Using Microbiome-Based Approaches to Deprogram Chronic Disorders and Extend the Healthspan following Adverse Childhood Experiences.

Adverse childhood experiences (ACEs) in early life are among the most devasting physiological and microbiological programming events that exist. During critical windows of vulnerability, these adverse experiences can significantly increase the disease and disability burdens across the lifespan. One of the early studies that utilized the term adverse childhood experience was a U.S. Centers for Disease Control and Prevention (CDC)-Kaiser Permanente study [ 7 ]. There is considerable debate about the full range of meaningful events that constitutes ACEs, and this has resulted in a general lack of standardization for studying the effects of adverse childhood experiences on future health [ 8 ]. One recent example was utilized by Lin et al. [ 9 ] in their study in China and includes the following 12 ACEs: physical abuse, emotional neglect, household substance abuse, household mental illness, domestic violence, incarcerated household member, parental separation or divorce, unsafe neighborhood, bullying, parental death, sibling death, and parental disability. Regardless of the difference in what spectrum of ACEs were included in various studies, it was clear that these ACEs, including events such as childhood trauma, readily program the child for NCDs and additional conditions such addictive behaviors [ 10 , 11 ]. Examples of ACE DOHaD-like programming of later-life NCDs include: asthma [ 12 ], obesity and diabetes [ 13 ], cardiovascular disease [ 14 ], neurobehavioral disorders [ 15 ], and cancer [ 16 ]. Furthermore, beyond the scope of this present review, ACEs can transmit elevated intergenerational risk for chronic disorders across generations [ 17 , 18 ]. The CDC developed an ACE pyramid to visually reflect the diverse outcomes of ACEs across the lifespan [ 19 ]. However, as with much of public health [ 20 ], it does not capture either the outcomes or interrelationships pertaining to the microbiome. Based on data from the most recent survey involving 25 states, the U.S. CDC estimated that approximately 61% of adults had at least one adverse childhood experience with approximately 16% reporting four or more experiences [ 21 ]. Unsurprisingly, the cost in human capital and even national economic sustainability is staggering. A recent survey of European countries estimated that the economic burden of ACEs amounted to more than 120 billion US dollars per annum for a country such as Germany and ranged up to 6% of Ukraine’s gross domestic product [ 22 ]. While an increased focus needs to be brought to bear on preventing these experiences, we have only begun to address the role of microorganisms particularly in conjunction with the mucosal immune system in both the disease state and in therapeutic applications. The present review is not intended to be a comprehensive tome covering all aspects of ACE-induced diseases. Instead, it focuses on six microimmunosome-dependent adverse outcomes: noncommunicable diseases and their comorbidities, circadian rhythm disruption, early-onset aging/shorter lifespan, predispositions to addiction, mood disorders, and sleep disorders. ACE-induced chronic disorders have often been medically treated at the level of the dysfunctional tissues or organs. Examples would be a focus on (1) the hypothalamic–pituitary–adrenal (HPA) axis for cortisol regulation, (2) the brain for mood disorders, (3) or the target tissue in which a given NCD arises (e.g., the lungs in pediatric and adult asthma). But these limited, end-result approaches can fail to restore crucial master regulations involving core cyclic rhythms, broad systems biology units, and the multiple levels of microbiome control over human systems biology (e.g., the microimmunosome, the gut–immune–brain axis). The following sections are designed to provide a broader view of potential ACE-driven programming and deprogramming beginning with the master controller of premature aging of both human systems biology and the microbiome.

ACE-induced programming has a broad range of adverse outcomes that appear across childhood and in the aging adult. Table 1 [ 7 , 9 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ] illustrates the extensive impact that these experiences in isolation or combination can have across multiple different systems biology units. It is emphasized that while these diseases and disorders emerge in different organs and physiological systems, their dysfunctional origins are either controlled by or significantly influenced by the genes, metabolic activity, signaling, and epigenetics regulation from the human microbiome. With this in mind, effective approaches to correcting and rebalancing the early life damages to the human holobiont need to include not only the microbiome but also the larger inflammation-controlling unit, the microimmunosome. While many approaches to treating ACE-induced conditions have focused on the downstream set of imbalances and symptoms (e.g., HPA axis, brain/neurological/psychological treatment), the inclusion of a more upstream and comprehensive approach that includes Microbiome First medicine is needed.

