a highly predictable indicator of post-deployment symptoms consistent with PTSD [32]. A study of patients who experienced orthopedic injuries found that those who exhibited higher levels of the pro-inflammatory cytokines IL-6 and IL-8 and lower levels of the anti-inflammatory cytokine TGF-β in the acute stage of injury were more likely to develop post-traumatic symptoms [33].

From a teleologic perspective, it follows that a nervous system response to threat resulting in hypervigilance may also manifest in an immunological response to threat, i.e., inflammation. It appears that stress/trauma begets inflammation, and inflammation begets mental health disorders and an increased the risk of developing PTSD.

Adverse childhood experiences, inflammation and chronic illness

The Adverse Childhood Experiences (ACE) study is an ongoing research project being conducted by the Centers for Disease Control and Prevention (CDC) and Kaiser Permanente. It is focused on the effect of traumatic childhood events on adult illness. The investigators surveyed 17,421 adult patients regarding their experiences of childhood abuse, neglect and family dysfunction, and correlated these histories with adult health issues. Each patient was given a score based on the reported history of the ten ACE categories [34]:

• Physical abuse
• Sexual abuse
• Emotional abuse
• Physical neglect
• Emotional neglect
• Parental separation/divorce
• Growing up in a household where there was substance abuse,
• Growing up in a household where there was violence perpetrated on a mother or step-mother
• Growing up in a household where there was mental illness
• Growing up in a household where there was incarceration of a family member.

It is no surprise that adults who experienced challenging childhoods with an ACE score of four or more were found to have a significantly higher incidence of mental health disorders including anxiety, depression, alcoholism, drug abuse and suicide attempts [35]. More notably, there was a graded relationship between ACE score and physical illness: an ACE score of four or more is associated with a significantly increased risk of heart disease, stroke, cancer, lung disease, diabetes, obesity, chronic lung disease and liver disease, as well as premature mortality [34,36-41].

This is not the only research to highlight this association. Danese, et al. [42] demonstrated that childhood maltreatment (ages 3-11) is a predictor of adult inflammation. Indices of childhood maltreatment included evidence of maternal rejection, harsh discipline, disruptive caregiver changes, physical abuse, and sexual abuse. After controlling for co-occurring risk factors including low birth weight, socioeconomic disadvantage, and low IQ, they found a significant correlation of childhood maltreatment with adult inflammation as measured by CRP.

It follows that childhood traumatic stress dramatically increases the risk of autoimmune disease. Dube, et al. [43] retrospectively studied 15,357 people who took part in the original ACE study and correlated the association of the ACE score with hospitalization for 21 autoimmune illnesses. In comparison to individuals with a zero ACE score, those with a score of two or greater were 70-100 percent more likely to be hospitalized, with this range dependent on the specific class of autoimmune illness.

It appears that stressful childhood experiences associated with a paucity of safety and stability render a physiologic environment that increases the risk of neuropsychiatric illness, autoimmunity and chronic disease.

Autoimmunity and mental illness

Autoimmune diseases are a well-documented cause of neuropsychiatric illness. Patients with Sjogren’s syndrome, [44] Systemic Lupus Erythematosus (SLE) [45], scleroderma [46], Inflammatory Bowel Disease (IBD) [47], Rheumatoid Arthritis (RA) [48], Multiple Sclerosis (MS) [49], and Graves’ disease [50] suffer from mental health disorders in significantly greater numbers than the general population. The most common disorders reported are major depressive disorder and anxiety syndromes, but there is also an increased incidence of bipolar disorder [51] and psychosis [52].

The converse has also been shown: epidemiologic studies have documented that patients with depression have a significantly higher risk of developing an autoimmune illness including RA, IBD, and SLE [53-56]. However, while Chan, et al. [18] documented an association between treatment-resistant depression and autoimmune illness in a population study, the same association did not hold in patients who responded to antidepressants [57]. Many studies have documented that high blood CRP levels in people with depression are associated with more severe symptoms and worse response to treatment. Treatment-resistant depression may therefore be a marker for neuroinflammation, with an increased risk of autoimmune illness.

