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Chronic inflammatory diseases are stimulated by current lifestyle: How diet, stress levels and medication prevent our body from recovering

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Serhan and colleagues introduced the term "Resoleomics" in 1996 as the process of inflammation resolution. The major discovery of Serhan's work is that onset to conclusion of an inflammation is a controlled process of the immune system (IS) and not simply the consequence of an extinguished or "exhausted" immune reaction. Resoleomics can be considered as the evolutionary mechanism of restoring homeostatic balances after injury, inflammation and infection. Under normal circumstances, Resoleomics should be able to conclude inflammatory responses. Considering the modern pandemic increase of chronic medical and psychiatric illnesses involving chronic inflammation, it has become apparent that Resoleomics is not fulfilling its potential resolving capacity. We suggest that recent drastic changes in lifestyle, including diet and psycho-emotional stress, are responsible for inflammation and for disturbances in Resoleomics. In addition, current interventions, like chronic use of anti-inflammatory medication, suppress Resoleomics. These new lifestyle factors, including the use of medication, should be considered health hazards, as they are capable of long-term or chronic activation of the central stress axes. The IS is designed to produce solutions for fast, intensive hazards, not to cope with long-term, chronic stimulation. The never-ending stress factors of recent lifestyle changes have pushed the IS and the central stress system into a constant state of activity, leading to chronically unresolved inflammation and increased vulnerability for chronic disease. Our hypothesis is that modern diet, increased psycho-emotional stress and chronic use of anti-inflammatory medication disrupt the natural process of inflammation resolution ie Resoleomics.
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REVIEW Open Access
Chronic inflammatory diseases are stimulated by
current lifestyle: how diet, stress levels and
medication prevent our body from recovering
Margarethe M Bosma-den Boer
*
, Marie-Louise van Wetten and Leo Pruimboom
Abstract
Serhan and colleagues introduced the term Resoleomicsin 1996 as the process of inflammation resolution. The
major discovery of Serhans work is that onset to conclusion of an inflammation is a controlled process of the
immune system (IS) and not simply the consequence of an extinguished or exhaustedimmune reaction.
Resoleomics can be considered as the evolutionary mechanism of restoring homeostatic balances after injury,
inflammation and infection. Under normal circumstances, Resoleomics should be able to conclude inflammatory
responses. Considering the modern pandemic increase of chronic medical and psychiatric illnesses involving
chronic inflammation, it has become apparent that Resoleomics is not fulfilling its potential resolving capacity. We
suggest that recent drastic changes in lifestyle, including diet and psycho-emotional stress, are responsible for
inflammation and for disturbances in Resoleomics. In addition, current interventions, like chronic use of anti-
inflammatory medication, suppress Resoleomics. These new lifestyle factors, including the use of medication,
should be considered health hazards, as they are capable of long-term or chronic activation of the central stress
axes. The IS is designed to produce solutions for fast, intensive hazards, not to cope with long-term, chronic
stimulation. The never-ending stress factors of recent lifestyle changes have pushed the IS and the central stress
system into a constant state of activity, leading to chronically unresolved inflammation and increased vulnerability
for chronic disease. Our hypothesis is that modern diet, increased psycho-emotional stress and chronic use of anti-
inflammatory medication disrupt the natural process of inflammation resolution ie Resoleomics.
Keywords: Chronic inflammation, Central stress system, Nutrition, Resoleomics, Sympathetic-adrenal-medulla axis,
Hypothalamus-pituitary-adrenal axis, Anti-inflammatory medication, Insulin resistance, Polyunsaturated fatty acids,
Glycemic index
Introduction
Thenumberofpeoplesufferingfromchronicdiseases
such as cardiovascular diseases (CVD), diabetes, respira-
tory diseases, mental disorders, autoimmune diseases
(AID) and cancers has increased dramatically over the
last three decades. The increasing rates of these chronic
systemic illnesses suggest that inflammation [1,2],
caused by excessive and inappropriate innate immune
system (IIS) activity, is unable to respond appropriately
to danger signals that are new in the context of evolu-
tion. This leads to unresolved or chronic inflammatory
activation in the body.
