Section 1: Neurovisceral Integration & the Vagal Tank
Introduction to Vagal Tank Theory
The theoretical foundation of this paper is based on the Vagal Tank Theory (VTT), which proposes that cardiac
vagal control can be viewed as an indicator of how effectively an organism can martial self-regulation
resources to maintain homeostasis.1 Visualize a tank filled with a fluid ‘resource,’ the level of which rises and falls as
it is depleted and replenished. The tank represents the vagal efferent fibers involved in cardiac vagal control.
The resource itself refers, in aggregate, to all the systems and processes that are involved in self-regulation. The level
of fluid in the tank represents the collective integrity and adaptability of these resources.1 It is important to note that
the vagal tank analogy does not refer to the vagus nerve itself, but to the many systems regulated by the nerve.
Further, the “fluid resource” does not represent cardiac vagal control per se, but rather, cardiac vagal control is an
indicator of the quality of these resources and the effectiveness with which they can be deployed.1 The theoretical
roots of vagal tank theory stem from the Neurovisceral Integration Model (NIM),2 and Polyvagal Theory.3 Both are
important in understanding the vagal tank theory. However, much of our discussion will fall under the NIM.
Neurovisceral Integration Model
The VTT is primarily based on the Neurovisceral Integration Model (NIM)2 and: a key component in the NIM is
cardiovascular control. Cardiac vagal control is the phasic output of the central autonomic network (CAN) located in
the brain.1 The link between self-regulation and cardiac vagal control is formed from the functional anatomy and
physiology of the vagus nerve and the CAN (Figure 1).1
Figure 1: Overview of the anatomical and functional role of the vagus nerve in neurovisceral integration. On the left side of the diagram the basic
functional role of vagal afferents and efferents is depicted. Vagal afferent fibers carry information from the visceral organs to the CNS structures
of the CAN. Vagal efferent fibers carry information from the CNS to the viscera. On the right-hand side, the anatomical structure of the vagus
nerve and the structures which it innervates. Some of the neuroanatomical structures that make up the CAN are depicted in the brain in the upper
right.4
The Central Autonomic Network
The CAN forms an essential piece of the body’s internal self-regulation systems. Functionally, it is the central hub
through which the brain controls the various physiological and behavioral responses to stress that are crucial to an
organism’s adaptability.2 Structurally, it includes regions of the prefrontal cortex, the amygdala, the hypothalamus,
the nucleus of the tractus solitarius (NTS), the nucleus ambiguous (NA), and several regions of the brainstem.2 The
reciprocally interconnected nature of these components allows for a bidirectional flow of information between the
higher and lower levels of the (CNS).2 An extensive discussion of CAN structure and function will help to build the
foundation for a discussion of the interconnectedness of central and peripheral inflammation and their effects on
vagal tank resources.
CAN: Neuroanatomy
The prefrontal cortical regions of the CAN are involved in high-order autonomic control. The central nucleus of the
amygdala is involved in autonomic expression of emotional states. Several areas of the hypothalamus as well as the
periaqueductal gray matter coordinate autonomic, neuroendocrine, and behavioral responses to stress. In the
midbrain, the parabrachial Kolliker-fuse region in the pons sends viscerosensory information to the forebrain and is
involved in the control of respiration, circulation, and vomiting.5 In the medulla, the NTS has two important roles.
The first is that of a controller where: the NTS initiates multiple brainstem reflexes that effect autonomic,
respiratory, and cardiovascular function. The second role is one of communication where: the NTS
receives viscerosensory information from the glossopharyngeal and vagus nerves and transmits this information to
all other parts of the CAN, including the amygdala, prefrontal cortex, and hypothalamus.5 The intermediate reticular
zone of the medulla houses neurons and interneurons involved in ‘premotor’ autonomic and respiratory output. The
ventrolateral medulla is home to a “cardiorespiratory network” consisting of vasomotor, cardiovagal, and respiratory
neurons which: control preganglionic, respiratory, and spinal motoneurons. Having thus described the anatomy of
the CAN, we will now explain how neurological and chemical information from the periphery makes its way to this
central integration network. We discuss two routes by which this may take place: viscerosensory and humoral
integration.
CAN: Viscerosensory Integration
The CAN receives viscerosensory information through the NTS via sensory (i.e., afferent) neurons in the periphery
such as: baroreceptors, pulmonary receptors, cardiac receptors, and chemoreceptors. The afferent fibers that carry
these messages may terminate in NTS subnuclei, where they are involved in reflex adjustment of the peripheral
organs (Figure 1).5 Other fibers, however, terminate in the commissural medial NTS, which projects to all other
regions of the CAN. Some travel to higher brain centers to initiate integrated responses involving autonomic,
endocrine, and behavioral centers. Others are routed through the parabrachial nucleus and ventrolateral medulla,
which form parallel pathways to the forebrain.5 The functional neuroanatomy of the NTS indicates its function as
the primary routing station of the CAN which operates based on the complex neurochemical coding of incoming
information. Peripherally, the primary source of this information comes from vagal afferent neurons.
The vagus is the 10th cranial nerve. In Latin, the name means “wandering,” as its widespread branches are distributed
throughout numerous organs of the body. The vagus nerve is composed of 90 percent afferent, and 10 percent
efferent fibers (Figure 1).4 Its vastly branching network makes it capable of rapid, widespread communication
throughout the body.1 The vagus originates in the brainstem, traveling through the neck where it innervates the
muscles of the throat involved in swallowing. Thoracic vagal branches innervate the heart, lungs and diaphragm.
The liver, pancreas, and spleen receive vagal innervation.4 In the abdomen, the vagal nerve branches out to innervate
the muscular and mucosal layers of the (GI) tract (Figure 1) where it interacts with the gut via the enteric nervous
system (ENS).
The ENS forms the functional interface between the vagus nerve and the gut. It consists of a neural mesh woven into
the lining of the entire GI tract from esophagus to anus. 4 This mesh is composed of two neural plexuses: a
submucosal plexus which regulates epithelial cell function, and a myenteric plexus which controls smooth muscle
function. The ENS contains some 100 – 500 million neurons, the largest peripheral accumulation of nerve cells in
the human body. It has been described as a ‘second brain’ or ‘the brain within the gut’.4 Thus, the
CAN recieves visceral input from the periphery via a neural route beginning in the ENS, traveling through
the vagus nerve, and terminating in the NTS where it is re-routed throughout the CAN.
CAN: Humoral Integration
The CAN receives humoral inputs through direct and indirect routes. The direct inputs involve circulating
hydrophobic molecules including sexual, adrenal, and calcitriol steroids which act on receptors located throughout
the CAN5. The indirect route involves circulating hydrophilic substances, which enter the CNS through the
circumventricular organs (CVO). The CVO are found in the wall of the cerebral ventricles at the blood-brain
interface. They comprise a ‘leaky’ area of the blood brain barrier (BBB) 5 due to the densely populated capillaries of
the CVO contain highly fenestrated endothelial walls. The decreased BBB integrity of the CVO’s allows hydrophilic
molecules to directly enter the CNS where they can access neural receptors throughout the brain. It is important to
note that inflammatory cytokines and many key neurotransmitters and hormones are composed of peptides and, thus,
are capable of direct access to the CNS through this mechanism. This will become important later in our discussion
as we explore the impact of inflammatory cytokines on the CAN.
CAN: Reciprocal Interconnection and Neurochemical Complexity
Bennaroch 1993 describes four key functional characteristics of the CAN and for the purpose of this paper we will
focus on two: reciprocal interconnectedness and neurochemical complexity. The structures within the CAN are
reciprocally interconnected via myelinated; and unmyelinated axons organized into complex fiber systems. These
include the median forebrain bundle, and dorsal longitudinal fasciculus.5 Through reciprocal interconnectedness, the
components of the CAN engage in continuous feedback with each other, allowing for the complex integration of
self-regulatory responses.5
Transmission of information along the axons of the CAN involves several key neurotransmitters, including: include
amino acids, neuropeptides, monoamines, and acetylcholine.5 Amino acids such as GABA (Gamma Amino Butyric
Acid) and L-glutamate act via ion channel receptors. Neuropeptides, monoamines, and acetylcholine primarily act
through G protein coupled receptors (GPCR). However, neuropeptides and monoamines may also affect neurons at a
distance by travelling through the extracellular fluid, a process called “volume transmission”.5 Thus, the origination
of incoming information will dictate the neurotransmitter use and, thus, shape the message and speed in which the
message is communicated.