Among the devastating disease-promoting programming that results from ACEs is the development of chronic underlying inflammation and a spectrum of specific comorbid NCDs. As discussed in prior reviews [ 60 , 61 ], the accumulation of NCDs, polypharmacy and in many cases caregiver needs is a path that increases medical needs and significantly reduces quality of life. One problem with these ACE-linked outcomes is that to date, both medicine and public health have produced few cures for NCDs, and the epidemic of these conditions continued across decades making NCDs the leading cause of death (estimated at 71% of all deaths) globally [ 62 ]. The lack of cures and emphasis to date on symptom management has permitted the inflammation-connected expansion of comorbidity and polypharmacy associated with aging [ 61 ]. The same pattern has arisen with ACE-connected NCDs and other imbalances during the aging process. However, the symptom driven healthcare approaches to NCDs to date have largely excluded microorganisms and the microbiome from priority consideration [ 61 ]. Table 2 [ 12 , 16 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ] illustrates examples of the specific NCDs to date that are connected to ACE through elevated prevalence. Of note is the fact that they span allergic, autoimmune, metabolic, and inflammatory diseases including diabetes and heart disease as well as neurodevelopmental and neurodegenerative diseases. As discussed by Dietert [ 61 ], childhood onset NCDs such as asthma and metabolic syndrome (e.g., obesity, diabetes) are entryway conditions that are connected to a large number of later-life comorbidities via the inflammation-NCD cascade. ACE-programmed NCDs and physiological changes present added challenges since behavioral programming drives this cohort toward exposures that further increase the risk of comorbid diseases. Among these are a predisposition for substance misuse/abuse and risky behaviors that could promote additional microbiome dysbiosis, degraded colonization resistance, and significant advantages for pathobionts to produce infections.

Two adverse outcomes received prior recent reviews within the Microbiome First series of papers. These concerned the capacity of the microbiome to regulate pain [ 95 ] and both the occurrence of substance abuse and the likelihood of successful withdrawal [ 20 ]. One of the characteristics of ACEs and programmed systems biology alteration is the increased likelihood of later-life chronic pain. Several studies have specifically examined the relationship between childhood adverse experiences and the appearance and persistence of adolescent and adult pain. Examples of recent ACE-pain studies are shown in Table 3 [ 40 , 41 , 42 , 43 , 44 , 96 ]. As recently reviewed in Dietert and Dietert [ 95 ], microbiome adjustment including treatment with probiotics and prebiotics has the capacity to alter a variety of different types of pain. These alterations include changes in the perception of pain and in its persistence at various life stages. A sample of the research papers and review analyses are included here [ 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. While the focus of this present review is on ACE-programmed dysfunction in holobiont regulatory cycles that lock in both NCDs and systems biology dysfunction, the reach of microbiome controls includes quite specific endpoints that impact quality of life functional capacities. This is one of the reasons that management of the early life both before and after ACE is the key to improved resiliency. In the later section discussion of circadian rhythms, it will become clear that disrupted circadian clocks are tightly associated with increases in pain. Therefore, ACE-associated damage to the more global body cycles appears to be one way for pain perceptions and threshold to change for the worse. ACEs have a strong association with substance abuse and addiction. Multiple systems are likely involved and changes in the reward system are thought to play a major role [ 107 , 108 , 109 ]. As with other programmed changes, substance abuse carries its own additional risks as aging progresses (e.g., the damages created by prolonged tobacco, alcohol, and drugs abuse). Table 4 [ 37 , 46 , 110 , 111 , 112 , 113 , 114 ] illustrates examples of substance abuse connected to ACE. Given the knowledge that this is a significant risk, preventative measures that include the microbiome and protection against dysbiosis not only reduce the risk of substance abuse, but also canaid in protection against impediments to withdrawal. This was previously discussed in two recent reviews [ 20 , 95 ].

In an early, collaborative article published in Environmental Health Perspective examining the comorbidities arising from immune dysfunction-inflammation-promoted NCDs [ 115 ], we noted a specific pattern of NCDs and related dysfunctions that were shared by most childhood-young adult onset NCDs. These were: sleep disorders, depression, sensory disorders, and cardiovascular disease. Of course, the question then was why were these specific conditions shared as comorbidities by most of the NCDs examined in our publication? Now more than a decade later, the answer would seem to be at hand. Sleep disorders, depression, and atherosclerosis are intimately linked to microbiome status, misregulated inflammation, and disruptions of circadian rhythms.