Inflammation is designed to limit invasions and
damage after injury, a process which has been essential
for the survival of Homo sapiens in the absence of med-
ication such as antibiotics. Recently, it has been discov-
ered that onset to conclusion of an inflammation is a
self-limiting and controlled process of the immune sys-
tem (IS). This process of inflammation resolution is
defined by Serhan as Resoleomics [3], a term which will
be used throughout this article.
Our genes and physiology, which are still almost identi-
cal to those of our hunter-gatherer ancestors of 100,000
years ago, preserve core regulation and recovery processes
[4,5]. Nowadays our genes operate in an environment
which is completely different to the one for which they
were designed.
* Correspondence: mirjam@praktijkoberon.nl
University of Girona, Plaça Sant Domènec, 3 Edifici Les Àligues, 17071,
Girona, Spain
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
© 2012 Bosma-den Boer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Modern man is exposed to an environment which has
changed enormously since the time of the industrial
revolution. In recent decades there has been a tremen-
dous acceleration in innovations which have changed
our lives completely. As a consequence, more than 75%
of humans do not meet the minimum requirement of
the estimated necessary daily physical activity [6], 72%
of modern food types is new in human evolution [7],
psycho-emotional stress has increased and man is
exposed to an overwhelming amount of information on
a daily basis. All these factors combine to produce an
environment full of modern danger signals which con-
tinuouslyactivatetheIISand central stress axes. The
question is whether the IIS and its natural inflammatory
response, Resoleomics, can still function optimally in
this modern, fast-changing environment, considering
that the IIS is designed to produce short, intensive reac-
tions to acute external danger [8,9]. It would seem that
in the bodies of people who have adopted a Western
lifestyle the inflammatory response is not concluded
because of an initial excessive or subnormal onset of the
response [10].
This article postulates how triggers from chronic
altered diet and psycho-emotional stress negatively
influence Resoleomics, thereby increasing susceptibility
to the development of chronic, low-grade, inflamma-
tion-based diseases due to the constant activation of
both the central stress axes and the IIS. In addition, an
attempt is made to demonstrate the ways in which the
use of anti-inflammatory medication could influence
Resoleomics.
Resoleomics, a self-limiting process of
inflammation
Serhan and his colleagues [3] introduced the term Reso-
leomics to describe a self-limiting process of inflammation,
executed and controlled by the innate immune system
(IIS) and regulated by the sympathetic nervous system
(SNS) and the hypothalamus-pituitary-adrenal (HPA) axis.
This process controls inflammation using metabolites pro-
duced from arachidonic acid (AA), eicosapentaenoic acid
(EPA) and docosahexenoic acid (DHA). Resoleomics oper-
ates locally when polymorphonuclear neutrophils (PMNs)
are attracted by increased pro-inflammatory cytokine and
eicosanoids production during microbial invasion, wound
healing or chemical injury. The function is to limit the
inflammation response. The central control system of the
inflammatory reaction is very complex. Local and central
processes influence each other and both are responsible
for an optimal resolving response (Figure 1). The local
process can be divided into three phases [11] (Figure 2):
1. Initiation phase
2. Resolution phase
3. Termination phase
Initiation phase
Pro-inflammatory eicosanoids, like leukotrienes B4
(LTB4) and prostaglandins (PGs) initiate the inflamma-
tory response. PMNs generate LTB4 and PGE2 from
precursor AA with the use of lipoxygenase-5 (LOX-5)
and cyclo-oxygenase 2 (COX-2). Both eicosanoids
enhance inflammation, LTB4 being the strongest che-
motoxic compound of cytotoxic neutrophils. PGE2 and/
or PGD2, although initially pro-inflammatory, determine
the switch to the next phase, the resolution of the
inflammation.