While it is reasonable that individuals suffering from a chronic illness that causes pain syndromes, fatigue and disability will experience anxiety and reactive depression, the high prevalence of psychiatric comorbidity suggests additional pathophysiology. In some cases, mental health issues may be the presenting complaint in an individual subsequently diagnosed with an autoimmune illness [20,53]. Ravan JR, et al. [20] described five patients diagnosed with autoimmune illnesses sjögrens syndrome, scleroderma, SLE and sarcoidosis—all of whom presented with depression and were treated with antidepressants without relief before the subsequent diagnosis of an autoimmune disorder. In four of the five subjects, the mood symptoms predated physical signs and symptoms suggestive of systemic autoimmunity. Significantly, treatment with immunosuppressive agents resulted in remission of depression, and each was able to discontinue her antidepressant medication. The sequence of events suggests that autoimmune neuroinflammation resulting in a mood disorder was an early symptom of an autoimmune illness.

Roberts, et al. [53] performed a prospective longitudinal study following 194,483 females over 20 years and found a significantly increased risk of SLE in those with a prior history of depression. While it is possible that depression in these patients was in fact an early sign of nervous system SLE, the lag time between the diagnosis of depression and the onset of symptoms of SLE was as much as four years. This extended lag time suggests that neuroinflammation associated with depression may be a risk factor for the development of a systemic autoimmune disorder. Alternatively, an autoimmune process, perhaps secondary to stress issues in a genetically prone individual, may have resulted in neuroinflammation with depression that later manifested in a systemic autoimmune illness, SLE.

Stress, inflammation and chronic disease

Heart disease continues to be the leading cause of death in the United States [58]. The pathogenesis of atherosclerosis involves endothelial dysfunction induced by inflammation leading to the subendothelial accumulation of lipoproteins and platelet activation [59]. Mounting evidence suggests that statins contribute significantly to the decrease in cardiac morbidity and mortality beyond lowering cholesterol by mitigating inflammatory processes within the vascular endothelium and stabilizing atherosclerotic plaques, thus reducing the risk of adverse cardiovascular events [60]. A corollary of research on the use of statin drugs in cardiac patients is that patients on statins were less likely to develop depression than a control population who were not on statins [61,62]. In fact, multiple studies have documented the increased benefit of adding a statin drug to an antidepressant in the treatment of major depression [63-66].

Cancer is the second leading cause of death in the United States [67]. Ninety percent of cancers are related to environmental factors, e.g., tobacco smoking, toxins, alcohol, dietary issues, infections, and stress [68,69]. The common link these factors share is their capacity to generate inflammation, which “…is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration” [69]. The NF-κB pathway plays a central role in inflammation-related cancer, regulating the expression of genes involved in the generation of pro-inflammatory cytokines, cell survival and proliferation. Persistent NF-κB activation can promote cell transformation and resistance to apoptosis [70].

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that affects 10-30% of adults over the age of 65 [71]. Abundant research has targeted deposition of β-amyloid (Aβ) plaques leading to the accumulation of abnormal tau proteins in neurofibrillary tangles. It has been proposed that these pathological changes account for the neuronal dysfunction that causes clinical dementia [72,73]. However, therapies directed at reducing Aβ or phosphorylated tau proteins have not been successful [73.] More recent research links peripheral inflammation with the pathogenesis as well as the progression of AD [72-76]. A review article by Kinney, et al. [72] titled “Inflammation as a Central Mechanism of Alzheimer’s Disease” details the role of macrophages and other immune cells in promoting amyloid and tau pathology.

In addition to heart disease, cancer and AD, other leading causes of morbidity and mortality worldwide include diabetes mellitus, cerebrovascular disease, autoimmune illness, chronic infections, chronic kidney disease, chronic pulmonary disorders, and chronic liver disease. These conditions are all associated with chronic systemic inflammation [77-80]. The pathogenesis of chronic disease is clearly multifactorial, and common risk factors in their pathogenesis include genetics, epigenetics, diet and nutritional status, obesity, infections, toxin exposure, level of physical activity, and stress related issues. All of these factors impact allostatic load and result in dysregulation of homeostasis with the promotion of chronic systemic inflammation.

