The microbiome-immune-host defense barrier complex (microimmunosome) and developmental programming of noncommunicable diseases
Introduction
The most significant health challenges of the 21st century are the group of diseases and conditions known originally as chronic diseases and more recently as noncommunicable diseases (NCDs). These include conditions such as asthma, obesity, depression, heart disease, various cancers, autism, diabetes, celiac disease, food allergies, inflammatory bowel disease, depression, Parkinson’s disease and Alzheimer’s disease. NCDs are part of an ongoing epidemic [1], are responsible for an estimated 75% of global deaths [2], are affecting quality of life in patients as well as caregivers [3], [4], and are exceeding the capacity of healthcare systems [5], [6]. Thus far, well-intentioned attempts to reverse this epidemic via lifestyle changes (e.g., reduced tobacco and alcohol use, reduced salt intake, other dietary adjustments, increased physical activity) and medical interventions have made limited inroads in the case of certain conditions [7]. But even the goals of meaningful benchmarks for blunting the NCD epidemic appear out of sight [8]. Many NCDs arise during childhood, but even those that are adult-onset are usually programmed in early life. Both biomarkers and clinical indicators of adult-onset NCDs can be evident during childhood (e.g., atherosclerosis markers) [9].
Several key measures indicate that the NCD epidemic is both pervasive and has not abated. Among these measures are the ever-increasing prevalence of autism spectrum disorders. For example, estimations of prevalence of autism spectrum disorders (ASD), even during the brief 21st century, have increased from 1 in 150 (in a 2007 report of 2002 data) to 1 in 45 in 2014 [10], [11]. Increasing NCDs prevalences are not restricted just to ASD. Prevalences of allergic disease have shown a continued increase over the last 50 years [12] as has prevalence for obesity [13]. The continued progression of this epidemic involves myriad multiple NCDs and provides an indication that a different approach to health protection and health promotion is required.
Researchers have called for a paradigm shift to address this NCD epidemic [14], [15]. Such a shift will likely include: 1) new medical approaches [6], [16], the application of systems biology-type approach to safety and treatments [17], and a different, more convergent thinking about fundamental human biology and NCDs [15], [18], [19].
This review considers the impact of inter-generational and developmental programming within a newly-defined, three component (microbiome, immune system, host defense barrier) systems biology unit as it affects embryo viability, fundamental host integrity, and risk of later life NCDs. This systems biology unit encompasses many regions of the body and, in particular, those sites where the body’s defense systems are in contact with the external environment (e.g., gut epithelium and mucus layer, airway lining, uterine lining and skin epidermis). The potential usefulness of this approach is discussed with several critical biological endpoints in mind: 1) inter-generational programming of embryonic tolerance and viability, 2) capacity to carry a pregnancy to term, 3) maintenance of immunological tolerance, and 4) effective regulation of inflammation.
Section snippets
Noncommunicable diseases as a primary target of DOHaD
Noncommunicable diseases have been on an epidemic increase for the past several decades, surpassing infectious diseases as the greatest cause of death world-wide [20]. The increase in prevalence of NCDs has strained not only the healthcare systems of developed nations but is also threatening the economic capacities of countries where such diseases were comparatively uncommon in the past [16]. The NCDs involved in this coordinated epidemic manifest in virtually every physiological system.
The inter-relatedness of NCDs
NCDs comprise a diverse array of manifestations affecting different physiological systems and organs. The diseases themselves are often studied and clinically treated in isolation. However, looking at commonalities among NCDs may be advantageous when it comes to both the early life origins and effective public health strategies to blunt the NCD epidemic.
One major question about the developmental origins of NCDs is whether a focal point exists for common ground among these diseases that could
Incorporating the microbiome into the NCD paradigm
There are numerous reasons why a different approach for considering the developmental programming of NCDs and the role of the microbiome might be useful. For the purpose of this review, four of these will be discussed.
