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The Effects of Stress and Meditation on the Immune System, Human Microbiota, and Epigenetics

Ayman Mukerji Househam, MS; Christine Tara Peterson, PhD; Paul J. Mills, PhD; Deepak Chopra, MD

ABSTRACT

Context • Globally, more than 25% of individuals are affected by anxiety and depression disorders. Meditation is gaining popularity in clinical settings and its treatment efficacy is being studied for a wide array of psychological and physiological ailments. An exploration of stress physiology is an essential precursor to delineation of the mechanisms underlying the beneficial effects of meditation practices.

Objective • The review outlines a model of interconnected physiological processes that might support the continued inclusion and expansion of meditation in the treatment of diverse medical conditions and to investigate the role that gut microbiota may play in realizing well-being through meditation.

Design • The authors conducted a scientific literature database search with the goal of reviewing the link between stress management techniques and human microbiota. Their goal was also to identify the extent of underlying epigenetic reactions in these processes. The review was completed in approximately 2 y. Databases searched included Medline via PubMed and Ovid, PsycINFO via Ovid, Spinet, ProQuest Central, SAGE Research Methods Online, CINAHL Plus with Full Text, Science Direct, Springer Link, and Wiley Online Library. Keywords searched included, but were not limited to,stress, meditation, mindfulness,immune system, HPA axis,sympathetic nervous system,parasympathetic nervous system, microbiota,microbiome, gut-barrier function, leaky gut, vagus nerve, psychoneuroimmunology, epigenetic, and NF-κB.

Setting • The study took place at New York University (New York, NY, USA), the University of California, San Diego (La Jolla, CA, USA), and the Chopra Foundation (Carlsbad, CA, USA).

Results • Psychological stress typically triggers a fight-or-flight response, prompting corticotropin-releasing hormone and catecholamine production in various parts of the body, which ultimately disturbs the microbiota. In the absence of stress, a healthy microbiota produces short-chain fatty acids that exert anti-inflammatory and antitumor effects. During stress, an altered gut microbial population affects the regulation of neurotransmitters mediated by the microbiome and gut barrier function. Meditation helps regulate the stress response, thereby suppressing chronic inflammation states and maintaining a healthy gut-barrier function.

Conclusions • The current research team recommends the integration of meditation into conventional health care and wellness models. Concurrently, studies to explore the effects of meditation on human microbiota are warranted. ( Adv Mind Body Med. 2017;31(4):10-25.)

Ayman Mukerji Househam, MS , is a research assistant and laboratory manager at the Child Study Center, Langone Medical Center, New York University, in New York, New York.Christine Tara Peterson, PhD , is a postdoctoral research fellow in the Department of Family Medicine and Public Health, University of California, San Diego, in La Jolla, California. Paul J. Mills, PhD , is director and professor in the Department of Family Medicine and Public Health, University of California, San Diego. Deepak Chopra, MD, is a voluntary clinical professor in the Department of Family Medicine and Public Health, University of California, San Diego; cofounder of the Department of Ayurveda and Yoga Research at the Chopra Foundation in Carlsbad, California; and cofounder of Chopra Center for Wellbeing in Carlsbad, California.

Corresponding author: Ayman Mukerji Househam, MS

E-mail address: aymanmukerjihouseham@gmail.com

The Buddha taught followers how to end suffering (ie, dukkha) and to rise above the inevitable experience of illness, aging, and death. A positive or even neutral mindset (ie, sukha) is the prescription to overcome suffering.

The undeniable truths that bewildered the Buddha still exist. The world has made apparent progress, yet life has become increasingly overwhelming. Globally, more than 25% of individuals are affected by anxiety and depression disorders.1 Anxiety-related disorders are now the predominant cause of mental illness, affecting 18% of the US population. 2

Perhaps the art and science of happiness has been overlooked in the process of realizing material potential. A revisiting of the ancient teachings of happiness is thus warranted. However, revisiting them through philosophy alone would have a finite reach in this age of scientific reason. Fortunately, with practitioners now empowered by an understanding of stress physiology, the teachings may be interpreted in terms of the underlying science.

The mental state of equanimity that can be achieved through the practice of meditation is, in part, characterized by an absence of stress. Meditation is gaining popularity in clinical settings, and its treatment efficacy is being studied for a wide array of psychological and physiological ailments, including psychiatric disorders, cardiovascular diseases, dermatological conditions, gastrointestinal dysfunction, and musculoskeletal disorders. This interest necessitates further investigation into the underlying mechanisms of its therapeutic value.

