Examining Sound, Light, and Vibrations as Tools to Manage Microbes and Support Holobionts, Ecosystems, and Technologies.

The vast array of interconnected microorganisms across Earth's ecosystems and within holobionts has been called the "Internet of Microbes." Bacteria and archaea are masters of energy and information collection, storage, transformation, and dissemination using both "wired" and wireless (at a distance) functions. Specific tools affecting microbial energy and information functions offer effective strategies for managing microbial populations within, between, and beyond holobionts. This narrative review focuses on microbial management using a subset of physical modifiers of microbes: sound and light (as well as related vibrations). These are examined as follows: (1) as tools for managing microbial populations, (2) as tools to support new technologies, (3) as tools for healing humans and other holobionts, and (4) as potential safety dangers for microbial populations and their holobionts. Given microbial sensitivity to sound, light, and vibrations, it is critical that we assign a higher priority to the effects of these physical factors on microbial populations and microbe-laden holobionts. We conclude that specific sound, light, and/or vibrational conditions are significant therapeutic tools that can help support useful microbial populations and help to address the ongoing challenges of holobiont disease. We also caution that inappropriate sound, light, and/or vibration exposure can represent significant hazards that require greater recognition.

Dietary Approaches from Moms, Farms, and Nature to Overcome Chronic Diseases and the Pharmacracy.

Chronic diseases, previously called noncommunicable diseases, are the leading cause of global death and were recently estimated by the World Health Organization to account for 74% of all deaths [...].

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

Adverse childhood experiences (ACEs), which can include child trafficking, are known to program children for disrupted biological cycles, premature aging, microbiome dysbiosis, immune-inflammatory misregulation, and chronic disease multimorbidity. To date, the microbiome has not been a major focus of deprogramming efforts despite its emerging role in every aspect of ACE-related dysbiosis and dysfunction. This article examines: (1) the utility of incorporating microorganism-based, anti-aging approaches to combat ACE-programmed chronic diseases (also known as noncommunicable diseases and conditions, NCDs) and (2) microbiome regulation of core systems biology cycles that affect NCD comorbid risk. In this review, microbiota influence over three key cyclic rhythms (circadian cycles, the sleep cycle, and the lifespan/longevity cycle) as well as tissue inflammation and oxidative stress are discussed as an opportunity to deprogram ACE-driven chronic disorders. Microbiota, particularly those in the gut, have been shown to affect host-microbe interactions regulating the circadian clock, sleep quality, as well as immune function/senescence, and regulation of tissue inflammation. The microimmunosome is one of several systems biology targets of gut microbiota regulation. Furthermore, correcting misregulated inflammation and increased oxidative stress is key to protecting telomere length and lifespan/longevity and extending what has become known as the healthspan. This review article concludes that to reverse the tragedy of ACE-programmed NCDs and premature aging, managing the human holobiont microbiome should become a routine part of healthcare and preventative medicine across the life course.

Microbiome First Approaches to Rescue Public Health and Reduce Human Suffering.

The is a sequential article to an initial review suggesting that Microbiome First medical approaches to human health and wellness could both aid the fight against noncommunicable diseases and conditions (NCDs) and help to usher in sustainable healthcare. This current review article specifically focuses on public health programs and initiatives and what has been termed by medical journals as a catastrophic record of recent failures. Included in the review is a discussion of the four priority behavioral modifications (food choices, cessation of two drugs of abuse, and exercise) advocated by the World Health Organization as the way to stop the ongoing NCD epidemic. The lack of public health focus on the majority of cells and genes in the human superorganism, the microbiome, is highlighted as is the "regulatory gap" failure to protect humans, particularly the young, from a series of mass population toxic exposures (e.g., asbestos, trichloroethylene, dioxin, polychlorinated biphenyls, triclosan, bisphenol A and other plasticizers, polyfluorinated compounds, herbicides, food emulsifiers, high fructose corn syrup, certain nanoparticles, endocrine disruptors, and obesogens). The combination of early life toxicity for the microbiome and connected human physiological systems (e.g., immune, neurological), plus a lack of attention to the importance of microbial rebiosis has facilitated rather than suppressed, the NCD epidemic. This review article concludes with a call to place the microbiome first and foremost in public health initiatives as a way to both rescue public health effectiveness and reduce the human suffering connected to comorbid NCDs.

