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
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.
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.
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,
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).
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.
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
Corresponding author: Ayman Mukerji Househam, MS
E-mail address: firstname.lastname@example.org
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
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.
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.
Stress may be viewed as an actual or perceived challenge to physiological
equilibrium.3Dukkha 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.
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.
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
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 centerconsists 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
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
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
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 cantrigger 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
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
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
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
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
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
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.
Thepathogen-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
TheHPA 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
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
Catecholaminergicreceptors 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
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.98,99Dukkha 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 betweentheTh1 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 througha
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
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
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
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
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.
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.136,137Although the biological mechanisms of meditation
are still being fully elucidated, its salutary effects are evident.
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.
The research team thanksVictor 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
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