The lateral tegmental system is a central monoamine pathway which innervates all components of the CAN. 5 It
includes epinephrine and norepinephrine producing neurons in the medulla located in the intermediate reticular
zone.5 Furthermore, its functional connections to the spine, brain stem, and hypothalamus (via the locus coeroelus)
allow for the regulation of autonomic and neuroendocrine responses.5 Other noteworthy monoamine components of
the CAN include neurons of the raphe nuclei, which contain serotonin, the paraventricular nucleus and zona incerta,
which contain dopamine, and the posterolateral hypothalamus, which synthesize histamine. All these monoamine
pathways also innervate neuroglia, and intrinsic blood vessels. 5 Taken together, the CAN characteristics of
neurochemical complexity and reciprocal interconnectedness indicate a complex network of neural structures which
requires fine-tuned highly coordinated communication in order to function as an effective regulator of vagal tank
resources. Later sections will explore how dysregulation of the CAN and the neurotransmitters upon which it
depends may impede this regulatory function, negatively impacting self-regulation ability.
HRV and situational adaptability
The CAN’s primary output is to the heart via the sympathetic neurons of the stellate ganglia, and the
parasympathetic neurons of the vagus nerve.2 Under resting conditions, vagal efferent fibers emit a tonus, or
continuous signal, to the sinoatrial node of the heart. This tonus results in the release of the vagus nerve’s primary
neurotransmitter acetylcholine, which suppresses sympathetic activity, slowing the heart rate.6 Heart rate is largely
determined by sympathovagal balance or the dynamic interaction between the sympathetic and parasympathetic
nervous systems that modulates heart rate according to the state of the organism.4
This sympathovagal interaction causes rhythmic oscillations in heart rate which can be measured by recording and
analyzing the time between consecutive R-R intervals on an electrocardiogram.4 The resulting metric, known as
HRV can be used to estimate the strength of the vagal influence on heart rate.4 Higher values of HRV indicate
stronger vagal tone and lower values indicate weaker vagal tone and greater sympathetic influence.4 In healthy
individuals, vagal tone dominates the resting state. Higher resting HRV suggests ‘autonomic flexibility’ or the
organism’s ability to respond appropriately across a wide range to physiological and environmental stressors.
Conversely, lower resting HRV indicates a lack of autonomic flexibility4 and may result in a mismatch between
ANS response or regulation of an incoming stressor. However, the general hypothesis that higher HRV is better may
be overly simplistic. For instance, if HRV becomes too high, it may cease to be adaptive, potentially resulting in
syncope, pulmonary constriction, and increased gastric secretion. According to polyvagal theory: when responding
to changes in the environment, both increased and decreased HRV can be considered adaptive depending upon the
circumstance. Successful adaptation involves “reliable systematic withdrawal and reengagement of the vagal brake”
in order to appropriately regulate metabolic output according to the demands of the situation.1
The prefrontal cortex and amygdala are particularly important in understanding the role of the CAN in effective
situational adaptation. The prefrontal cortical areas of the CAN tonically inhibit the amygdala 2 Disinhibition
(activation) of the amygdala may lead to increased HR and, thus, decreased HRV via two basic pathways (Figure 2).
First, by disinhibiting (activating) sympatho-excitatory neurons in the brainstem, resulting in an increased
sympathetic output. Secondly, through inhibition of the NTS, and subsequently the NA and the dorsal vagal motor
nucleus, decreasing parasympathetic output to the heart via the vagus nerve2 (Figure 2). Therefore, a decrease in
prefrontal cortex activation would lead to disinhibition of the amygdala, resulting in a simultaneous increase in
sympathetic output and a decrease in parasympathetic output to the heart (Figure 2).2
Figure 2: A schematic diagram of the influence of sympathovagal balance upon HRV composed of the pathways whereby the SNS and PSNS
exert influence upon the heart rate. The amygdala is under tonic inhibitory control of the prefrontal cortex. Activation of the central nucleus of the
amygdala (CeA) inhibits the nucleus of the soilitary tract (NTS). The NTS, in turn, inhibits the inhibition of the RVLM by the CVLM, thereby
allowing RVLM sympathoexcitatory activation. Simultaneously, the NTS also inhibits vagal motor neurons in the nucleus ambiguous (NA) and
the dorsal vagal motor nucleus (DVN). The CeA can also directly activate the RVLM. In short, A decrease in frontal cortical activity due to
environmental stressors can lead to disinhibition of the CeA, leading to vagal suppression, disinhibition of brainstem cardioaccellerators and thus
an increase in heart rate and a reduction in HRV.2
Evolutionarily, this process is essential for energy mobilization toward the fight or flight response.7 When this
sympathetically aroused state becomes chronic, it leads to excessive wear and tear on the body’s physiological
regulation systems. This is referred to as ‘allostatic load’ and the processes which contribute to it can be termed
allostatic processes. Namely, the HPA (Hypothalamic Pituitary Adrenal) axis and inflammation. 7
Conclusion
The vagus nerve and CAN are profoundly interwoven with the body’s self-regulation systems. Their vastly
branching bidirectional communication networks are involved in complex feedback mechanisms. Together they
form the anatomical foundation of the neurovisceral integration model, upon which vagal tank theory is based. In the
next section we will introduce the concept of inflammation and discuss how it may affect the integrity of the vagal
tank by compromising vital self-regulatory systems via the neurovisceral integration pathways.
Section 2: Inflammation & The Vagal Tank
Introduction
In the previous section, we laid the foundation for the vagal tank. The objective of section two is to describe how
inflammation can impact the integrity of the vagal tank. In other words, we aim to describe the mechanisms and
pathways by which inflammation can disrupt, dysregulate, or degrade the body’s vagally mediated self-regulation
systems. We will begin with a brief overview of inflammation and inflammatory cytokines. Then, we will describe
the pathways and mechanisms through which peripheral inflammation which originates in the gastrointestinal (GI)
tract can access the brain. We will then discuss the effects of inflammatory cytokines on neurotransmitter function.
Finally, we will describe the vagally mediated anti-inflammatory feedback systems involved in the neuroimmune
axis. In conclusion, we will discuss how these effects might impair CAN function, thus negatively impacting all
systems involving central autonomic control. Taken together, these concepts support our hypotheses that excessive
peripheral inflammation originating in the gut leads to increased central inflammatory activity, which may
significantly contribute to the decreased integrity of vagal tank self-regulation resources.
Inflammation
Inflammation is a key component of the body’s innate defensive reaction against damage and foreign pathogens.
