Elsevier

Reproductive Toxicology

Volume 68, March 2017, Pages 49-58
Reproductive Toxicology

The microbiome-immune-host defense barrier complex (microimmunosome) and developmental programming of noncommunicable diseases

https://doi.org/10.1016/j.reprotox.2016.04.026Get rights and content

Highlights

  • The microimmunosome is introduced as a systems biology unit for DOHaD-driven NCDs.

  • The microbiome, host barriers, and the immune system comprise the microimmunosome.

  • Inter-regulation within the microimmunosome affects tolerance and self integrity.

  • Specialized immune cells contribute to risk of misregulated inflammation.

  • Six developmental windows of vulnerability are described for the microimmunosome.

Abstract

Through its role as gatekeeper and filter to the external world, the microbiome affects developmental programming of physiological systems including the immune system. In turn, the immune system must tolerate, personalize, and prune the microbiome. Immune and host barrier status in early life significantly effects everything from embryo viability and pregnancy duration to the likelihood of misregulated inflammation, and risk of noncommunicable diseases (NCDs). Since the programming of and interactions among the microbiome, the host defense barrier, and the immune system can affect inflammation-driven health risks across the lifespan, a systems biology-type understanding of these three biological components may be useful. Here, I consider the potential utility of focusing on programming of a newly-defined systems biology unit termed the “microimmunosome.”

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.

References (134)

  • A. Paun et al.

    Immuno-ecology how the microbiome regulates tolerance and autoimmunity

    Curr. Opin. Immunol.

    (2015)
  • M.A. Zijlmans et al.

    Maternal prenatal stress is associated with the infant intestinal microbiota

    Psychoneuroendocrinology

    (2015)
  • A.V. Golubeva et al.

    Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood

    Psychoneuroendocrinology

    (2015)
  • N.T. Mueller et al.

    The infant microbiome development: mom matters

    Trends Mol. Med.

    (2015)
  • K. Kristensen et al.

    Cesarean section and disease associated with immune function

    J. Allergy Clin. Immunol.

    (2016)
  • R. Dheer et al.

    Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism

    Toxicol. Appl. Pharmacol.

    (2015)
  • M. Spite et al.

    Resolvins specialized proresolving lipid mediators, and their potential roles in metabolic diseases

    Cell Metab.

    (2014)
  • C.N. Serhan et al.

    The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution

    Semin. Immunol.

    (2015)
  • J.L. Bolton et al.

    SD prenatal air pollution exposure induces sexually dimorphic fetal programming of metabolic and neuroinflammatory outcomes in adult offspring

    Brain Behav. Immun.

    (2014)
  • World Health Organization Global status report on noncommunicable diseases 2014, WHO, Geneva, 2014. ISBN: 978 92 4...
  • Centers for Disease Control and Prevention Global Noncommunicable Diseases....
  • I. Abdollahpour et al.

    Caregiver burden: the strongest predictor of self-rated health in caregivers of patients with dementia

    J. Geriatr. Psychiatry Neurol.

    (2014)
  • R.R. Dietert et al.

    The microbiome and sustainable healthcare

    Healthcare

    (2015)
  • J.L. Colquitt et al.

    Surgery for weight loss in adults cochrane database

    Syst. Rev.

    (2014)
  • V. Kontis et al.

    Regional contributions of six preventable risk factors to achieving the 25 × 25 non-communicable disease mortality reduction target: a modelling study

    Lancet Glob. Health

    (2015)
  • Centers for Disease Control and Prevention Prevalence autism spectrum disorders −autism and disabilities monitoring...
  • B. Zablonsky, L.I. Black, M.J. Maenner, L.A. Schieve, S.J. Blumberg, Estimated prevalence of autism and other...
  • R. Panwankar, Ruby Pawankar, S.T. Holgate, G.W. Canonica, R.F. Lockey, M.S. Blaiss, WAO White Book on Allergy 2013...
  • National Institute of Diabetes and Digestive and Kidney Diseases,...
  • J. De Maeseneer et al.