Circadian rhythms are recognized as not simply a novel occurrence within the human body but, more significantly, a key cycle that: (1) spans the operation of systems biology units [ 116 , 117 ], (2) connects the microbiome with those units [ 118 ], and (3) ultimately can result in healthy metabolism and physiology [ 119 ] or disease [ 120 , 121 , 122 ]. Table 5 [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 ] illustrates examples of NCDs and other disorders that are intimately connected to a disruption in circadian rhythms. Because of the tight interconnects that exist between the circadian clock, the microbiome, and systems biology homeostasis or dysbiosis, it is sometimes difficult to distinguish what elements are actually the penultimate controllers. When it comes to managing health and disease, the interconnections are probably what matters most. For example, aligning circadian rhythms may not inherently repair microbiome dysbiosis and/or a compromised gut barrier. On the other hand, microbiome rebiosis and adjustments to the microimmunosome, gut–immune–brain axis, or HPA axis may only endure if not repeatedly undermined by a circadian rhythm defect. As will become apparent in the following sections, attention to both factors in combination is likely to be a more successful health promoting strategy. In support of the idea of a combined effort to promote a healthy microbiome, downstream systems biology units (e.g., the microimmunosome) and balanced circadian rhythms, Table 6 illustrates recent studies demonstrating the interconnectivity between microbiome status and circadian rhythms. Importantly, as Microbiome First applications become increasingly utilized across medicine and public health [ 20 , 61 ], the status of the circadian clock will be a critical co-factor in successful outcomes.

Insomnia and other sleep disorders are a prevalent outcome not only of adverse childhood experiences but also of many NCDs [ 115 ]. Sleep disorders are very interconnected to circadian disruption, specific NCDs, pain and inflammation, and microbiome dysbiosis. The tight interconnectivity between these can make the cause–effect relationship challenging to determine. A recent review by Kang et al. [ 143 ] examined the gut microbiome as a target for adjunct therapies to address insomnia. Defining the tipping point causes in sleep disruption constitutes a large part of ongoing research. However, it is already clear that microbiome dysbiosis can lock in NCDs, systems biology dysfunctions (e.g., neuro-brain, HPA axis, bile acid metabolism, microimmunosome), and sleep disorders. Correcting imbalances within the microbiome is significant if healthy sleep-circadian rhythm patterns are to be restored and maintained. We can no longer afford to ignore the microbiome in NCD-systems biology oriented therapies [ 61 ]. Table 7 [ 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ] illustrates the impact of microbiome status on sleep.

As shown in Table 1 one of the outcomes of adverse childhood experiences is premature aging including shortened telomeres. At the heart of both ACEs and NCDs is misregulated inflammation. Chronic unresolving tissue inflammation even at low levels creates increased oxidative damage to a variety of macromolecules, tissue pathology, and eventually NCDs ranging from asthma, cardiovascular, metabolic, inflammatory bowel, and psoriasis diseases to cancer. It has been suggested that aging is a multifactorial, multisystem event that is best characterized by a network of biomarkers ranging from functional to molecular in nature. In fact, Wagner et al. [ 156 ] listed 22 different biomarkers that capture the different level of potential evaluation of aging. One of the biomarkers reflecting the persistent inflammation, increased oxidative stress and premature aging is the shortening of chromosomal telomeres [ 157 ]. Telomere length is thought to reflect the number of cell cycles that a population of cells can undergo. When certain cells can no longer divide, the body is incapable of maintaining critical functions. Table 8 [ 158 , 159 , 160 , 161 , 162 , 163 ] illustrates examples of the relationship between inflammation, oxidative damage and telomere length. It should be noted that efforts to minimize the symptoms of NCDs rather than correcting underlying systems biology defects (e.g., unresolving tissue inflammation) have two very negative outcomes. First, comorbid NCDs and increasing polypharmacy are not abated by the symptom management based on the pattern of the last several decades [ 61 ]. Second, the shortened telomeres and increased oxidative stress from the unrelenting misregulated inflammation means that the patient will invariably have a shortened life compared with a cohort that is disease free (i.e., cured). Symptom-only management should be viewed at best as a transient goal when compared to disease-free, life-extending therapeutic outcomes.

One of the recent findings that pertains to longevity concerns the relationship between immune senescence and aging. As we age quite specific changes occur in the immune system that affect not only the risk of NCDs but also the relationship between the tissue-distributed immune system and organ homeostasis. As the immune system fails, ultimately it impacts our organs and physiological systems [ 164 ]. A recent discovery is that the immune system has its own epigenetic clock and by youthanizing the immune system, the effect spreads across our other systems biology units. Fahy et al. [ 165 ] published results of reversing the path toward immune senescence by tapping regenerative processes within the thymus and bone marrow. Because the overriding theme of ACEs is premature aging with chronic inflammation and oxidative stress, the capacity to initiate multi-system age regression within the microimmunosome and to potentially correct misregulated inflammation is very promising.