The word inflammation comes from the Latin word “inflammatio,” meaning “fire”. Inflammation is traditionally
characterized by heat, redness, pain, swelling, and impaired functioning of bodily tissues.8 The inflammatory
response begins with cellular recognition of a ‘danger’ signal. This may come in the form of a pathogen or the
components of dead or damaged cells. Once activated, this signal initiates a cascade of events including the release
of inflammatory cytokines and immune cell mobilization. 9 Inflammation can become systemic,
resulting in increased plasma concentrations of inflammatory biomarkers and a greater number of inflammatory
cells in the bloodstream.10 The magnitude of the inflammatory response is of critical importance. If chronic
or excessive, it can become pathologic.11
Inflammatory Cytokines
A major feature of systemic inflammation is the increased concentration of inflammatory cytokines in tissues,
organs, blood, and the cerebrospinal fluid.9 Cytokines are a category of protein based signaling molecules which act
as regulators of inflammation and cellular function.12 Peripherally, cytokines are produced by a variety of cell
types including: epithelial, endothelial, parenchymal, and stromal cells, adipocytes, and fibroblasts. Cytokines are
also produced by immune cells such as macrophages, lymphocytes, and mast cells. Centrally, cytokines are
produced by neurons, microglia, and astrocytes.12
Some 30 cytokines have been identified and those most relevant to systemic inflammation and a potential role in the
vagal tank theory include interleukins (ILs), tumor necrosis factors (TNFs), interferons (IFNs), and transforming
growth factors (TGFs).13 It is difficult to place them in distinct categories. For example, IFN-alpha, and IL-6,
generally considered pro-inflammatory cytokines, may also exhibit anti-inflammatory properties.12 However,
several broad categories have been described. The two most relevant to our discussion are pro-inflammatory
cytokines (IL-1, IL-6, IL-8, IL-17, IL-21, IL-22, IFN-a, TNF-a) and anti-inflammatory cytokines (IL-4, Il-10, IL-11,
IL-13, TGF-b). The former, as their name suggests, tend to initiate, escalate, and perpetuate the inflammatory
process. The latter, under the influence of regulatory T-cells, tend to prevent, or attenuate the escalation of
inflammation.12
Inflammatory Routes of CNS Infiltration
At least three pathways of inflammatory access to the brain have been described in the literature. First, the humoral
route, whereby cytokines from the gut enter systemic circulation and either pass through leaky regions of the blood
brain barrier (BBB) or are actively taken into the brain by cytokine specific transporters.9 These active transport
mechanisms have been identified for IL-1, TNF-a, and IL-1ra (IL-1 receptor agonist) .13 It is worth clarifying that
the humoral route of cytokine access to the brain is not the same thing as the humoral integration described in
section 1. Rather, it is a subcomponent of the broader humoral integration pathway, which includes not only
cytokines and other inflammatory mediators, but also hormones and neurotransmitters. Second, the neural route,
which involves the transduction of cytokine signals to the brain via activation of cytokine receptors on vagal afferent
fibers innervating the visceral organs.9 This is supported by the presence of IL-1 mRNA in vagal afferent neuronal
bodies. Furthermore, IL-1 has been shown to directly stimulate vagal afferent nerve activity.13 Third, the cellular
route, which primarily involves the release of chemokines by activated glial cells, the primary inflammatory cell in
the brain.9 Furthermore, cytokines in the brain can bind to endothelial receptors, causing the release of inflammatory
mediators such as chemokines, adhesion molecules, nitric oxide, and prostaglandins.13 The release of chemokines
and other inflammatory mediators can induce chemotaxis of peripheral immune cells such as monocytes, T cells,
and neutrophils to the brain via the parenchyma and meninges. 9 12 Furthermore, the excessive expression of
inflammatory mediators in the brain can lead to impaired integrity of the BBB, thereby increasing inflammatory
access to the brain through the humoral route mentioned above.13 Through these three pathways, and their
synergistic interaction, it is hypothesized that peripheral inflammation can spread to the brain, thereby precipitating
a central inflammatory response.9
Inflammatory Cytokine Impact on Neurotransmitter Function
The disruptive effects of cytokines on neurotransmitter function can be divided into three categories: synthesis,
release, and reuptake.9 The synthesis of monoamine neurotransmitters can be influenced by at least two pathways.
First, the presence of cytokines can lead to activation of the enzyme Indolamine 2,3 dioxygenase (IDO).9 IDO
breaks down tryptophan into kynurenine. Tryptophan is the primary precursor of serotonin. If it is broken down into
kynurenine, it is not metabolized to serotonin. Thus, activation of IDO leads to a depletion of serotonin
levels.9,12 Serotonin depletion has been widely associated with depressive symptoms. Thus, depression research may
be a potential source of evidence supporting the notion of cytokine-induced serotonin depletion. In patients
administered IFN-a for cancer or infectious disease, increased kynurenine and decreased tryptophan levels were
associated with depressive symptom severity and incidence of major depression.9
The second pathway through which cytokines disrupt monoamine synthesis is through the depletion of
tetrahydrobiopterin (BH4). BH4 is an essential cofactor for the rate limiting enzymes involved in the synthesis of
serotonin, dopamine, and norepinephrine.9 Cytokines lead to the depletion of BH4 through both the stimulation of
nitric oxide synthase and the generation of nitrogen and oxygen radicals. Nitric oxide synthase increases the
utilization of BH4, and nitrogen and oxygen radicals lead to its irreversible degradation.9 In one study on patients
treated with IFN-a, an association was found between increased levels of pro inflammatory cytokine IL-6, and
decreased levels of BHR in the cerebrospinal fluid (CSF).9
In addition to interfering with monoamine synthesis, inflammatory cytokines may also impact the release of certain
neurotransmitters including dopamine and glutamate. Disruption of dopamine is thought to occur via cytokine
induced decreases in the release of dopa, a precursor of dopamine. This may be related to the above-mentioned
increase in kynurenine due to IDO activation.9 Increased levels of inflammatory cytokines are also associated with
increased glutamate expression by astrocytes. The increased presence of glutamate leads to increased activation of
n-methyl-D-aspartate (NMDA) receptors, which leads to a reduction in brain-derived neutrophic factor (BDNF).
This is noteworthy since BDNF is an important contributor to neurogenesis.9 A reduction in BDNF may impair the
ability of the neuronal structures of the CAN to recover from insult or injury, including the neurotoxic and
neurodegenerative effects of inflammatory cytokines.
Other neurotransmitters effected by inflammatory cytokines, such as IL-1, include GABA and acetylcholine. GABA
can attenuate cytokine release via inhibition of nuclear factor kappa beta (NF-kB) and p38 mitogen activated protein
kinase (p38 MAPK) signal pathways.9 Acetylcholine, the primary neurotransmitter of the vagus nerve, plays a key
role in the vagal anti-inflammatory pathways. Il-1 has been shown to inhibit the release of acetylcholine from
neurons in the hippocampus.9 Thus, reduced levels of GABA may blunt central anti-inflammatory factors, and the
reduction of acetylcholine may blunt the peripheral anti-inflammatory effects of the vagus nerve.
Finally, inflammatory cytokines may affect neurotransmitter reuptake through the activation of signaling pathways
in the brain such as p38 MAPK. Increased MAPK activation is associated with increased reuptake pump transporter
activation. This in turn leads to decreased expression of key neurotransmitters including serotonin, norepinephrine,
and dopamine.9 For instance, increased activity of the serotonin reuptake transporter (SERT) has been demonstrated
in response to TNF and IL-1. Furthermore, the pharmacological inhibition of p38 MAPK has been shown to reverse
this effect.9
These findings indicate that the synthesis, release, and reuptake of dopamine, epinephrine, norepinephrine,
and serotonin may be detrimentally affected by excessive elevation of inflammatory cytokines including TNF-a,
IFN-y, Il-1 and Il-6. This represents the depletion of key chemical substrates required for effective coordination of
the CAN. This cytokine-induced depletion of neurotransmitters and subsequent dysregulation of the CAN, the
commander of vagal tank resources, is a core component of our hypothesis.
Neurotoxic and Neurodegenerative effects of Cytokines
Figure 3: Schematic representation of the neurotoxic and neurodegenerative effects of inflammatory cytokines, particularly neurotransmitter
dysregulation, oxidative stress, apoptosis or neuronal cell death, ultimately resulting in neurodegeneration and depletion of an individual’s
“cognitive reserve”13
In addition to disrupting neurotransmitter function, certain inflammatory cytokines are thought to have a destructive
effect on neurons themselves. For example, IL-1 has been shown to exacerbate neuronal damage in the cerebral
ventricles.13 IL-1B and TNF-a have been shown to inhibit glutamine synthetase, which converts excess glutamate to
glutamine. Excess glutamate levels are associated with excitotoxicity. Thus, elevated inflammatory cytokines in the
brain may exacerbate glutamate induced excitotoxicity.13 IL-1 may also promote neurodegeneration by stimulating
nitric oxide production by glial cells. Increased nitric oxide levels may lead to neurodegeneration due to increases in
reactive nitrogen species.13 Additional neurotoxic effects of Il-1 include damage to the blood brain barrier, and
induction of amyloid-B protein.13 It is also worth noting here that the PFC, the location of crucial components of the
CAN, has a high concentration of IL-6 receptors and may thus be a target for IL-6-mediated neurotoxicity and
neurodegeneration. Il-6 may impair neurogenesis and neuroplasticity.12 Glial cells may also play a key role in the
cycle of neuronal damage caused by inflammatory cytokines. In vitro studies have shown that cytokines can activate
glial cells. Glial cells, in turn, can release cytokines when activated. Cytokines have been shown to damage neurons,
causing the release of cellular debris. This debris may in turn activate cytokines and astrocytes, stimulating the
further release of cytokines, thus creating a vicious cycle of inflammatory escalation and neuronal damage in the
CNS.13 Together these effects of inflammatory cytokines may contribute to degradation of the CAN. Prolonged
excessive manifestation of these neurodegenerative processes may “breach an individual’s homeostatic limit, a socalled “cognitive reserve” .13 We therefore hypothesized that neuronal health and integrity may itself be considered a
vagal tank resource that may be depleted under conditions of excessive neuronal damage and degradation.