Therefore, exploration of stress physiology is an essential precursor to delineation of the mechanisms underlying the beneficial effects of meditation practices. Stress physiology includes processes across the autonomic nervous system, the immune system, and the gut microbiota.

In the current review, the research team outlines a model of interconnected physiological processes that might support the continued inclusion and expansion of meditation in the treatment of diverse medical conditions. It discusses the role of physiological systems in the context of dukkha and sukha, with the intention of providing a novel framework in which to understand and conceptualize the beneficial effects of meditation practices.

The current research team hypothesized a significant role for the gut microbiota in realizing well-being through meditation. In describing this process model, the research team has underscored the profundity of the effects of these states by highlighting their epigenetic nature. Ultimately, the review highlights the potential avenues of meditation research and encourages the integration of meditation as a treatment modality in conventional medicine.

METHODS

Procedures

The review took place across 3 locations: New York University (New York, NY, USA), the University of California, San Diego (La Jolla, CA, USA), and the Chopra Foundation (Carlsbad, CA, USA). The goal was to identify details of the stress pathway consisting of the hypothalamic–pituitary–adrenal (HPA) axis, the autonomic nervous system, human microbiota (ie, especially the widely studied gut microbiota), and epigenetics. The review consists of studies reflecting the processes underlying the state of stress and the state devoid of stress. Therefore, the study aimed to examine more than
400 scientific papers and book chapters across the fields of neuroendocrinology, nervous system, human microbiota, immunology, mind-body medicine, and epigenetics. Databases searched include Medline via PubMed and Ovid, PsycINFO via Ovid, Spinet, ProQuest Central, SAGE Research Methods Online, CINAHL Plus with Full Text, Science Direct, Springer Link, and Wiley Online Library. Keywords searched included, but were not limited to, stress, meditation, mindfulness,immune system, HPA axis,sympathetic nervous system,parasympathetic nervous system, microbiota,microbiome, gut barrier function, leaky gut, vagus nerve, psychoneuroimmunology, epigenetic, and NF-κB. The number of citations was then narrowed to 144. The selection criterion was primarily to cite multiple studies that have been conducted in each of the aforementioned fields of discipline to support the theoretical arguments in this review. All members of the research team reviewed the articles and resulting analyses. Each team member vetted and signed off on the appropriateness of including the articles within this review.

RESULTS

Stress may be viewed as an actual or perceived challenge to physiological equilibrium.3 Dukkha is a psychological state that triggers a physiological stress response, (ie, dukkha is psychological stress and sukha is a psychological state of ease that is devoid of stress).

The interplay of physiological pillars shapes the cycle of sukha and dukkha, namely (1) the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) regulate the involuntary processes of the body, such as respiration, with the SNS initiating the fight-or-flight response in times of stress, and the PSNS restoring a resting state; (2) the neuroendocrine organs of the HPA axis also regulate the stress response, enabling the start, continuation, and end of the stress management process and maintaining physiological balance (ie, homeostasis); (3) the lymphoid organs of the immune system produce and activate an army of cells and a cascade of chemical reactions, ultimately neutralizing or destroying pathogens; and (4) the microbiota, a collection of 100 trillion microbes prevalent in the parts of the body that interface with the external environment (eg, the gut) and prompts chemical reactions in the body in response to environmental changes.

Dukkha hijacks the body’s stress management machinery (Figure 1) and triggers a fight-or-flight response. The state of mental balance in sukha leads to homeostasis.

Stress Appraisal

Some form of somatosensory stimulus often initiates what is ultimately perceived as a stressor. Upon detection, the stimulus is analyzed to determine whether any action should be taken. Interestingly, this stress appraisal process may be affected by judgment. The limbic system, cerebral cortex, and hypothalamus integrate and analyze raw environmental stimuli (Figure 2).4

Limbic Integrative Center. The limbic system is responsible for the instinctual fear response. A conditioned fear response originates when it identifies an event as a threat based on past memories. Dukkha could trigger this fear response. The limbic system includes the amygdala, hippocampus, thalamus, hypothalamus, basal ganglia, and cingulate gyrus.