Microbiome First Medicine in Health and Safety.

Microbiome First Medicine is a suggested 21st century healthcare paradigm that prioritizes the entire human, the human superorganism, beginning with the microbiome. To date, much of medicine has protected and treated patients as if they were a single species. This has resulted in unintended damage to the microbiome and an epidemic of chronic disorders [e.g., noncommunicable diseases and conditions (NCDs)]. Along with NCDs came loss of colonization resistance, increased susceptibility to infectious diseases, and increasing multimorbidity and polypharmacy over the life course. To move toward sustainable healthcare, the human microbiome needs to be front and center. This paper presents microbiome-human physiology from the view of systems biology regulation. It also details the ongoing NCD epidemic including the role of existing drugs and other factors that damage the human microbiome. Examples are provided for two entryway NCDs, asthma and obesity, regarding their extensive network of comorbid NCDs. Finally, the challenges of ensuring safety for the microbiome are detailed. Under Microbiome-First Medicine and considering the importance of keystone bacteria and critical windows of development, changes in even a few microbiota-prioritized medical decisions could make a significant difference in health across the life course.

Evaluation of Cell-Mediated Immune Function Using the Cytotoxic T-Lymphocyte Assay.

Evaluation of cell-mediated immunity (CMI) is a significant component in any assessment designed to predict the full range of potential immunotoxic risk underlying health risks. Among measures of CMI, the cytotoxic T-lymphocyte (CTL) response is recognized as perhaps the most relevant functional measure that reflects cell-mediated acquired immune defense against viral infections and cancer. The CTL response against T-dependent antigens requires the cooperation of at least three different major categories of immune cells. These include professional antigen-presenting cells (e.g., dendritic cells), CD4+ T helper lymphocytes, and CD8+ T effector lymphocytes. It is also among the few functional responses dependent on and, hence, capable of evaluating effective antigen presentation via both class I and class II molecules of the major histocompatibility complex (MHC). For this reason, the CTL assay is an excellent candidate for evaluation of potential immunotoxicity. This chapter provides an example of a mouse CTL assay against influenza virus that has been utilized for this purpose.

Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic.

Metabolic Syndrome and Associated Diseases: From the Bench to the Clinic, a Society of Toxicology Contemporary Concepts in Toxicology (CCT) workshop was held on March 11, 2017. The meeting was convened to raise awareness of metabolic syndrome and its associated diseases and serve as a melting pot with scientists of multiple disciplines (eg, toxicologists, clinicians, regulators) so as to spur research and understanding of this condition. The criteria for metabolic syndrome include obesity, dyslipidemia (low high-density lipoprotein and/or elevated triglycerides), elevated blood pressure, and alterations in glucose metabolism. It can lead to a greater potential of type 2 diabetes, lipid disorders, cardiovascular disease, hepatic steatosis, and other circulatory disorders. Although there are no approved drugs specifically for this syndrome, many drugs target diseases associated with this syndrome thus potentially increasing the likelihood of drug-drug interactions. There is currently significant research focusing on understanding the key pathways that control metabolism, which would be likely targets of risk factors (eg, exposure to xenobiotics, genetics) and lifestyle factors (eg, microbiome, nutrition, and exercise) that contribute to metabolic syndrome. Understanding these pathways could also lead to the development of pharmaceutical interventions. As individuals with metabolic syndrome have signs similar to that of toxic responses (eg, oxidative stress and inflammation) and organ dysfunction, these alterations should be taken into account in drug development. With the increasing frequency of metabolic syndrome in the general population, the idea of a "normal" individual may need to be redefined. This paper reports on the substance and outcomes of this workshop.

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

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."

The Microbiome and Sustainable Healthcare.