Vagally mediated Anti-Inflammatory Pathways
Figure 4: Vagally mediated anti-inflammatory pathways. TNFa = tumor necrosis factor alpha, NE = norepinephrine, EPI = epinephrine,
a7nAChR = alpha 7 nicotinic acetylcholine receptor, CAN = central autonomic network, NTS = nucleus of the solitary tract, HPA axis =
hypothalamic pituitary adrenal axis, VN = vagus nerve, DVMN = dorsal motor vagal nucleus, Ach = acetylcholine 14
To understand the impact of cytokines on autonomic regulatory functions, it will be helpful to describe the pathways
by which the CAN and vagus nerve interact to regulate inflammation in the body. The vagus nerve plays a vital role
in the neuroimmune axis, a group of dynamic anti-inflammatory feedback systems.14 There are four vagally
mediated anti-inflammatory pathways: The HPA axis; the vago-splenic pathway; the cholinergic anti-inflammatory
pathway (CAIP) also referred to as the vago-vagal or vago-parasympathetic reflex; and the vago-sympathetic
reflex.4,14
The anti-inflammatory function of the HPA axis involves the detection of inflammation by IL-1 receptors located on
vagal afferent nerve endings in the periphery. These vagal afferents, when activated, fire a signal which terminates
centrally in the NTS where they activate noradrenergic neurons in the NTS. These NTS neurons project to neurons
in the paraventricular hypothalamus. These hypothalamic neurons release corticotropin releasing hormone (CRH).
CRH then triggers the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates
the adrenal glands, causing them to release glucocorticoids such as cortisol into the blood stream.14 Cortisol, a major
stress hormone, is a potent anti-inflammatory agent.7
The vagus nerve is also involved in a second pathway, known as the ‘vago-splenic’ or splenic sympathetic antiinflammatory pathway. It begins like the HPA axis pathway, with the peripheral detection and central
communication of inflammation by vagal afferent fibers. This information is routed through the NTS and distributed
throughout the CAN to be processed and translated into outgoing efferent signals. Vagal efferent fibers stimulate the
splenic sympathetic nerve, which releases norepinephrine (NE) from its distal end. NE docks to its receptors on
splenic lymphocytes, triggering the release of ACh. ACh then docks to the nicotinic ACh receptors on spleen
macrophages. This blocks the release of TNF-a, a powerful inflammatory mediator.4
The third pathway is the CAIP. This so called ‘vago-vagal’ reflex involves both afferent and efferent fibers of
the vagus nerve.14 In this pathway, inflammation is once again detected by vagal afferents and communicated to the
CAN. This signal is integrated in the CAN and results in the activation of vagal efferent fibers that innervate the
entire GI tract.14 ACh is released into the synapse with enteric neurons of the enteric nervous system (ENS). These
enteric neurons share synaptic junctions with gut macrophages. Like the splenic pathway, ACh released by these
neurons then docs to the macrophages via nicotinic ACh receptors, inhibiting the release of TNF-a.4 Thus, the
neuroimmune axis functions to regulate inflammation through a variety of feedback loops that involve multiple
response pathways, both sympathetic and parasympathetic, which interact dynamically with one another.15
A fourth neuroimmune pathway, referred to as the ‘vago-sympathetic’ reflex, has also been described in which vagal
afferents activate the CAN as described above. The CAN then responds by increasing sympathetic outflow through
the tractus intermediolateralis in the spinal cord. Sympathetic efferent neurons innervating the adrenal glands trigger
the activation of adrenal chromaffin cells, which release catecholamines (epinephrine, norepinephrine) into the
blood stream, thus increasing global sympathetic activity.14
These vagally mediated reflexes comprise a physiological network of interactive feeback systems responsible for
global inflammatory regulation. The proper adaptive functioning of these vital self-regulation mechanisms is
critically dependent on the coordinated function of neural structures that compose the CAN. Excessive inflammatory
infiltration of the CNS may compromise the function of these anti-inflammatory vagal tank resources via
neurotransmitter dysregulation and neuronal degradation.
Inflammatory effects on Vagal Tank Resources
Thus far we have established the routes by which inflammation may enter the brain. Further, we have established
how inflammatory cytokines in the brain may affect neurotransmitter function. We also discussed the potential
neurotoxic and neurodegenerative effects of inflammation. We now turn to a discussion of how the central effects of
inflammation might negatively impact the functional integrity of the vagal tank resources including: regulation of
cardiac vagal control and allostatic processes such as inflammation and the HPA axis.
Disruption of neurotransmitter function may lead to dysregulation and disfunction of the CAN. According to the
NIM, the CAN functions as the command center of neurophysiological regulation. Its proper functioning requires a
highly orchestrated communication process between structures that involves both neurochemical complexity and
reciprocal interconnection.5 It also requires a high degree of sensitivity to a variety of internal conditions. Finally,
effective CAN function requires the effective coordinated action of multiple response pathways involving both the
sympathetic and parasympathetic nervous system.15 Thus, dysregulation of the CAN may lead to dysregulation of
the vagally mediated feedback loops and control mechanisms over which it presides. These feedback systems, such
as the HPA axis, the CAIP, and cardiac vagal control, are critical components of the body’s ability to regulate
allostatic factors such as inflammation and stress, and therefore must be considered vagal tank resources.
For example, CAIP functioning may lead to decreased peripheral inflammatory suppression and thus, a further
increase in peripheral inflammation. Furthermore, IL-1 can increase the expression of acetylcholinesterase, thereby
creating a deficit of acetylcholine. Acetylcholine is the primary neurotransmitter involved in parasympathetic output.
Therefore, in addition to dysregulation of the CAN via neurotransmitter disfunction, IL-1 may impact
parasympathetic outflow directly by depleting the supply of acetylcholine.13 As a primary mechanism for
suppressing peripheral inflammation, The CAIP can be considered a vagal tank anti-inflammatory resource.
Therefore, its degradation or disfunction would constitute a detrimental reduction in self-regulatory ability.
The HPA axis is effective at regulating acute inflammation in the short term. However, prolonged, or excessive
levels of cortisol can lead to chronic sympathetic hyperactivity, which is associated with increased production of
pro-inflammatory cytokines such as IL-1, IL-6, C-reactive protein (CRP), and TNF-a.4 One explanation for this
effect is that prolonged expression of glucocorticoids can lead to glucocorticoid resistance, thus blunting the antiinflammatory effects of cortisol.12 Furthermore, glucocorticoids can increase the expression of PIC receptors. They
can also potentiate increased expression of acute phase proteins by IL-1 and IL-6.13 These effects may be
exacerbated by the fact that the sympathetic and parasympathetic systems often interact antagonistically with one
another.15 Thus, prolonged inflammatory or stress response may lead to dysregulation of the HPA axis such that it
shifts from an anti-inflammatory actor to a more pro-inflammatory actor. In addition, excessive activation of the
HPA axis may have an antagonistic effect on vagally mediated parasympathetic outflow, further impairing the
body’s ability to fight inflammation. As an integral component of the body’s response to stress and inflammation,
the HPA axis is deeply involved in allostatic processes and must also be considered a vagal tank resource.