The hippocampus helps individuals to remember the context of past events that were perceived as fearful, and the hippocampus-lateral-septum pathway helps them associate the context with an appropriate stress response. 5,6 The midline thalamus plays a role in predicting a threat based on past experiences.7 The amygdala, which is activated in emotional responses, acts as a switch for the stress alarm system and initiates sympathetic and HPA responses.8,9 The amygdala is the seat of the instinctual fear response and does not necessarily thoroughly appraise the threat.10

In summary, the limbic integrative center is where the threat level of an event is judged based on primal instincts and a subjective version of past memories; thus, it is possibly prone to emotional bias and judgment errors.

Cortical Integrative Center. The cerebral cortex supervises and facilitates limbic fear processing. The structures of the limbic and cortical integrative centers have intricate connectivity, supporting their close alliance.11 The medial prefrontal cortex (mPFC) regulates the emotional response and plays an integral role in decision making.12 Interestingly, the infralimbic cortex in the mPFC is part of a circuit that determines whether a stressor is under control.4,11,13-15 It helps humans learn to control overreactions during times of danger.16 In general, the cerebral cortex has the power to override emotional responses.17 In contrast, a misguided cortical integrative center has the power to trigger false alarms.

Hypothalamic Control Center. The hypothalamic stress control center consists of the hypothalamic paraventricular nucleus (PVN), which is heavily innervated with afferents from the limbic and cortical integrative centers. It integrates and translates these inputs into a net excitatory or inhibitory response. If the response is excitatory, a series of stress-related regulatory hormones are secreted.18,19

Parvocellular neurons of the PVN release corticotropin-releasing hormone (CRH), triggering an HPA axis response. The parvocellular neurons project both to the SNS (eg, the parabrachial nucleus) and to the PSNS (eg, the dorsal nucleus of the vagus nerve), thereby exerting regulatory control over both.18 In addition, the PVN’s magnocellular neurons release oxytocin and arginine vasopressin (AVP). Oxytocin downregulates stress responses.20 Among its other functions, AVP plays a crucial role in reducing the stress response of the HPA axis through a negative feedback mechanism,21 toward the conclusion of a stressful event.

In summary, the hypothalamic stress control center integrates information from the limbic and cerebral cortices, promotes a fight-or-flight response if necessary, and regulates the neuroendocrine pillars (ie, the HPA, SNS and PSNS) of the cycle of sukha, (ie, homeostasis) and dukkha (ie, suffering). Ironically, these inputs can carry a faulty interpretation of upstream signals, thus resulting in an erroneous fight-or-flight response.

Stress Response

A phased fight-or-flight response initiates (1) an immediate induction of sympathetic hormones; (2) a longer lasting, intermediate effect facilitated by the SNS; and (3) a prolonged effect induced by the HPA axis. 22

Immediate Stress Response. The immediate effects, which last for 2 to 3 seconds, provide urgent physical responses, such as sweating, rapid heart rate, and muscle tension. To enable a rapid response, the inputs of this phase are based on a quick assessment of the triggering event. This relatively hardwired response pathway originates in sympathetic premotor neurons of the brainstem and hypothalamus.23,24 The brainstem receives somatosensory stimuli and mediates arousal.25 It quickly detects danger.8 The brainstem is implicated in instinctual primitive responses that are not muddled by subjective interpretation.26 Therefore, this pathway is not biased by judgment.

The second branch of sympathetic premotor neurons originates in hypothalamic regions (eg, the PVN) and receives enough information about the somatosensory trigger and the psychological interpretation to offer an immediate threat assessment.27,28 However, a quick assessment, instead of a complete analysis, can lead to a false alarm, as follows: (1) the sympathetic premotor neuronal pathway projects to sympathetic preganglionic neurons, which innervates the sympathetic ganglia with cholinergic projections (ie, secreting neurotransmitter acetylcholine [ACh])22 and (2) the postganglionic neurons emerge from those projections and innervate the internal organs, directly injecting catecholamines and immediately eliciting the physical stress response.22,29 However, a prolonged stress response is needed to ward off a potential danger effectively.

Intermediate Stress Response. The chromaffin cells of the adrenal medulla have the same embryological origin as the sympathetic ganglia and, thus, are innervated by cholinergic sympathetic preganglionic nerves.29,30 When stimulated, these cells release catecholamines directly into circulation. It takes longer for the neurotransmitters to travel to effector organs than those being directly delivered by hardwired sympathetic nerves. However, the effects of the intermediate stress response last longer (ie, 20 to 30 seconds) than the immediate effects and are more global.22

Prolonged Stress Response. After stress stimuli are fully analyzed, the hypothalamic control center secretes CRH and AVP into the hypophyseal blood vessels that connect the hypothalamus to the anterior pituitary gland. These hormones stimulate the anterior pituitary gland to produce and secrete adrenocorticotropic hormone (ACTH) into the general circulation. ACTH induces glucocorticoid (GC) synthesis and release from the adrenal cortex.