Increasing prevalences, morbidity, premature mortality and medical needs associated with non-communicable diseases and conditions (NCDs) have reached epidemic proportions and placed a major drain on healthcare systems and global economies. Added to this are the challenges presented by overuse of antibiotics and increased antibiotic resistance. Solutions are needed that can address the challenges of NCDs and increasing antibiotic resistance, maximize preventative measures, and balance healthcare needs with available services and economic realities. Microbiome management including microbiota seeding, feeding, and rebiosis appears likely to be a core component of a path toward sustainable healthcare. Recent findings indicate that: (1) humans are mostly microbial (in terms of numbers of cells and genes); (2) immune dysfunction and misregulated inflammation are pivotal in the majority of NCDs; (3) microbiome status affects early immune education and risk of NCDs, and (4) microbiome status affects the risk of certain infections. Management of the microbiome to reduce later-life health risk and/or to treat emerging NCDs, to spare antibiotic use and to reduce the risk of recurrent infections may provide a more effective healthcare strategy across the life course particularly when a personalized medicine approach is considered. This review will examine the potential for microbiome management to contribute to sustainable healthcare.

Lead exposure and increased food allergic sensitization in U.S. children and adults.

BACKGROUND: Whether blood lead levels are associated with sensitization to food allergens in adults and children is unclear. Prior studies have shown that exposure to lead is associated with atopic sensitization and modulation of several cytokines (eg, interleukin [IL]-12, IL-10, interferon [IFN]-γ, and IL-4 production) and with T-cell dysregulation and bias toward T helper 2 (Th2) activity. The objective of this work was to assess whether exposure to lead is independently associated with allergic symptoms and sensitizations in a large nationally representative sample of children and adults. METHODS: We studied 2712 children and 4333 adults enrolled in the 2005-2006 cycle of the National Health and Nutritional Examination Surveys (NHANES). Participants were tested for serum-specific immunoglobulin E (IgE) levels to food allergens as well as blood lead levels. Food allergens tested included shrimp, egg, peanut, and milk. Logistic regression models adjusted for demographic factors, body mass index, history of asthma, smoking, housing characteristics, and current exposure to animals in the home, to assess the association of blood lead levels with sensitization to food allergens. RESULTS: Median (interquartile range [IQR]) for serum blood was 0.87 µg/L (0.61 to 1.31) in children and 1.48 µg/L (0.92 to 2.34) in adults. At baseline, 672 (24.7%) of children participants and 719 (16.6%) of adult participants tested positive for increased sensitization to food allergens. A 2-fold increase in blood lead levels in adult participants was associated with increased sensitization to food allergens (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.02 to 1.22). Blood lead was not associated with sensitization to food allergens among pediatric participants (OR, 0.95; 95% CI, 0.82 to 1.10). CONCLUSION: Exposure to lead was associated with increased odds of sensitization to food allergens in adult but not children participants.

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

This minireview considers the benefits of refocusing attention away from treating the patient as a mammalian human to managing the complete patient: a majority microbial superorganism. Under the "completed self" model for formation of the human-microbial superorganism, the single, most pivotal sign in distinguishing a life course of health versus that filled with disease is self-completion (i.e., seeding of the minority mammalian human by the majority microbial portion of the symbiont). From a disease prevention perspective, microbial seeding at birth and subsequent nurturing of the microbiota are significant steps to reduce the risk of both noncommunicable diseases (e.g., type 1 diabetes) and certain infectious diseases. Management of the microbiome during pregnancy, birth, and shortly thereafter appears to be the most significant critical window for healthy superorganism formation. However, the bolus for microbiota seeding at birth and the nurturing process are subject to environmental influences and disruption, such as exposure to toxic chemicals and drugs, infections, and other physical and psychological stressors. Additionally, childhood and adult corrective measures, such as fecal transplantation and administration of prebiotics and probiotics, while potentially useful, may have limitations that are yet to be fully defined. This minireview considers (1) basic features of management of the microbiome to facilitate self-completion, (2) protection of the microbiota from environmental hazards, and (3) the benefits of using a superorganism focus for health management beginning with pregnancy and extending throughout childhood and adult life.

Developmental Immunotoxicity, Perinatal Programming, and Noncommunicable Diseases: Focus on Human Studies.