Therefore, inappropriate HPA axis function due to CAN dysregulation may contribute to the degradation of selfregulatory ability.
Oxidative Stress and Inflammation
Reactive oxygen species (ROS) are highly reactive, enzymatically produced molecules which attack biomolecules
such as lipids, DNA, and proteins, causing damage to cells and tissues and triggering the pathways of cell death.
Sources of ROS production include: cellular metabolic enzymes, xanthine oxidase, metabolism of arachidonic acid,
and cytochrome P-450.16 Activation of inflammatory cells involves contact of the cell membrane with an
inflammatory stimulus. It is worth noting here that ROS and cytokines are both key inflammatory stimuli. When
activated, cells involved in the inflammation process take up oxygen and release ROS. Additionally, these cells
release cytokines, chemokines, and other mediators which activate other inflammatory cells, generating yet more
ROS. As a result of ROS, transcription factors are activated including NF-kB. NF-kB increases the expression of
genes involved in cytokine production, thus leading to further release of cytokines. The resulting vicious cycle
fosters an environment of sustained oxidative and inflammatory stress.17
NF-kB Pathway
NF-kB is a cardinal cellular transcription pathway involved in both inflammation and oxidative stress. Prominent
stimuli of NF-kB include oxidative stress, proinflammatory cytokines, hyperglycemia, toxic metals, UV radiation,
alcohol, and benzopyrene. NF-kB is found in the cytoplasm, where it is bound to a high-affinity inhibitor which
keeps it retained in the cytosol. When the cell contacts an inflammatory stimulus, a signaling cascade is triggered,
resulting in the phosphorylation of IkB. When IkB is phosphorylated, NF-kB is dissociated from it, becoming free to
translocate to the nucleus where it activates the expression of pro inflammatory genes. 18 In turn, when activated, NFkB upregulates the expression of a variety of genes responsible for the production of inflammatory mediators,
including: proinflammatory cytokines, chemokines i.e., monocyte chemoattractant protein (MCP-1), adipokines
(i.e., leptin, adiponectin) adhesion molecules (i.e., E-selectin, P-selectin, soluble vascular cell adhesion molecule-=1)
(sVCAM-1), and soluble intercellular adhesion molecule-1 (sICAM-1), and acute phase proteins (i.e., C-reactive
protein (CRP), fibrinogen). phospholipaseA2 (PLA2), COX-2, and PGE2, inducible nitric oxide synthase (iNOS).18
Thus, the NF-kB pathway represents another aspect of the vicious cycle where inflammatory mediators activate NFkB and in turn NF-kB leads to further production of inflammatory mediators.
Arachidonic Acid Cascade
Arachidonic acid (ARA) is the most common n-6 polyunsaturated fatty acid found in the phospholipid membrane of
macrophages, neutrophils, and lymphocytes. When these and other cells encounter an inflammatory stimulus, the
PLA-2 enzyme is activated. PLA-2 is responsible for the cleavage of ARA from the phospholipid membrane. Once
released, free ARA becomes a substrate for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes. COX
enzymes lead to the production of inflammatory eicosanoids such as prostaglandins (PGs) and thromboxanes (TXs).
A variety of eicosanoids derived from ARA are widely recognized as pro-inflammatory mediators.19 The release of
ARA is precipitated by inflammatory stimuli. As a result of its activation, more inflammatory stimuli are produced.
Thus, the ARA cascade is yet another source of cyclical inflammatory acceleration.
NrF2 System
Nuclear factor erythroid-2 related factor 2 (Nrf2) is another common factor related to oxidative stress and
inflammation.20 Nrf2 is a cellular transcription factor located in the cytoskeleton which is highly sensitive to
oxidative stress. Nrf2 is widely expressed in the major organs and tissues including muscle, heart, vasculature, liver,
kidney, brain, lung, skin, and digestive tract.16 During homeostatic conditions, Nrf2 is associated to Keap1, an actinbound protein. However, when exposed to ROS, Nrf2 accumulates in the nucleus, leading to increased production of
antioxidant response elements (ARE). Through upregulation of antioxidant enzymes, the Keap1-Nrf2 system
protects DNA from oxidative damage caused by ROS and decreases tissue sensitivity to inflammation-related
oxidative damage.16 Finally, research suggests that Nrf2 may also play an anti-inflammatory role due to reciprocal
regulation of Nrf2 and NF-κB.20 Thus, increased activation of Nrf2 represents another potential target mechanism
whereby anti-inflammatory foods may exert their effects.
Biomarkers of Inflammation
In order to explore the effects of anti-inflammatory nutrition, it will be useful to establish a list of common
biomarkers used to measure inflammation. A number of biomarkers are considered to be appropriate indicators
of inflammatory status. In research and clinical practice, the primary means of studying pro-inflammatory and antiinflammatory phenomena involves measuring the concentration of circulating inflammatory
mediators including: acute phase proteins, cytokines, eicosanoids, chemokines, and adhesion molecules.17 Common
pro-inflammatory markers include: CRP, TNF-a, IL-6, IL-1B, IL-8, MCP-1, PGE-2, sVCAM-1, and sICAM-1.
Common anti-inflammatory markers include adiponectin and IL-10.17 The changes in concentration of these markers
in response to various conditions is generally considered to be measurable. Normal ranges of fluctuation in
concentration have been defined in healthy individuals. Assessment of nutritional effects on inflammation involves
examining patterns of change in these biomarkers against a normal reference range. Assessment may also involve
observing whether nutrition can prevent modulation induced by other factors such as poor diet, IFN-y, or
endotoxin.17 For the purposes of this paper, we will focus on the following biomarkers: CRP, TNF-a, IL-6, IFN-y,
IL-1B, IL-8, COX-2, PGE-2, MCP-1, VCAM-1, ICAM-1, and IL-10. In addition to these, evidence of
decreased NFkB activation or increased NRF2 activation will be included as indicative of anti-inflammatory
effects.
Conclusion
Vagal tank theory proposes a metaphorical description of adaptive autonomic function.1 The ‘vagal tank’ is
represented by the vagal efferent fibers between the CAN and the heart. The CAN is the command-and-control
center for vagally mediated self-regulatory resources such as the CAIP, the HPA axis, and cardiac vagal control. If
CAN function is dysregulated, ability of the organism to effectively modulate these systems according to internal
and external situational demands may be significantly impaired. According to VTT, this depletion of adaptive vagal
tank resources will be reflected in HRV measurements. It is important to clarify that cardiac vagal control, or
HRV, “is not to be seen as resource itself but should be considered a physiological indicator reflecting how
efficiently self-regulatory resources are mobilized and used”.1
Inflammation is a primary component of the body’s innate defenses. Pro inflammatory cytokines initiate, perpetuate,
and accelerate inflammatory processes. If left unchecked, the inflammatory response can go systemic, resulting in
excessive levels of proinflammatory cytokines entering the peripheral circulation. Peripheral inflammation may
access the brain via humoral, neural, or cellular routes. Once in the brain, high concentrations of pro-inflammatory
cytokines can disrupt neurotransmitter synthesis, reuptake, and release. Furthermore, certain cytokines have been
found to exert neurotoxic and neurodegenerative effects. Based on these findings, excessive systemic inflammation
may lead to impaired function of the CAN. As the command center of autonomic regulatory processes,
dysregulation of the CAN may have a significant negative impact on the function of vagally mediated antiinflammatory systems, thus creating a cyclical spiral of accelerating inflammation and dysregulation, resulting in
further degradation of vagal tank resources, which represent “the integrity and adaptability of the general selfregulation mechanisms of the organism”1
Section 3 – Anti-Inflammatory Effects of Select Nutritional Components
Our objective thus far was to lay the foundation for our hypothesis that vagal tank resources might be replenished,
preserved, or protected through dietary interventions. Our exploration of these dietary factors will focus on their
inflammatory or anti-inflammatory actions in the body. Nutritional target mechanisms likely to be responsible for
these anti-inflammatory effects include: oxidative stress, the NF-kB pathway, the Nrf2 system, and the arachidonic
acid cascade. We propose that if dietary intervention can stem the tide of systemic inflammation, and systemic
inflammation degrades vagal tank resources, then these dietary factors may represent a relatively inexpensive and
noninvasive method to prevent, slow down, or reverse this degradation.