First, an inherent assumption of developmental toxicity has been that if we identified toxicants prior to massive exposures of pregnant women and children to hazardous chemicals, drugs or food additives and acted on those identifications, we would significantly reduce disease
Early life risk factors and the microbiome
A significant research focus on the microbiome in recent years through the human microbiome project and other major consortiums has shown that the status of the human microbiome is key to both present and future human health, and that the microbiome is malleable and can be affected by a variety of environmental factors and conditions. Furthermore, the status of the microbiome at any point during development can have ramifications in later life. For example, it has been suggested that
The microimmunosome as a programmable unit
The microimmunosome, encompassing the microbiome, immune system and host defense barriers, is first introduced and discussed in this review as a systems biology unit that manages biological integrity, tissue homeostasis, immune tolerance, control of inflammation, and human interactions with the external environment. The opportunity to examine the interface between the human mammalian and microbial compartment has as much to do with recent thinking about NCDs as it does the new understanding of
The microimmunosome as an arbiter of higher organisms
A recent surprising finding is that within the microimmunosome, there is the capacity to determine whether a higher organism thrives or dies as an embryo. Having an intact immune system and sufficient microbiome are sometimes not sufficient in combination for embryonic survival. As is discussed in the next section, there needs to be a critical level of compatibility between the two. If such compatibility is lacking, then even if the immune system and microbiome are comparatively intact, their
The microimmunosome as a front line responder
Because the microbiome is positioned at the portal of human exposure to the environment, the microbiome is both the gatekeeper and filter for human mammalian cell exposure [41]. From a toxicological perspective, the internal dose for exposure to a xenobiotic in the exposome is largely determined by the microbiome. Numerous examples of this gatekeeper role can be seen in the handling of xenobiotics by the microbiome [74], [75]. For example the bioavailability and, hence, the therapeutic dose of
The microimmunosome as a regulator of inflammation
Importantly, one of the hallmarks of fetal programming for cardiovascular disease (CVD) and most other NCDs is low-grade, chronic inflammation [86]. In fact, unresolving or misregulated inflammation in tissues is seen in virtually all NCDs examined to date and usually reflects immune dysfunction that initiates and/or facilitates the disease or condition state [30]. The importance of the role of inflammation in these conditions is also seen with the comparative effectiveness of treatments that
Critical windows of vulnerability for the microimmunosome
Because the microbiome, immune system, and host defense barrier are virtually inseparable in terms of inter-regulation [96], [97], significant changes including dysfunction in any one of these three biological units invariably affects gene expression and function in the other two. This is particularly evident in early life when developmental programming within and among the three components occurs. Beyond critical windows of vulnerability already defined for the developing immune system [98],
Host barrier function
Host defense barriers, including the epithelial cell linings and mucus barriers, are included in the systems unit specified as the microimmunosome as they are: 1) the go-between in the microbiome-immune, inter-regulatory communication, 2) critical component driving many innate immune responses, and 3) the key to internal tissue homeostasis. Epithelial barrier integrity can be developmentally programmed via both prenatal factors such as maternal obesity [108] and by high glucocorticoid
Proactive developmental programming using the microimmunosome
Protection of the young has been a major priority in health protection due to two factors: 1) the understanding that developmental disruption and programming of physiological dysfunction leads to later-life disease [28], [124] and 2) an even longer, inter-generational view that involves bioarcheology and the co-mingling of life courses [125]. These concepts fall under the umbrella of DOHaD. Yet, the effort to apply DOHaD to date has largely been centered on one specific aspect of developmental
Conclusions
Research into the developmental origins of adult health and disease has established the importance of early life programming in the ongoing epidemic of noncommunicable diseases. However, there are five comparatively recent findings that encourage a change in the recent paradigm that has emphasized individual physiological system based analysis, a single disease focus, and exposure/lifestyle avoidance: 1) the microbiome plays a dominant role in the hologenome and can greatly affect the internal
Conflict of interest
The author declares that he has no conflict of interest.
Acknowledgement
The author thanks Janice Dietert, Performance Plus Consulting, for her editorial assistance.
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