Systems biology distributed changes that occur with adverse childhood experiences can also occur with early life chemical and drug toxicity or inadequate seeding and feeding of the infant microbiome. These interconnected changes are centered around a pattern of chronic inflammation, immune-, mitochondrial-, telomere-, and microbiome aging and the NCD comorbid cascade. The weakness in providing better protection of a major cohort of early life programmed children is to selectively work on only one aspect or biomarker of the complex premature aging pattern. The overall goal in looking toward gerobiotics is not simply increased longevity but rather extending the healthspan, the number of healthy years within a person’s life [ 166 ]. The present review emphasizes the important role of using microbiota, their metabolism, signaling and epigenetic control of multiple physiological systems to facilitate an unwinding of the DOHaD installed NCD-rich, premature death programming. Table 9 [ 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 ] provides some of these examples.

Early life adverse environmental, emotional, and physical experiences can have a heightened impact on the development of tissues, organs, and physiological (systems biology) units when compared with similar exposures in the adult. This was codified in the mantra that children are not simply small adults and never should be treated as such. When benchmark maturational events are disrupted via chemicals, drugs, food, food additives, physical or emotional exposure, inappropriate maturation and subsequent dysfunction of the body’s systems are likely. In effect, human systems are readily programmed for later life dysfunction and chronic disease when the fetus, newborn, infant, and adolescent are inadequately protected during critical windows of developmental vulnerability. This special vulnerability in early life and the need for special protections of the young have been described in a series of papers and reports [ 1 , 2 , 3 , 4 , 5 ] that contributed to what became known as the scientific field of Developmental Origins of Health and Disease (DOHaD). Two developments within the DOHaD umbrella during the past decade are changing how we view the ongoing epidemic of noncommunicable diseases and conditions (NCDs). First, the microbiome is now recognized as central to the maturation of human systems biology units (e.g., gut–brain, microimmunosome, gut–hypothalamic–pituitary–adrenal (HPA) axis, gut–liver, gut-bile acid metabolism). Disruption of microbiome maturation in early life invariably results in disrupted systems biology units and elevated risk of childhood and adult NCDs. Unless the dysbiotic microbiome is addressed in dealing with systems biology malfunction and NCDs, the epidemic of NCDs is likely to continue unabated. Second, physical and emotional trauma in early life (often called adverse childhood experiences, ACEs) damage not only organ/tissue development (e.g., brain, gut, immune) but also microbiome status, thereby, impacting the risk of a diverse range of later-life, comorbid NCDs. In many ways, physical and emotional “toxicity” for the microbiome and multiple systems biology units have been understudied and potentially underappreciated. While adverse effects of ACEs on the brain are important, those changes do not occur in a vacuum nor are they the only mis-programming that occurs in early life. This review article is not intended to provide an exhaustive review on any single disciplinary-related topic (e.g., the HPA axis). Instead, it draws primarily upon the last five years of research to examine the intersection of the microbiome and systems biology units as it pertains to ACE-induced programming. Specifically, the article examines: (1) the prevalence of ACEs, (2) the inadequate protection of the young from physical and emotional abuse (including child trafficking), (3) the significance of premature aging and NCDs resulting from ACEs, (4) the interconnections between microbiome status, circadian rhythms, sleep quality, NCDs including depression, and longevity, and (5) the opportunities to broaden historic organ-centric approaches to focus on microbiome-systems biology correcting solutions. The importance of microbiome status in early life cannot be overemphasized. This was captured in a recent paper describing the connection of infant antibiotic exposure to risk of a broad range of childhood NCDs [ 6 ].