Table 1: Anti-inflammatory nutritional components and associated biomarkers of inflammation
CRP TNF-a
x
EPA/DHA
Anthocyanin
x
x
IL-6
IFN-y
x
x
IL-1
MCP-1
PGE2
COX-2
IL-8
x
x
x
x
x
x
x
x
x
x
IL-10
x
VCAM-1
ICAM-1
NFkB
NRf2
x
x
x
x
x
x
x
x
Curcumin
x
x
x
x
x
SFN
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
CRP = c-reactive protein, TNF-a = tumor necrosis factor alpha, IL-6 = interleukin 6, IL-1 = interleukin 1, IL-8 = interleukin 8, IL-10 = interleukin 10,
IFN-y = interfeuron gamma, MCP-1 = monocyte chemoattractant protein 1, PGE2 = prostaglandin E2, COX-2 = cyclooxygenase II, VCAM-1 =
vascular cellular adhesion molecule 1, ICAM-1 = intercellular adhesion molecule 1, NFkB = nuclear factor kappa beta, NRf2 = Nuclear factor
erythroid 2-related factor 2, EPA = eicosapentaenoic acid, DHA = docosahexaenoic acid, SFN = sulforaphane
#1: Marine n-3 PUFAs
Omega 3s are a family of molecules that belong to a group of lipids called polyunsaturated fatty acids (PUFA’s).
Their name Omega 3 or n-3 is derived from the position of the double bonded carbon that is closest to the methyl
terminus, the end of the acyl chain of the fatty acid. In Omega 3’s or n-3 PUFAs, the double bond is on the third
carbon, if the methyl carbon is counted as one.19 For now, we aim to introduce the key anti-inflammatory players of
the n-3 PUFA family. These are eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Because they are
only found in significant quantities in marine sources, EPA and DHA are often referred to as ‘marine’ n-3 PUFAs.
The most abundant source of EPA and DHA is the liver and flesh of oily fish such as salmon or mackerel, or the
bodies of krill. One serving of salmon or mackerel may provide 1.5 to 3.0 g of EPA and DHA.19 A single 1000mg
over the counter fish oil capsule contains around 120 mg of EPA and 180 mg DHA for a total of 300 mg of marine
n-3 PUFAs per 1g of fish oil (around 30%). However, the relative proportions of EPA and DHA may vary across
products. There are also concentrated versions of fish oils available which contain a higher proportion of n-3 PUFAs
per unit of fish oil. The PUFAs in fish oil capsules are typically in triacylglycerol (triglyceride) form, whereas in
krill oil they can be found in phospholipid form.19
One unique mechanism through which marine n-3 PUFAs exert their anti-inflammatory actions is the alteration of
cell membrane phospholipid composition. The membranes of human cells are composed primarily of phospholipids.
These form a fluid matrix in which float a variety of signaling and transport proteins. PUFA’s are a primary
component of these membrane phospholipids. Of particular interest to our discussion are the primary cell types
involved in inflammation. Namely macrophages, neutrophils, and lymphocytes. The phospholipid membranes of
these cells contain a high proportion of arachidonic acid, an n-6 PUFA that is a key substrate of inflammatory
eicosanoids. However, there is often very little EPA or DHA contained in the phospholipids of these immune cells.19
plethora of studies have shown that the administration of fish oil to healthy human subjects can increase EPA and
DHA accumulation, and consequently, decreased ARA concentration in the cell membrane. These observed changes
typically begin within days and reach their peak within a few weeks.19
Increased membrane content of EPA, and DHA has been shown to increase the synthesis of resolvins and protectins.
These are lipid mediators derived from EPA and DHA via the COX and LOX pathways.19 anti-inflammatory effects
of these molecules have been extensively demonstrated in both cell culture and animal models. These effects are
likely mediated by GPCRs in the membranes of inflammatory cells.19 relatively newly discovered anti-inflammatory
lipid mediators may play a key role in the inflammation-preventing and resolving effects attributed to marine n-3
PUFAs.
EPA and DHA were shown to reduce production of IL-6 in response to endotoxin in cultured human endothelial
cells and monocytes. In endotoxin-injected mice, fish oil supplementation was associated with a reduced
concentration of circulating TNF-a, IL-1b, and IL-6 as well as reduced production of TNF-a, IL-1b, and IL-6 by
macrophages (Table 1). DHA in particular showed decreased expression of vascular cell adhesion molecule
(VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in vitro on the surface of monocytes and endothelial cells
(Table 1).20 Resolvins and protectins were both shown to inhibit neutrophil migration across the
endothelium. Resolvins were shown to inhibit IL-1b production (Table 1). Additionally, protectins inhibited the
production of both TNF-a and IL-1b. In healthy human volunteers, fish oil supplementation was associated with
decreased production of TNF-a, IL1-b, and IL-6 by monocytes and mononuclear cells in response to endotoxin
(Table 1). One common mechanism to explain these effects would be an impact on the NF-kB system. Indeed,
administration of EPA or fish oil decreased activation of NF-kB in LPS-treated human monocytes.20 Furthermore,
DHA reduced NF-kB activation in cultured macrophages treated with LPS (Table 1).20 EPA and DHA have been
shown in animal studies to decrease production of the arachidonic acid-derived eicosanoid PGE2.19 Additionally, a
number of studies have shown decreased production of PGE2 in healthy human subjects after a period of weeks to
months of fish oil supplement use (Table 1).19
#2: Anthocyanins
Anthocyanins, a type of flavonoid, are a category of water-soluble polyphenolic pigments that give many fruits and
vegetables their red, blue, or purple color.18,21 They can be found in the fruits, seeds, flowers, and other vegetal
tissues of most plants. In fact, nearly all angiosperms express these pigments in some form, and they are thus
ubiquitous to the plant kingdom.16 Over 600 unique anthocyanins have been identified, most derive from the
primary 6 types commonly found in fruits and vegetables including: cyanidin, peonidin, delphinidin, pelargonindin,
petunidin, and malvidin. Common nutritional sources of anthocyanins include: blueberries, currants, blackberries,
raspberries, cranberries, pomegranates, cherries, strawberries, red grapes, cabbage, black rice, red rice, and
soybeans.18,21 Anthocyanins are purported to have numerous health benefits including: anti-oxidant, antiinflammatory, anti-obesity, anti-angiogenic, anti-cancer, anti-diabetes, anti-microbial, neuroprotective, and
immunomodulatory properties.21
Traditionally, research on anthocyanins has focused on their antioxidant capacity, which has been widely
established. Like other flavonoids, anthocyanins can directly target oxidative stress by scavenging molecular species
of active oxygen including hydrogen peroxide, singlet oxygen, superoxide, OH and peroxyl radicals. 16 Furthermore,
anthocyanins in black currant skin were shown to ease oxidative stress by activating the Nrf2 signaling pathway
(Table 1).21 However, more recently, there has been growing interest in their anti-inflammatory potential.17 A major
proposed mechanism for anthocyanin anti-inflammatory effects is a reduction in NF-kB activation (Table 1).18
The effects of anthocyanins have been studied in both in Vitro and In Vivo on animals (mostly mice and rats) and
human. The results of these studies have been extensively reviewed in a number of publications.21,17,16,18 For
example, administration of anthocyanins in mouse models of colitis showed reduction in IL-6, IL-1B, TNF-a, and
IFN-y (Table 1).21 Much of the in-depth knowledge of cellular mechanisms involved in anthocyanin antiinflammatory effects comes from in vitro studies conducted with cell cultures. However, there is no consensus
regarding the bioavailability of anthocyanins. Although anthocyanins have been detected in the plasma shortly after
intake, some estimates place the overall bioavailability of anthocyanins at less than 1%.21
Joseph et al (2014) studied the effects of berries and berry extracts on human subjects. They have divided their
results into common berries, less common berries, and berry extracts. With respect to the effects of common berries
in humans, blueberries were shown in one study to increase the production of pro-inflammatory cytokine IL-10
(table 1). In another study, cranberries were associated with decreased serum ICAM-1 and VCAM-1 (Table 1).