Developmental immunotoxicity (DIT) is a term given to encompass the environmentally induced disruption of normal immune development resulting in adverse outcomes. A myriad of chemical, physical, and psychological factors can all contribute to DIT. As a core component of the developmental origins of adult disease, DIT is interlinked with three important concepts surrounding health risks across a lifetime: (1) the Barker Hypothesis, which connects prenatal development to later-life diseases, (2) the hygiene hypothesis, which connects newborns and infants to risk of later-life diseases and, (3) fetal programming and epigenetic alterations, which may exert effects both in later life and across future generations. This review of DIT considers: (1) the history and context of DIT research, (2) the fundamental features of DIT, (3) the emerging role of DIT in risk of noncommunicable diseases (NCDs) and (4) the range of risk factors that have been investigated through human research. The emphasis on the human DIT-related literature is significant since most prior reviews of DIT have largely focused on animal research and considerations of specific categories of risk factors (e.g., heavy metals). Risk factors considered in this review include air pollution, aluminum, antibiotics, arsenic, bisphenol A, ethanol, lead (Pb), maternal smoking and environmental tobacco smoke, paracetamol (acetaminophen), pesticides, polychlorinated biphenyls, and polyfluorinated compounds.

Lung dendritic cell developmental programming, environmental stimuli, and asthma in early periods of life.

Dendritic cells (DCs) are important cells of our innate immune system. Their role is critical in inducing adaptive immunity, tolerance, or allergic response in peripheral organs-lung and skin. The lung DCs are not developed prenatally before birth. The DCs develop after birth presumably during the first year of life; exposures to any foreign antigen or infectious organisms during this period can significantly affect DC developmental programming and generation of distinct DC phenotypes and functions. These changes can have both short-term and long-term health effects which may be very relevant in childhood asthma and predisposition for a persistent response in adulthood. An understanding of DC development at molecular and cellular levels can help in protecting neonates and infants against problematic environmental exposures and developmental immunotoxicity. This knowledge can eventually help in designing novel pharmacological modulators to skew the DC characteristics and immune responses to benefit the host across a lifetime.

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

This review introduces a potential unifying concept involving the risk of chronic diseases in which early-life exposure to endocrine-disrupting chemicals (EDCs) can program host responses for misregulated inflammation. Inflammation is a part of host defense against pathogenic challenges and one of the processes necessary for normal tissue homeoregulation and for reproduction (e.g., implantation, labor). Deviations from tightly regulated inflammation present a significant health risk because unresolved inflammation can compromise tissue function and increase the risk for later-life cancer in the affected target tissue. The critical windows of innate immune vulnerability during prenatal and neonatal maturation are when developmental programming and the trajectory for childhood and adult inflammatory responses are largely established. Misregulated inflammation is a common thread that links most significant chronic diseases and conditions across all physiologic systems as well as the associated comorbid conditions. As a result, chronic diseases exist both as a myriad of conditions and as an integrated, dysfunctionally connected unit. Because the hormone microenvironment exerts a significant effect on resident innate immune cell function, endocrine disruption is likely to produce misregulated inflammation in tissues. Among the factors determining specific health risks and disease outcomes across a lifetime are the age of exposure, sex, genetic background, and transgenerational epigenetic experiences. Additional research into early-life EDC exposure and misregulation of inflammation appears to be a useful avenue for reducing environmental health risks.

Juvenile toxicity testing protocols for chemicals.

There is increased awareness of the specific position of children when it comes to hazards of xenobiotic exposures. Children are not small adults, since their exposure patterns, compound kinetics and metabolism, and sensitivity of their developing organs may differ extensively from adults. Current international hazard assessment test guidelines do not specifically address juvenile exposures and effects. In conjunction with the Annual Meeting of the European Teratology Society, a satellite meeting was organized to specifically address juvenile toxicity testing issues for chemicals. The workshop focused on developmental neurotoxicity and developmental immune toxicity testing in juvenile animals. A clear case was made for the importance of juvenile toxicity testing, showing that in animal studies developmental neurotoxicity and immunotoxicity parameters express specifically high sensitivities after exposure during the juvenile period. Additional data will be generated in the coming years, and OECD initiatives will need to further the issue at the global regulatory level.

Developmental immunotoxicity (DIT): assays for evaluating effects of exogenous agents on development of the immune system.