GC mediates the stress management process by regulating metabolic, cardiovascular, and immunological activities. It stimulates the adrenal medulla to produce an increased amount of epinephrine for the sympathetic response31 and to restore homeostasis after stress subsides. 27 Depending on the nature of the stressor, these effects may persist from minutes to weeks.

In summary, the hypothalamic control center initiates the HPA axis response, thereby generating potent steroids that remain active until the body recovers from stress. Thus, a fight-or-flight response triggered by judgment errors has harsh results. The processes underlying the immediate, intermediate, and prolonged stress responses are shown in Figure 3. The overall stress response has an expansive effect. The HPA axis also stimulates an immune response.

Immune Response to Dukkha

From an evolutionary perspective, a fight-or-flight response serves as a survival mechanism against physical injury or pathogenic invasion and infection. An immune response helps to prevent infection. Thus, in part, an immune reaction in stress offers an evolutionary advantage to humans. 32 However, dukkha can trigger a fight-or-flight response, including the accompanying immune response and inflammation, as elaborated in Figure 4.32

Catecholaminergic varicosities of postganglionic neurons innervate the lymphoid organs where lymphocytes are formed, matured, and activated. 33,34 During stress, sympathetic nerves release catecholamines that bind to the adrenergic receptors expressed on lymphoid tissues,35 which then signal and regulate the activity of lymphocytes. 36 During stress, an altered gut microbial population affects the regulation of neurotransmitters mediated by the microbiome and gut barrier function, which will be discussed in the following section. 37

The signals generated by B- and T-lymphocytes trigger the partial degradation of p100 protein that leads to the release of p52/relB proteins, which are the precursors of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex.38 When NF-κB is expressed and activated, a cascade of signaling events leads to the production of proinflammatory cytokines. These cytokines induce the maturation and activation of both B and T cells, which upregulate the NF-κB pathways, thus intensifying a self-perpetuating proinflammatory cycle. 38-40 T-helper 1 (Th1) cells, a T-cell subtype, play a key role in this proinflammatory phase of the immune response, which is known as a Th1 response.

The HPA axis is activated during stress and produces GC molecules that bind to glucocorticoid receptors (GRs) located on target tissues. GRs signal lymphocytes to move toward effector sites.41 Concurrently, the NF-κB pathway induces the transcription of adhesion proteins expressed on endothelial tissues at effector sites, which instruct lymphocytes to persist locally.42,43

Gut Microbial Response to Dukkha

Lymphoid tissues generate disease-fighting immune cells. Some are located near places where the body interfaces with the external environment. Environmental microbes are also picked up at these interfaces. Therefore, the microbiota, including gut microbes, is in close proximity to lymphoid tissues and engages in active bidirectional communication with the immune system. An immune response thus affects gut microbes and vice versa (Figure 5).

Gut Microbial CRH Pathway in Dukkha. Inflammation resulting from stress affects various parts of the body, including the gut. Proinflammatory cytokines interact with enteric nerves to stimulate the secretion of CRH locally.44 CRH binds to CRH receptors found on the gut epithelium. Mast cells are found near these receptors and offer immune protection. Upon CRH receptor binding, the receptor signals mast cells to degranulate.45

A healthy gut wall selectively allows specific molecules (eg, nutrients) in while it keeps others (eg, pathogens) out. Tight junction protein (TJP) prevents permeability via the paracellular route between epithelial cells. Mast cell degranulation prompts the release of chymase, which is thought to degrade the cellular matrix including TJP, resulting in increased gut-barrier permeability.46

A permeable gut epithelium exposes the underlying immune system to bacterial and food-derived antigens that induce inflammation. Sustained inflammation due to leaky gut perturbs the balance of the gut microbiota and leads to dysbiosis that can feature an increased abundance of pathogenic organisms with the capacity to breach the epithelium, gain access to immune-sensitive compartments, and proliferate systemically via the bloodstream. The cell wall of
Gram-negative bacteria contains lipopolysaccharide (LPS). Acute-phase LPS-binding protein binds with LPS and subsequently forms a ternary complex with cluster of differentiation 14 (CD14) protein. This action allows LPS to bind its receptor complex, which consists of toll-like receptor 4 (TLR4) proteins and myeloid differentiation protein 2 (MD-2).47