Three studies showed anti-inflammatory effects of strawberries. The first showed a reduction in VCAM-1, the
second, a reduction in IL-6 and CRP (Table 1), and the third, a reduction in IL-1 (table 1).17 With respect to the less
common berries, bilberries boast the strongest evidence of anti-inflammatory effects in humans. Two studies with
bilberries showed a reduction in CRP, two showed a reduction in TNF-a (Table 1), and one showed a reduction in
VCAM-1.17 One study on black raspberries showed a reduction in IL-6. Two studies observed anti-inflammatory
effects with sea-buckthorn berries. One showed a reduction in CRP, and another a reduction in TNF-a.17 In addition
to fresh berries, Joseph et al (2014) reviewed studies involving berry extracts. In one study, chokeberry extract
showed decreased IL-6, CRP, VCAM-1, ICAM-1, and MCP-1 (Table 1). Sea buckthorn berry extract was shown in
one study to reduce TNF-a and ICAM-1. Anthocyanins have been shown in vitro and in vivo to can suppress COX-2
expression (Table 1).21 In human intestinal cells, anthocyanins reduced PGE2 production (Table 1).21 Additionally, a
six-week berry extract treatment on UC patients showed reductions in serum TNF-α, IFN-γ, and NF-kB activation
(Table 1).21
#3 Turmeric (Curcumin)
Turmeric (curcuma longa) has a long history of use in China and Southeast Asia as a dye, spice, and medicinal herb.
It derives its rich golden color from a group of polyphenolic pigments known as curcuminoids. The three
curcuminoids found in turmeric are: curcumin, demethoxycurcumin and bisdemethoxycurcumin.20 Curcumin was
first identified in 1910 as being responsible for the vibrant yellow color of turmeric. Curcumin is lipophilic, nearly
insoluble in water, and is stable in the acidic environment of the stomach. Since ancient times, turmeric has been
prized for its healing properties. The anti-inflammatory and anti-oxidant properties of curcumin are widely thought
to be responsible for the pharmalogical benefits associated with turmeric. 22
Thousands of articles have been written over the past few decades describing the molecular basis of these medicinal
properties. As of 2015, over 100 clinical trials were conducted investigating the effects of curcumin in individuals
with chronic diseases including: diabetes, cancers, autoimmune, cardiovascular, neurological, and psychological
diseases.20 Proposed mechanisms include antioxidant and anti-inflammatory effects via activation of the Nrf2
pathway (Table 1),20 and blocking the translocation of NF-kB to the nucleus (Table 1), preventing the production of
inflammatory mediators such as interleukins and TNF-a.23 Curcumin may also block inflammatory signaling
pathways by binding to TNF-a directly, preventing it from binding to its cellular receptor, thus further reducing NFkB activation (Table 1).20 Indeed, curcumin has been shown to suppress numerous biomarkers of inflammation
(Table 1) including: TNF-a, IL-1, IL-6, IL-8, PGE-2, COX-2, MCP-1, VCAM-1, and ICAM-1.22,23,24
A potential concern with respect to the therapeutic use of curcumin in vivo is low bioavailability. Curcuminoids
have been shown to exhibit poor absorption. Furthermore, curcumin is rapidly metabolized and eliminated from the
system.25 One strategy shown to overcome these pharmacokinetic obstacles involves the combination of curcumin
with the alkaloid piperine, an active component of black pepper.25 The combined use of piperine with curcumin was
shown to increase the half-life and bioavailability and reduce the clearance of curcumin. Proposed mechanisms for
these effects of piperine include: improved absorption due to reduced activity of glucuronidase enzymes in the
intestine and liver, increased intestinal perfusion, and increased enterocyte permeability.25 In one study, daily
administration of 2,000 mg of curcumin combined with 20 mg piperine was shown to increase curcumin
bioavailability by 2,000%.23 Curcumin is generally recognized as safe by the United States Food and drug
Administration. Supplements containing curcumin have been approved for human use. Even at high doses, no
significant side effects have been observed. One study on the anti-inflammatory effects of curcumin administered 5g
per day and another study administered 6g per day with no adverse effects. 24
#4 Cruciferous Vegetables (Sulforaphane)
A variety of plant-derived molecules have been examined in recent years for their anti-oxidant, anti-inflammatory,
disease prevention, and anti-aging properties. Particularly promising among these compounds is sulforaphane, 26 a
compound belonging to a group of plant-derived chemicals called isothiocyanates. To date, dozens of clinical
studies have investigated the effects of SNF on chronic diseases including cancer, asthma, kidney disease, diabetes,
cystic fibrosis, autism, and schizophrenia.27 In addition, a number of studies have shown beneficial effects of SFN
on the neurodegenerative processes involved in stroke, traumatic brain injury, Alzheimer’s disease, and Parkinson’s
disease.28
SFN is derived from its precursor glucoraphanin, a molecule belonging a group of amino-acid derived compounds
known as glucosinolates.27 Rich sources of glucoraphanin can be found in cruciferous vegetables of the plant genus
Brassica, including: broccoli, cauliflower, brussels sprouts, kale, collards, kohlrabi, and mustard. Brocolli, in
particular, is a significant source of glucoraphanin, which can be converted to SFN. 29 When the plant tissues are
mechanically damaged via cutting, chewing, chopping, or during digestion, a plant enzyme called myrosinase,
which is usually stored in separate subcellular compartments, is released and allowed to hydrolyze glucoraphanin,
resulting in the production of sulforaphane.29 Hydrolysis of glucoraphanin can also take place via digestive enzymes
in the gut.30 However, heat exposure decreases myrosinase activity within the plant tissues. Thus, cooking these
vegetables can reduce the bioavailability of sulforaphane by diminishing activity of the enzyme needed to catalyze
its production.26
Owing to its small molecular weight and lipophilic nature, SFN can be rapidly absorbed across the enteric cells of
the jejunum. SFN is also capable of crossing the blood-brain barrier and accumulating in cerebral tissues.28 Peak
plasma concentrations are reached between 1 and 3 hours after consumption and decrease fairly rapidly thereafter
with a half-life of only 2.2 hours.26 SFN is excreted through the urine and is completely eliminated within 12 to 24
hours post-consumption Thus, repeated daily consumption of SFN is likely required in order to maintain significant
concentrations of SFN metabolites in the body.28
Intracellularly, SFN is metabolized by phase II enzymes to produce its byproducts, which are considered to be
responsible for the biological effects associated with SFN. These byproducts include sulforaphane-glutathione,
sulforaphane N-acetyl cysteine, and sulforaphane-cysteinyl-glycine (SFN-CG).26 SFN metabolism occurs primarily
in the intestinal walls, liver, kidneys, and bladder. These are also the primary locations of SFN accumulation in the
body. Lower levels of accumulation have also been observed in the plasma, skin, and lung tissues. 26
The most widely recognized mechanism through which SFN exerts its effects is the NrF2 Pathway (Table 1).26
Another commonly proposed mechanism is direct inhibition of the NF-kB pathway (Table 1). It has been shown that
SFN can diminish the ability of NF-kB to translocate to the nucleus. SFN has also been shown to reduce the DNA
binding capacity of NF-kB. Indeed, inflammatory cytokines including IL-6, and IFN-γ are show dose-dependent
inhibition in response to SFN.26 Furthermore, as mentioned earlier, NrF2 is considered a master regulator of
antioxidant activity, and thus exerts an indirect effect on NF-KB activity.27 With respect to mechanisms, it is also
worth noting that SFN was shown to exert a protective effect on the blood-brain barrier in models of traumatic brain
injury by reducing barrier permeability and mitigating the loss of endothelial cells and tight junction proteins.