Developmental immunotoxicity (DIT) occurs when exposure to environmental risk factors prior to adulthood, including chemical, biological, physical, or physiological factors, alters immune system development. DIT may elicit suppression, hyperactivation, or misregulation of immune responses and may present clinically as decreased resistance to pathogens, allergic and autoimmune diseases, and inflammatory diseases. Immunotoxicity testing guidelines established by the Environmental Protection Agency for adult animals (OPPTS 8703.7800) require functional tests and immunophenotyping that are suitable for detecting immunomodulation, especially immunosuppression. However, evaluating immune function in offspring that are not fully immunocompetent yields results that are challenging to interpret. Therefore, this unit will describe an optimum exposure scenario, reference two assays (immunophenotyping and histopathology) appropriate for detecting immunomodulation in weaning-age offspring, and reference four assays (immunophenotyping, histopathology, T cell-dependent antibody responses, and delayed-type hypersensitivity) appropriate for detecting immunomodulation in immunocompetent offspring. The protocol also will reference other assays (natural killer cell and cytotoxic T lymphocyte) with potential utility for assessing DIT.

Current status of developmental immunotoxicity: early-life patterns and testing.

Developmental immunotoxicity (DIT) occurs when exposure to environmental risk factors prior to adulthood, including chemical, biological, physical, or physiological factors, alters immune system development. DIT may elicit suppression, hyperactivation, or misregulation of immune responses and therefore may present clinically as decreased resistance to pathogens, allergic and autoimmune diseases, and inflammatory diseases. When evaluating DIT in an animal model, specific endpoints are assessed, which can reveal the potential for a risk factor to alter immune system development. However, linking DIT evaluation in an animal model with clinical realities observed in human populations requires that DIT testing regimens evaluate critical windows in immune system development. In addition, pathways leading to DIT may not be apparent without the stressors that induce aberrant and detectable responses. This review contains brief descriptions of recently published work that addresses disease patterns associated with DIT and solutions for altering such patterns of disease. We also comment on gaps between DIT testing in animal models and the clinical manifestation of immune-based diseases in children that can be filled by a better understanding of critical windows in immune system development and DIT testing that includes multiple functional assays.

Maternal and childhood asthma: risk factors, interactions, and ramifications.

Asthma is emerging as a premier example of a health risk that can largely be molded by the status of the mother and the environmental conditions encountered during sensitive windows of prenatal and early childhood development. While genetic background, allergic status of parents, and predisposition for atopy and inflammation play a role, early-life environmental conditions can completely alter the course of immune and respiratory system development. Environmentally induced alterations that (1) maintain the Th2 bias seen during gestation, (2) block the maturation of innate immune cells and (3) create inflammatory dysfunction in the infant provide the foundation for childhood asthma. No single risk factor can fully explain the increased prevalence of asthma in recent decades but it is assumed that the rapid increase is due to environmental and/or epigenetic changes. Well-established and suspected environmental risk factors cover all categories of early life interactions from diet, exposure to environmental contaminants and drugs, maternal and neonatal infections, hygiene, timing of vaccinations and even the mode of birth delivery. Because asthma is connected to the risk of several comorbid chronic conditions, the benefit of asthma risk reduction and prevention is greater than initially may be apparent. This review discusses strategies to optimize preventative and therapeutic options across life stages.

Fractal immunology and immune patterning: potential tools for immune protection and optimization.

Fractals are self-similar geometric patterns that are inherently embedded throughout nature. Their discovery and application have produced significant benefits across a wide variety of biomedical applications. Recently, complex physiological systems (e.g., neurological, respiratory, cardiovascular) have been shown to exhibit fractal dimensions that are capable of distinguishing among physiologic function versus dysfunction and, in turn, health versus disease. Additionally, fractal data suggest that the immune system operates under similar patterned relationships, and this is in keeping with the recent findings that immune-based diseases are organized according to specific patterns. This review considers the potential benefits of using fractal analysis along with considerations of nonlinearity, scaling, and chaos as calibration tools to obtain holistic information on immune-environment interactions. The potential uses of both synthetic and artificial immune systems for improved protection of the biological immune system are also discussed. The addition of holistic measures of immune status to currently collected biomarkers of immunotoxicity has the potential to increase the effectiveness of health risk assessment. The objective of extending fractal physiology analyses to the immune system would be to promote immune optimization as a public health benefit, which would include improved: (1) immunotoxicity testing and effective health risk reduction and (2) measures of effective immune management for children, adults, and aged individuals.