The LPS-MD-2 binding triggers TLR4 oligomerization, signaling the recruitment of the adaptor proteins (1) myeloid differentiation primary response gene88 (MyD88), (2) toll/interleukin (IL) 1 receptor (IL-1R) domain-containing adaptor (TIRAP), (3) TIR-domain-containing adaptor-inducing interferon-β (TRIF), (4) TRIF-related adaptor molecule (TRAM), and (5) sterile A and HEAT-Armadillo Motifs (SARM). 48

TIRAP activates a MyD88-dependent inflammatory pathway, generating NF-κB and proinflammatory cytokines.49,50 TRAM activates TRIF, which leads to the production of NF-κB and type 1 interferons. The MyD88 pathway recruits IL-1R-associated kinase-4 (IRAK-4) enzyme, which increases the stability of tumor necrosis factor alpha (TNF-α) mRNA. An activated TNF-α promotes inflammation and vasodilation of the intestinal endothelium, prompting an efflux of leukocytes.51,52 In summary, adaptor-protein recruitment triggers an immune response in local lymphoid tissues,53-55 thus increasing systemic inflammation.

Gut Microbial Zonulin Pathway in Dukkha. Systemic inflammation and exaggerated pathogenic stimulation often accompany anxiety and depression.56-58 The resulting MyD88-dependent inflammatory pathway leads to the upregulation of zonulin, a scaffolding protein. Under normal circumstances, zonulin binds TJP to the gut epithelial cytoskeleton59; however, its upregulation leads to actin-microfilament polymerization and results in TJP disassembly. 56

The microbiota is greatly affected by conditions of reduced gut-barrier function. A healthy microbiota has a diversity of species and functions. However, when gut-barrier activity is reduced, a shift occurs toward a less diverse microbial population.60 The host’s genetic predisposition plays a role in determining the microbial species that are more likely to bloom.61 Moreover, as one microbial species often cross-feeds on the byproducts generated by another, new sets of intermicrobial relationships emerge.62 These effects collectively affect processes, including biochemical, physical, and ecological processes within each gut microbial community, thus disturbing their equilibrium.63

Stress Recovery

Restoration of the HPA Axis. The fight-or-flight response is meant to be short lived. In a healthy organism, its effects tend to dampen appropriately. The GR detects when GC plasma levels reach a threshold and starts revoking the fight-or-flight response.64 The bound receptor then translocates to the nucleus and thereafter triggers the transcriptional activities to initiate restoration (Figure 6).

GC induces transcription of the NF-κB inhibitor protein (ie, inhibitor of κB [IκB]), thereby downregulating the inflammatory NF-κB cascade.65 GC retracts NF-κB that was already released. 66 GC and NF-κB transcription factor proteins bind to each other to create a mutual suppression.67 Moreover, GC promotes the transcription of
anti-inflammatory proteins.67,68 Collectively, these processes terminate the inflammation that was triggered by a fight-or-flight response.

Restoration of the PSNS. Signaled by the negative feedback from the HPA axis, the PSNS takes an active role in restoring homeostasis. Its effects are communicated via the vagus nerve, which innervates many internal organs, including lymphoid organs. The main neurotransmitter in the PSNS is ACh. ACh binds to ACh receptor (AChR) and triggers a cascade of reactions that reduce inflammation.

Vagal innervations at the celiac-superior mesenteric ganglion modulate the adrenergic input to the spleen via the splenic nerve. Toward the resolution of a fight-or-flight response, vagal ACh suppresses adrenergic stimulation of the spleen, thereby stifling the production of immune cells. 69 Moreover, it binds to AChR found on immune cells to suppress the NF-κB pathway and the subsequent production of proinflammatory cytokines.69,70 Furthermore, vagal afferents stimulate the anti-inflammatory pathway of the HPA axis, thus reinforcing its restorative function (Figure 7).70

Restoration of the Immune System. The pathogen-detecting, major histocompatibility complex (MHC) is upregulated on cell surfaces during a stressful event. 71 Circulating catecholamines reach a threshold level, signaling that pathogens have been eliminated. Cell surfaces thus downregulate MHC expression.72 MHC modulates T-cell receptor signaling and, therefore, the resulting immune response. Downregulated MHC induces a weaker T-cell-receptor signal.72 An attenuated signal serves as a trigger for the restorative T-helper 2 (Th2) cell pathway, 32,73,74-75 which ultimately releases cytokines that promote recovery from inflammation.76 Cytokines IL-4 and IL-13 induce expression of proteins required for wound repair.76 IL-4, IL-5, IL-10, and IL-13 activate macrophage scavenger cells to clear any persistent pathogens (Figure 8).76