    Care for noncommunicable diseases (NCDs): time for a paradigm-shift

    World Hosp. Health Serv.

    (2011)
  • R. Dietert

    The Human Superorganism Dutton

    (2016)
  • M.E. Kruk et al.

    Redesigning primary care to tackle the global epidemic of noncommunicable disease

    Am. J. Public Health

    (2015)
  • R. Faner et al.

    Network medicine multimorbidity and the lung in the elderly

    Eur. Respir. J.

    (2014)
  • R.R. Dietert

    The microbiome in early life: self-completion and microbiota protection as health priorities

    Birth Defects Res. B Dev. Reprod. Toxicol.

    (2014)
  • D.E. Bloom et al.

    The Global Economic Burden of Noncommunicable Diseases World Economic Forum, Geneva

    (2011)
  • D.J. Barker

    The fetal infant origins of adult disease

    BMJ

    (1990)
  • D.J. Barker et al.

    Fetal and infant origins of cardiovascular disease

    Arch. Dis. Child.

    (1992)
  • L.S. Birnbaum et al.

    Prenatal programming and toxicity (PPTOX) introduction

    Endocrinology

    (2015)
  • J. Bousquet et al.

    Developmental determinants in non-communicable chronic diseases and ageing

    Thorax

    (2015)
  • J.J. Heindel et al.

    Developmental origins of health and disease: integrating environmental influences

    Endocrinology

    (2015)
  • R.R. Dietert et al.

    Breaking patterns of environmentally influenced disease for health risk reduction: immune perspectives

    Environ. Health Perspect.

    (2010)
  • R.R. Dietert

    Misregulated inflammation as an outcome of early-life exposure to endocrine-disrupting chemicals

    Rev. Environ. Health

    (2012)
  • P. Almeda-Valdes et al.

    Common features of the metabolic syndrome and nonalcoholic fatty liver disease

    Rev. Recent Clin. Trials

    (2014)
  • Immunotoxicity, Immune Dysfunction and Chronic Disease

  • J. Camps et al.

    Introduction oxidation and inflammation, a molecular link between non-communicable diseases

    Adv. Exp. Med. Biol.

    (2014)
  • H.M. Lam et al.

    Bisphenol A disrupts HNF4α-regulated gene networks linking to prostate preneoplasia and immune disruption in noble rats

    Endocrinology

    (2016)
  • B. Chassaing et al.

    Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome

    Nature

    (2015)
  • J.R. Araújoa et al.

    Exposure to non-nutritive sweeteners during pregnancy and lactation: impact in programming of metabolic diseases in the progeny later in life

    Reprod. Toxicol.

    (2014)
  • B. Zhu et al.

    Human gut microbiome: the second genome of human body

    Protein Cell

    (2010)
  • R.R. Dietert et al.

    Biomarkers for the 21st century: listening to the microbiome

    Toxicol. Sci.

    (2015)
  • Cited by (13)

    • Modeling of the luminal butyrate concentration to design an oral formulation capable of achieving a pharmaceutical response

      2019, PharmaNutrition
      Citation Excerpt :

      NCDs are diseases in which chronic low-grade inflammation plays an important role. This low-grade inflammation could be caused by damage of the gastrointestinal barrier which is pivotal for efficient host defense [1]. Butyrate might influence gut integrity via different mechanisms of action.

    • Food contact materials and gut health: Implications for toxicity assessment and relevance of high molecular weight migrants

      2017, Food and Chemical Toxicology
      Citation Excerpt :

      The more specific methods for assessing functional changes at different levels of complexity in the GI tract, although available, are usually not used (Harrison et al., 2004; Vojdani, 2013). Similarly, to date, the gut microbiome has been rarely if ever taken into account in safety assessments of FCCs or most other types of chemical uses (Dietert, 2017). As reviewed above, many FCCs may induce various gut-related effects.

    • Microorganisms as drivers of host-parasite interactions

      2023, Parasitic Infections: Immune Responses and Therapeutics
    View all citing articles on Scopus
    View full text