This review is novel in its consideration of early life programming resulting from Adverse Childhood Experiences. Not only are the specific, extensive ACE-programmed childhood and adult onset NCDs (i.e., chronic diseases and conditions) presented but also the connections between ACE and the destruction of microbiome balance, the circadian rhythm cycle, and the healthy portion of the longevity cycle (i.e., the healthspan). The presented material within the tables and narrative illustrates a key point: The microbiome and the circadian rhythm cycle are master regulators of the very diseases that are the number one cause of global death [W62]. Longevity and the healthspan are outcomes of the master regulation. This is significant because both the prevention of ACE-programmed NCDs and the therapeutic plans that follow NCD diagnoses often fail to include the correction of microbiome and circadian cycle/sleep defects. Yet, disease “cures” become less likely when the master regulators are left in a dysfunctional state. Dietert discussed this very issue relative to the microbiome dysbiosis in two recent review articles [ 3 , 61 ]. Additionally, the significance of including the circadian cycle [ 119 , 120 , 129 ] and the longevity cycle [ 195 ] in healthcare/public health plans has been stressed in a number of recent publications. Much as the microbiome has bidirectional communication with the immune system through the microimmunosome [ 60 , 61 ], microbiota and circadian cycles are involved in cross-talk [ 196 ]. Therefore, both need to be considered together much like one would approach a systems biology unit. For the longevity cycle, prior treatments have largely included dietary recommendations [ 197 , 198 ]. However, a larger collection of factors is now being considered. For example, numerous factors have been examined for anti-aging activity including 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C based on protection against stem cell senescence [ 199 ]. At least one existing drug, metformin, a plant derived drug, has shown considerable promise for its capacity to serve as a longevity drug [ 200 , 201 ]. Numerous down-stream effects have been seen with metformin treatment, making it clear that many benefits from this drug arise via its direct effects on the microbiome [ 202 , 203 , 204 ]. As many investigators have pointed out when examining anti-aging/longevity initiatives, the ultimate goal is not simply more years added to a disease-filled life but actually more years spent in a healthy life. This is how the concept of the “healthspan” has emerged [ 205 , 206 ]. It is healthy longevity that is the sustainable healthcare prize and not a few extra polypharmacy-riddled, low quality of life days added to our current multimorbid final years. What is clear is that reduced prevalence of NCDs, balanced circadian rhythms, effective pain management, effective sleep quality, and a longer healthspan can only occur if supported by a healthy microbiome across the life stages [ 3 , 61 , 207 , 208 , 209 , 210 ]. The microbiome can regulate overlapping systems biology units, and this combined status can affect the risk of NCDs. To capture the relationships between the microbiome, the systems biology units and ACE programming, Figure 1 illustrates a “sun-flower” model of this interconnectivity. Inattention to microbiome status and incomplete therapeutic efforts can undermine necessary corrections when it comes to sleep regulation, circadian rhythms, the microimmunsome, anti-aging factors, and the HPA axis. For this reason, the more holobiont-focused the approach, the better. Finally, one of the significant contributors to ACEs and the resulting adverse health challenges that follow is child trafficking [ 211 ]. This form of modern slavery has been difficult to accurately estimate at a global or even a national level [ 212 ]. There is a bi-directional relationship between child trafficking and ACEs. In a study in Florida, Reid et al. [ 213 ] found that prior childhood adversities increased the likelihood that a given child would be trafficked. But pediatric associations have recognized that child trafficking itself presents a critical health threat [ 214 , 215 , 216 ]. It is clear that preventing ACEs and child trafficking is the highest priority. Revelations concerning child trafficking activities may help to raise public awareness and reduce its prevalence [ 217 , 218 ]. When prevention fails, microbiome-driven, multi-systems biology approaches offer a comprehensive strategy to reduce the burden of ACE-programmed NCDs.

Adverse childhood experiences (ACEs) including the trafficking of children represent a significant health risk. ACEs program microbiome dysbiosis, increased risk of specific NCDs (e.g., depression), increased chronic inflammation, increased oxidative stress, increased mitochondrial dysfunction, disrupted circadian rhythms, shortened telomeres, reduced longevity, and a greatly abbreviated healthspan. A first priority should be to keep children out of harm’s way as much as possible and to better protect children from those experiences that are preventable. They should never face preventable trauma. However, it is also important to enhance resiliency and better prevent and treat chronic disorders, including NCDs. A healthy microbiome is a route to provide enhanced resiliency in childhood and to deprogram both comorbid NCDs and multiple systems biology dysfunctions. The circadian rhythm cycle and sleep quality respond to and affect many biological functions, longevity, and microbiome status. But it is clear that healthy circadian rhythm, sleep, as well as effective longevity cannot persist in the face of: (1) microbiome dysbiosis, (2) damage to the microimmunosome, and (3) the all-too-common outcome of misregulated inflammation. Ensuring both an optimized microbiome and balanced microimmunosome should be top priorities for ACE deprogramming of the human holobiont. Otherwise, efforts to correct ACE-based problems using classical disciplinary-based approaches are likely to produce underwhelming outcomes when viewed across the lifespan. This present review illustrates the benefits of utilizing a microbiome-driven, systems biology approach to unwind the devastating lifelong programming established through multiple adverse childhood experiences.