Restoration of Microbial Health. The shift from the Th1 to the Th2 immune response upregulates nicotinic AChR on the gut epithelial surface, which is also heavily innervated by vagal ACh afferents, thereby upregulating ACh-AChR binding on the epithelium, ultimately to trigger anti-inflammatory responses (Figure 9).77

Chronic Dukkha or Suffering

The HPA axis restores homeostasis by lowering inflammation that accompanies a fight-or-flight response. However, the proinflammatory SNS continues to be activated by psychological stress. Thus, 2 opposing forces emerge during chronic stress. The SNS offers the more urgent protection from physical distress. Ultimately, survival is chosen over homeostasis (Figure 10).78

The HPA axis adapts to chronic stress. GC-GR binding normally signals homeostasis, but the HPA axis may become GR-resistant during chronic stress.79 The GR facilitates a healthy immune response. 43 Thus, a blunted GR-sensitivity leads to weak immune responses, suppresses proinflammatory responses, and prevents Th 1 cytokine levels from reaching the levels necessary for disease fighting. 75,80 Natural killer cells that normally prevent tumors and microbial infections are less cytotoxic than Th1-cells, which may explain, at least in part, the observed susceptibility to cancer during chronic stress.81,82

The PSNS attenuates vagal ACh-signaling, and the SNS remains activated. 83 Sympathetic overactivation promotes excessive catecholamine production.84 A constantly stimulated SNS induces a steady production of cytokines, such as interferon gamma (IFN-γ). IFN-γ encourages TJP uptake from the gut epithelium to form vesicles, thus disturbing the integrity of the gut epithelial barrier.85 IFN-γ also triggers the NF-κB pathway within the gut. 86

Catecholaminergic receptors reuptake and store excess extracellular catecholamines. In chronic stress, the receptors desensitize themselves to prevent excessive catecholaminergic reuptake.87-89 The stored catecholamines are eventually depleted. Because catecholamines are crucial for essential physiological functions, such as maintaining a normal heart rate, the adrenal medulla increases catecholamine production during chronic stress.90 Prolonged stress can create a predictable, maladaptive pattern in which the SNS remains activated but slightly attenuated.90

Epigenetics of Dukkha and Sukha

The illness- and health-inducing effects of dukkha and sukha, respectively, can become epigenetically imprinted. Genetic modifications that occur throughout a lifetime are called epigenetics and can be inherited by future generations.91

An epigenetic change does not alter the structure of deoxyribonucleic acid (DNA); it instead increases or decreases the rate of gene expression, through modifications of acetylation, deacetylation, messenger ribonucleic acid (mRNA), and microRNA (miRNA).92 Acetylation loosens the histone protein that packages the DNA strand, thus opening up the DNA to be transcribed. Deacetylation by histone deacetylase (HDAC) causes the histone to wrap more tightly around the DNA, thus preventing the gene from being easily expressed. Methylation adds a methyl group to genes and typically silences gene expression. In addition, after a gene is expressed, mRNA decays. Modifications to mRNA can trigger early mRNA that suppresses gene expression. Finally, miRNA binds with target mRNA to regulate its translation. When an epigenetic modification occurs repeatedly, an epigenetic memory is formed, which is interpreted as a survival necessity and often is transmitted to offspring.91,93

During the cycle of sukha and dukkha, the body’s physiological pillars undergo epigenetic modifications that result in a decrease or increase in inflammatory gene expression.94

Epigenetic Reactions of the HPA Axis. In chronic stress, methylation of GR promoter genes is upregulated, which results in suppression of the GR expression and, therefore, the GC signaling that follows GC-GR binding.95,96

Pleasant experiences or sukha promote serotonin production, which is associated with cyclic adenosine monophosphate (cAMP) activation. The cAMP pathway facilitates cellular communication. An activated cAMP pathway results in increased production of the cAMP-response element-binding (CREB) protein, which recruits the CREB-binding protein (CBP). CBP acetylates promoter regions of GR genes, ultimately to upregulate the number of GRs during sukha (Figure 11).95

Epigenetic Reactions of the SNS and PSNS. In chronic dukkha, the SNS ultimately adapts by silencing its reuptake transporter genes through methylation (Figure 12).97

The PSNS helps restore homeostasis primarily through ACh. Dukkha and sukha both exert epigenetic effects on ACh neurotransmission. Because excessive ACh accumulation is toxic, acetylcholinesterase (AChE) clears ACh postneurotransmission through deactivation.98,99 Dukkha downregulates acetylation and upregulates methylation of the promoter gene for AChE and thus represses AChE expression.99 Therefore, ACh is not effectively cleared during dukkha. PSNS neurotransmission is dependent on the presence of synaptic ACh. During dukkha, high levels of ACh accumulate; PSNS neurotransmission is interrupted; and the restoration of homeostasis becomes challenging.