It is well established that genetic variations can play a crucial role in an individual’s risk of developing inflammation and autoimmunity [81]. However, there are other factors that contribute to susceptibility. Diet plays a fundamental role in modulating the inflammatory response [82,83]; the impact of diet on the gut microbiome may be singularly important in this regard [84,85]. Obesity is a source of chronic inflammation, and has been linked to heart disease and diabetes as well as several cancers [86,87]. Regular exercise has anti-inflammatory effects, reduces adipose tissue inflammation, enhances the production of anti-inflammatory cytokines and improves insulin sensitivity [88,89]. Exposure to environmental toxins including air pollutants, heavy metals, pesticides and other xenobiotic agents is also associated with chronic inflammation [90,91]. Infectious microbes that are able to resist host defenses can persist in tissues and result in autoimmunity and chronic inflammation [24,25,77]. The role of stress and trauma as drivers of inflammation resulting in adult illnesses has previously been elucidated.

The impact of these risk factors is compounded by their epigenetic transmission, in which gene expression is changed from one generation to the next without a change in the underlying DNA [92-100]. A wealth of data is consistent with epigenetic regulation as an essential driver of inflammation leading to chronic illness including heart disease [101], autoimmune diseases [102], neurodegenerative disorders [103], diabetes [104], obesity [104], and cancers [105]. This includes the epigenetic transmission of stress from adverse childhood experiences to chronic stress in adulthood [106,107]. A review paper by Yehuda and Lehrner on intergenerational transmission of trauma and the role of epigenetic mechanisms states, “There is now converging evidence supporting the idea that offspring are affected by parental trauma exposures occurring before their birth, and possibly even prior to their conception. On the simplest level, the concept of intergenerational trauma acknowledges that exposure to extremely adverse events impacts individuals to such a great extent that their offspring find themselves grappling with their parents’ post traumatic state” [107].

This paper explores the intricate interplay between genetics, epigenetics, stress, trauma, inflammation, mental illness, autoimmunity, and the development of chronic disease. It is increasingly evident that individuals’ genetic makeup can significantly influence their susceptibility to certain conditions; however, this predisposition is modulated by epigenetic mechanisms that respond to environmental cues, including stress and trauma. Chronic stress and traumatic experiences, which themselves can induce epigenetic modifications, potentially lead to dysregulation of immune responses. Subsequently, chronic inflammation can, in turn, trigger mental illness, exacerbate autoimmunity, and lead to chronic disease. The implications for health care policy are far-reaching and transformative. Given the personal and cultural attitudinal factors that impact these issues, it is clear that integrating proactive policies into public health initiatives and medical practice has profound potential to benefit our population’s mental and physical well-being.

This article alludes to the potential role of lifestyle modifications, including exercise, diet, nutrition, and management of toxin exposure in mitigating inflammation and thereby reducing the risks of both mental and physical illnesses. Regular physical activity has been consistently shown to have anti-inflammatory effects [108]. Dietary choices that avoid refined carbohydrates, red meat and processed meats and are rich in anti-inflammatory nutrients such as omega-3 fatty acids, antioxidants, and fiber will also contribute to the attenuation of inflammation [109]. Likewise, managing toxin exposure, including minimizing exposure to environmental pollutants, will contribute to reducing the inflammatory burden on the body [110].

Recognizing the profound impact of stress on both mental and physical health, the imperative to mitigate stress emerges as a pivotal strategy in reducing the risk of inflammation and associated illnesses. While it is not in the purview of this report to analyze the myriad sources of stress in the U.S. population, it is important to note that the numbers of people describing themselves as stressed have increased substantially in the past two decades [111-113].

The American Psychological Association (APA) performs an annual survey of “Stress in America”. In 2010, the APA survey reported that “Chronic stress—stress that interferes with your ability to function normally over an extended period—is becoming a public health crisis” [111]. Those numbers increased substantially by 2019 [112], but since the pandemic they spiked again: the 2022 APA survey “shows a battered American psyche, facing a barrage of external stressors that are mostly beyond personal control…We are facing a mental health crisis that could yield serious health and social consequences for years to come” [113]. Just one example: 75% of adults agree that violence and crime are a significant source of stress in their lives [114].