Numerous studies have shown evidence of the anti-inflammatory effects of SFN. These include in vitro and in vivo
studies conducted on both animals and humans (Table 1). For example, administration of broccoli sprout powder to
type II diabetes patients resulted in the decrease of CRP and IL-6. In a rat model of spinal cord injury, SFN
administration showed reduced neuroinflammation, reflected in the reduction of IL-6 and TNF-a.27 One study
conducted with smokers showed that a 10-day broccoli intervention decreased CRP by 48%. Another study on
humans using broccoli sprouts observed a 38% reduction in IL-6 and 59% reduction in CRP concentration as well as
a significant decrease in PGE2 metabolites.30 In the cultured microglial cells of mice, SFN treatment was shown to
decrease the expression of IL-1b and IL-6 in response to LPS.26 In rats, SFN prevented memory impairment and
neuroinflammation after administration of okadoic acid, evidenced by reduced NF-kb activity and TNF-a
concentration and increased IL-10 levels.26 another study conducted on mice, SFN decreased TNF-α, IL-6, iNOS,
COX2, and NF-κB activation in response to 3-NP.26 SFN is safe, bioavailable, and widely accessible to the public.
Its purported anti-inflammatory, antioxidant, neuroprotective, disease prevention, and anti-aging properties make it
an attractive candidate for further study and a potential source of protection for the resources of the vagal tank.
References
1.
Laborde S, Mosley E, Mertgen A. Vagal Tank Theory: The Three Rs of Cardiac Vagal Control Functioning –
Resting, Reactivity, and Recovery. Front Neurosci. 2018;12:458. doi:10.3389/fnins.2018.00458
2.
Thayer JF, Hansen AL, Saus-Rose E, Johnsen BH. Heart Rate Variability, Prefrontal Neural Function, and
Cognitive Performance: The Neurovisceral Integration Perspective on Self-regulation, Adaptation, and
Health. Ann Behav Med. 2009;37(2):141-153. doi:10.1007/s12160-009-9101-z
3.
PORGES SW. The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system.
Cleve Clin J Med. 2009;76(Suppl 2):S86-S90. doi:10.3949/ccjm.76.s2.17
4.
Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric
and Inflammatory Disorders. Front Psychiatry. 2018;9. doi:10.3389/fpsyt.2018.00044
5.
Benahrroch E. The central autonomic network: functional organization, dysfunction, and perspective. Mayo
Clin Proc. 1993;68(10):988-1001.
6.
Carnevali L, Sgoifo A. Vagal modulation of resting heart rate in rats: the role of stress, psychosocial factors,
and physical exercise. Front Physiol. 2014;5. doi:10.3389/fphys.2014.00118
7.
Thayer JF, Sternberg E. Beyond Heart Rate Variability. Ann N Y Acad Sci. 2006;1088(1):361-372.
doi:https://doi.org/10.1196/annals.1366.014
8.
Hakansson A, Molin G. Gut Microbiota and Inflammation. Nutrients. 2011;3(6):637-682.
doi:10.3390/nu3060637
9.
Miller AH, Haroon E, Raison CL, Felger JC. Cytokine Targets in the Brain: Impact on Neurotransmitters and
Neurocircuits. Depress Anxiety 1091-4269. 2013;30(4):297-306. doi:10.1002/da.22084
10.
Rogero MM, Calder PC. Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids. Nutrients. 2018;10(4).
doi:10.3390/nu10040432
11.
Williams DP, Koenig J, Carnevali L, et al. Heart rate variability and inflammation: A meta-analysis of human
studies. Brain Behav Immun. 2019;80:219-226. doi:10.1016/j.bbi.2019.03.009
12.
Roohi E, Jaafari N, Hashemian F. On inflammatory hypothesis of depression: what is the role of IL-6 in the
middle of the chaos? J Neuroinflammation. 2021;18. doi:10.1186/s12974-021-02100-7
13.
Wilson CJ, Finch CE, Cohen HJ. Cytokines and Cognition—The Case for A Head-to-Toe Inflammatory
Paradigm. J Am Geriatr Soc. 2002;50(12):2041-2056. doi:https://doi.org/10.1046/j.1532-5415.2002.50619.x
14.
Bonaz B, Sinniger V, Pellissier S. The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology
of the Gastrointestinal Tract. Front Immunol. Published online November 2, 2017.
doi:10.3389/fimmu.2017.01452
15.
Appelhans BM, Luecken LJ. Heart Rate Variability as an Index of Regulated Emotiohnal Responding. Rev
Gen Psychol. 2006;10(3):229-240. doi:10.1037/1089-2680.10.3.229
16.
Reis JF, Monteiro VVS, de Souza Gomes R, et al. Action mechanism and cardiovascular effect of
anthocyanins: a systematic review of animal and human studies. J Transl Med. 2016;14. doi:10.1186/s12967016-1076-5
17.
Joseph SV, Edirisinghe I, Burton-Freeman BM. Berries: Anti-inflammatory Effects in Humans. J Agric Food
Chem. 2014;62(18):3886-3903. doi:10.1021/jf4044056
18.
Vendrame S, Klimis-Zacas D. Anti-inflammatory effect of anthocyanins via modulation of nuclear factor-κB
and mitogen-activated protein kinase signaling cascades. Nutr Rev. 2015;73(6):348-358.
doi:10.1093/nutrit/nuu066
19.
Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J
Clin Pharmacol. 2013;75(3):645-662. doi:10.1111/j.1365-2125.2012.04374.x
20.
Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans.
2017;45(5):1105-1115. doi:10.1042/BST20160474
21.
Li S, Wu B, Fu W, Reddivari L. The Anti-inflammatory Effects of Dietary Anthocyanins against Ulcerative
Colitis. Int J Mol Sci. 2019;20(10). doi:10.3390/ijms20102588
22.
Shehzad A, Rehman G, Lee YS. Curcumin in inflammatory diseases. BioFactors. 2013;39(1):69-77.
doi:https://doi.org/10.1002/biof.1066
23.
Chin K-Y. The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis.
Drug Des Devel Ther. 2016;10:3029-3042. doi:10.2147/DDDT.S117432
24.
Fernández-Lázaro D, Mielgo-Ayuso J, Seco Calvo J, Córdova Martínez A, Caballero García A, FernandezLazaro CI. Modulation of Exercise-Induced Muscle Damage, Inflammation, and Oxidative Markers by
Curcumin Supplementation in a Physically Active Population: A Systematic Review. Nutrients. 2020;12(2).
doi:10.3390/nu12020501
25.
Panahi Y, Hosseini MS, Khalili N, Naimi E, Majeed M, Sahebkar A. Antioxidant and anti-inflammatory
effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled
trial and an updated meta-analysis. Clin Nutr Edinb Scotl. 2015;34(6):1101-1108.
doi:10.1016/j.clnu.2014.12.019
26.
Santín-Márquez R, Alarcón-Aguilar A, López-Diazguerrero NE, Chondrogianni N, Königsberg M.
Sulforaphane - role in aging and neurodegeneration. GeroScience. 2019;41(5):655-670. doi:10.1007/s11357019-00061-7
27.
Cuadrado A, Manda G, Hassan A, et al. Transcription Factor NRF2 as a Therapeutic Target for Chronic
Diseases: A Systems Medicine Approach. Pharmacol Rev. 2018;70(2):348-383. doi:10.1124/pr.117.014753
28.
Tarozzi A, Angeloni C, Malaguti M, Morroni F, Hrelia S, Hrelia P. Sulforaphane as a potential protective
phytochemical against neurodegenerative diseases. Oxid Med Cell Longev. 2013;2013:415078.
doi:10.1155/2013/415078
29.
Zolnourian A, Galea I, Bulters D. Neuroprotective Role of the Nrf2 Pathway in Subarachnoid Haemorrhage
and Its Therapeutic Potential. Oxid Med Cell Longev. 2019;2019:6218239. doi:10.1155/2019/6218239
30.
López-Chillón MT, Carazo-Díaz C, Prieto-Merino D, Zafrilla P, Moreno DA, Villaño D. Effects of long-term
consumption of broccoli sprouts on inflammatory markers in overweight subjects. Clin Nutr Edinb Scotl.
2019;38(2):745-752. doi:10.1016/j.clnu.2018.03.006