In sukha, a normally functioning PSNS activates the AChR alpha-7 nicotinic acetylcholine receptors, initiating production of microRNA miR-124, which induces an anti-inflammatory response (Figure 13). 100,101

Epigenetic Reactions of the Immune System. In sukha, a healthy balance between the Th1 response and the Th2 response is maintained via epigenetic regulation. Both T h1 and Th2 cells differentiate from naive T cells after being stimulated by IFN-γ and IL-4, respectively. During a T h1 response in sukha, IFN-γ is acetylated, resulting in subsequent IFN-γ expression. DNA methylation is subsequently downregulated at the IFN-γ promoter region of T h1 cells, stimulating Th1 cell development. Concurrently, Th2-stimulating IL-4 expression is silenced through methylation.102 During a Th2 response in sukha, acetylation of the IL-4 gene leads to IL-4 expression, promoting Th2 proliferation. Meanwhile, IFN-γ is silenced through methylation, suppressing the Th1 response.34

In dukkha, a timely shift from a Th1 to a Th 2 response does not occur due to underlying epigenetic reactions, which can lead to immune dysfunction.103

Epigenetic Reactions of Gut Microbiota. The human microbiota is a potent agent of epigenetic modification. In dukkha, an imbalanced or dysbiotic structure of the microbial population can develop. Microbes undergo DNA mutation, adjusting to this change. The new genes are passed on to the next generation of microbes in as little as 20 minutes.104 This exceptionally fast evolution signals the rest of the body to adapt. Meanwhile, inflammatory microbes continue displacing beneficial microbes.105

In sukha, the microbiota preserves well-being through a multitude of epigenetic effects, such as its anti-inflammatory and antiproliferative benefits and improved barrier function. In healthy individuals, the gut microbiota produces short-chain fatty acids (SCFAs), such as butyrate, in abundance.106,107

Butyrate, a potent HDAC inhibitor, promotes acetylation and thus gene expression through several mechanisms. The metabolic products propionate, lactate, and pyruvate are HDAC-inhibitory as well but to a lesser degree than butyrate, with propionate being the most potent HDAC inhibitor of the 3 products.108 This HDAC-inhibitory property often leads these metabolic products to hyperacetylate histones that ultimately exert beneficial effects on health.

For example, butyrate uses its acetylation properties to put a brake on the NF-κB pathway. This pathway employs cytochrome c oxidase 2 (COX2) to generate inflammatory cytokines. A set of proteins keeps the COX2 mRNA stable. Butyrate is hypothesized to acetylate these proteins, thus destabilizing COX2 mRNA and downregulating its proinflammatory pathway. 109 In addition, butyrate modulates the immune system by inhibiting HDAC classes I and IIa.

HDAC classes I and IIa suppress regulatory T-cell (Treg) proliferation. Therefore, their inhibition leads to Treg proliferation and, thus, downregulation of effector T-cell functions.110 Another study found that the copious amount of butyrate produced in sukha hyperacetylates pyruvate dehydrogenase kinase (PDK) histones, thereby upregulating PDK expression, which inhibits the pyruvate dehydrogenase complex (PDC).106,107,111

PDC helps divert pyruvate to the mitochondrial oxidative pathway as a source of energy for tumor growth.111 Therefore, through PDC inhibition, butyrate may arrest tumor survival and growth.

In a final example, the acetylative properties of the ample butyrate and propionate in sukha promote the barrier function by upregulating mucin expression.112,113 Mucin, a protein found in the epithelial layer, forms viscous gels to trap pathogens and promotes gut-barrier function. Moreover, the SCFAs produced in the gut are speculated to influence miRNA acetylation and methylation patterns. 114,115 These miRNAs, in turn, regulate intestinal barrier functions and immune defense (Figure 14).115,116

Due to the pervasiveness and system-wide effects of human microbiota, these epigenetic effects are not limited to the gut. Moreover, microbes communicate with the body via the general circulation by triggering immune pathways.53,54,117 Therefore, their epigenetic effects may also be systemic.