The experience of distress due to factors beyond individual control has been exacerbated by COVID-19 pandemic-enforced loneliness, escalating an issue that was already endemic in the U.S. [115]. In May 2023, Dr. Vivek Murthy, the Surgeon General of the United States, released a report on “Our Epidemic of Loneliness and Isolation” [116]. In his report, Dr. Murthy states that 50% of Americans experience loneliness, which “… is associated with a greater risk of cardiovascular disease, dementia, stroke, depression, anxiety, and premature death.” This is consistent with loneliness as a source of stress-induced inflammation. Van Bogart K, et al. [117] found higher levels of CRP in older subjects who met criteria for loneliness compared to a matched control population. Koyama Y, et al. [118] demonstrated similar results in a study investigating social isolation and loneliness and chronic systemic inflammation during the COVID-19 pandemic in Japan.

It is increasingly clear that stress itself is an epidemic with abundant and serious mental and physical health consequences. Numerous studies have demonstrated that stress-reduction techniques such as mindfulness, meditation and exercise can modulate stress responses and thereby curtail the risk of inflammation-related afflictions [119,120]. It is also clear that loneliness itself is a significant stress and threat to well-being, and healthy social connections need to be encouraged and supported. In recognition of this health threat, Great Britain’s Prime Minister Theresa May appointed a Minister for Loneliness with a broad mandate to initiate a national multipronged strategy to address and combat the epidemic of loneliness in her country; this occurred in 2018, notably in the pre-pandemic era [121].

In 2015, Case and Deaton described the increasing incidence of ‘deaths of despair’ attributable to suicide, drug overdose and alcohol-related liver disease [122]. These tragedies have increased progressively over two decades, and loneliness is likely a significant contributor. Deaths of despair clearly mark a failure of our collective society and our medical-health care system to support and emphasize healthy life choices with community-based social networks. The peak life expectancy in the United States was reached in 2014 (78.9 years), and has declined since [123].

It is clear that a serious source of stress often begins in childhood. Implementing targeted socioeconomic policies and proactive social work interventions to address childhood trauma holds the potential for transformative improvements in both mental and physical health outcomes. By focusing on creating supportive environments, with access to quality education and stable housing, socioeconomic policies can mitigate adverse childhood experiences and reduce the prevalence of trauma. Social work interventions that provide early identification, counseling, and support for at-risk families can further break the cycle of trauma [124-127].

Dramatic improvements in the quality of lives as well as in life expectancy can be achieved with a nationwide emphasis on healthy lifestyle issues, social support networks, and stress-reduction techniques combined with socioeconomic policies that improve wealth distribution and address early childhood intervention. In general, children growing up in low-income families have poorer health outcomes as adults [128]. The upfront investment, although requiring significant resources, would ultimately yield substantial returns by promoting a healthier and more resilient population and fostering a virtuous cycle of improved mental and physical health outcomes.

Future research that will help elucidate improved health benefits from lifestyle changes and social policy can focus on the populations in countries such as Denmark and the Netherlands where the healthcare of an entire nation’s population registry computer base. In the United States there are towns and cities giving out monthly payments and the short term response is promising; if this financial support yields long term health benefits it has significant implications in economic policy. Similarly, studies that can document the long term health benefits of early childhood interventions of at risk children would be helpful in determining social policy.

While the bulk of the proposed recommendations lie in the fields of social policy and lifestyle education, modern medicine can continue its trajectory of progress. The emerging field of epigenetics offers a promising avenue for enhancing health outcomes by potentially reversing epigenetic changes. Epigenetic modifications, such as DNA methylation, histone acetylation, and non-coding RNA regulation play a pivotal role in regulating gene expression patterns and are influenced by environmental factors, lifestyle choices, and aging processes [129].

Finally, the pursuit of novel anti-inflammatory treatments that effectively target systemic inflammation including neuroinflammation without compromising immune function is of paramount importance. Traditional anti-inflammatory therapies generally entail immune-suppressive effects that may compromise the body's defense mechanisms. The evidence in this review demonstrates that an intact immune response is required for achieving overall PNEI health, thereby highlighting the need for precision in therapeutic interventions. Developing interventions that specifically modulate inflammatory pathways associated with disease pathology while preserving immune responses against infections and other threats is a critical challenge.

The author reports no conflicts of interest in this work.

The author wishes to thank Hilary Schlinger and Robert Bransfield for their editorial suggestions and Emily Hagny-Downs for the schematic in figure 1.

Figure 1: The central role of inflammation in the genesis of mental and physical illness.

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