Meditation to End Chronic Dukkha

Meditation, a common technique to calm the mind, exerts marked physiological influence and ultimately reduces the effects of dukkha.

Effects on the HPA Axis. On average, meditators exhibit lower levels of cortisol compared to nonmeditators.118-121 Interestingly, some studies reported elevated levels of plasma cortisol following meditation, which also correlated with an increase in positive affect.122,123 Although seemingly counterintuitive, meditation is speculated to have a regulatory effect on plasma cortisol. In 2 groups of participants with higher and lower than normal baseline cortisol levels, a normalizing effect was observed.123,124

Effects on the SNS and the PSNS. Meditators tend to have a lower heart rate, blood pressure, respiratory rate, and oxygen metabolism.120,121,125-127 In addition, increased heart-rate variability is observed during meditation, which is often associated with activation of the anterior cingulate cortex (ACC). 128-130 The engagement of attention and working memory during meditation can be attributed to ACC activation, which in turn exerts autonomic control over cardiac functions.129,130 Interestingly, greater coactivation of the SNS and PSNS in cardiac function is observed in meditators, which represents a mechanism that promotes healthier cardiac function by regulating ventricular contractility and heart rate. 130-132

Effects on the Immune System. IL-6 and C-reactive protein—both biomarkers of inflammation—are reduced after meditation, and the magnitude of the reduction correlates with the amount of meditation experience.124 Meditators also produce an increased antibody response compared to nonmeditators following flu vaccine administration.133,134

The biological mechanisms underlying the beneficial effects of meditation on the immune system are being investigated currently. Receptor-interacting serine-threonine kinase 2 (RIPK2), which promotes generation of NF-κB,135 is downregulated in meditators.136 COX2 genes are also downregulated in meditators.136 NF-κB employs COX2 to generate inflammatory cytokines; thus, COX2 inhibition reduces inflammation. Among differentially expressed inflammatory pathways, NF-κB is observed as being frequently affected in mind-body practices.137,138

Interestingly, meditation upregulates HDAC inhibition,136 and the degrees of RIPK2 and COX2 downregulation in meditators are correlated with the level of HDAC inhibition.136 However, the cause of these positive changes is yet to be determined.

Effects on the Gut Microbiota. Meditation practice improves the symptoms of functional gastrointestinal disorders, such as irritable bowel syndrome.139-142 Changes in the structure of the microbial population of the gut are thought to underlie both physiological and psychological symptoms of such disorders. 143 A healthy microbiota, on the other hand, promotes homeostasis and a robust immune system.144 Although the effects of meditation on the microbiome have yet to be established, it would not be surprising that the microbiome, at least in part, mediates some of the beneficial effects of meditation on such disorders.

DISCUSSION

Psychological stress often triggers a fight-or-flight response, prompting CRH production in various parts of the body, including the gut where more than 100 trillion microbes reside.144 Stress-induced factors such as CRH disturb the microbiota. In the absence of stress, a healthy microbiota produces SCFAs that exert anti-inflammatory and antitumor effects, potentially through such mechanisms as HDAC inhibition and NF-κB suppression. Interestingly, meditation induces epigenetic changes that mirror these latter effects, which include upregulated histone deacetylase inhibitors (HDACi) and downregulated inflammatory NF-κB.

The current research team speculates that meditation helps regulate the stress response, thereby suppressing inflammation and maintaining healthy gut-barrier function. In addition, the team hypothesizes that the microbiota then generates healthy amounts of HDAC inhibitory SCFAs, which can contribute to the HDAC inhibition and downregulation of NF-κB that has been observed in contemplative practices.136,137 Although the biological mechanisms of meditation are still being fully elucidated, its salutary effects are evident.

CONCLUSIONS

The current research team recommends the integration of meditation into conventional health care and wellness models. Concurrently, further studies to explore the effects of meditation on human microbiota are warranted.

ACKNOWLEDGEMENTS

The research team thanks Victor Hewitt for the illustrations that he provided.

AUTHOR DISCLOSURE STATEMENT

Paul J. Mills is director of research at the Chopra Foundation. Deepak Chopra is the cofounder of the Chopra Center for Wellbeing and the Chopra Foundation and Christine Tara Peterson (CTP) is a postdoctoral fellow at the University of California, San Diego, and CTP is partially funded by the Chopra Foundation.

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