Resolution phase
This phase starts with the Eicosanoid Switch to resolution.
When the PGE2 and/or PGD2 level is equal to the level of
LTB4, the PMNs activate the switch from pro-inflamma-
tory to anti-inflammatory eicosanoids production by limit-
ing the production of LOX-5. This switch is responsible
for the production of anti-inflammatory lipoxins (LXs)
from AA through activation of lipoxygenase -12 (LOX-
12), lipoxygenase-15 (LOX-15) and acetylated COX-2
[13,14]. This last mechanism has been found to be respon-
sible for the production of more stable aspirin-triggered
LXs (ATLs) with a longer half-value period [15]. Other
resolving metabolites that support LXs are resolvins,
(neuro)protectins and maresins produced from respec-
tively EPA and DHA [11,16]. A second substantial increase
of COX-2 activity will produce anti-inflammatory PGs
(PGD2 and PGF2a) during this phase [17].
Termination phase
This phase starts when the Stop Signal takes place. This
happens when sufficient anti-inflammatory mediators
such as LXs are available to stop the pro-inflammatory
process [13,14]. LXs are capable of inhibiting both PMN
infiltration and the activity of cytotoxic cells of the ISS,
inducing phagocytosis to clear debris by non-cytoxic
macrophages and attenuating an accumulation of the pro-
inflammatory transcription factors, ie nuclear factor-
kappaB (NF-kB) and activator protein 1 (AP-1) [18,19].
Central stress axes and Resoleomics
This section deals solely with the effect of the sympathetic,
parasympathetic and the HPA axis on Resoleomics. The
systemic stress system is closely linked to the IIS via the
stress axes of our body. Anything that can activate the
sympathetic-adrenal-medulla (SAM) and HPA axes will
have its effect on the IIS [20] and therefore on Resoleo-
mics. Seen in reverse, it is precisely the IIS that can trigger
stress axes, inducing a systemic stress reaction in the body
[21]. In the SNS, which initially activates the IIS, inhibition
of the IIS is provided by the strong anti-inflammatory neu-
rotransmitter acetylcholine (ACh), produced by the para-
sympathetic nervous system [22].
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
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Page 2 of 14
The systemic stress reaction follows a two-wave pattern.
Activation of the SAM axis is considered the first wave,
giving rise to the excretion of brain norepinephrine (NE)
by the Locus Coeruleus (LC). The descending pathway
activates sympathetic motor neurons in the medulla
oblongata, which stimulate the adrenal glands (through
sympathetic efferent nerves). The adrenal gland will now
excrete catecholamines, which activate and induce prolif-
eration of ISS cells. NF-kB increases pro-inflammatory
cytokines production, such as interleukin 1-beta (IL1-b),
interleukin 6 (IL-6) and tumor necrosis factor (TNF). Both
the IIS and Th1 of the adaptive IS contain receptors sensi-
tive to catecholamines. Cerebral catecholamines affect the
activity of spleen, thymus, bone marrow and lymphoid
nodes [23]. NE has been shown to activate the IIS at the
onset of inflammation, while long-term activation of the
SNS induces IIS inhibition [24].
The second wave of the systemic stress reaction corre-
sponds with the activation of the HPA axis, with gluco-
corticoids (GCs) as end product. Cortisol is capable of
inhibiting the IIS through the upward regulation of inhi-
biting factor kappa B (IkB), while informing the immu-
nological cortex through the migration of different
immune cells to the brain [25,26]. Cortisol, the regulator
of the IIS response, can guide the inflammation into
resolution phase. Termination is instigated when cortisol
overrulesthe NE effect on NF-kB signalling through
genetic influence and reduction of transcription of the
NF-kB sensitive pro-inflammatory gene, resulting in the
finalization of the inflammatory response (Figure 2).
Figure 1 Start and finish of a physiological inflammatory reaction in wound healing and situations of microbial challenge. Cellular
damage and leakage of alarmins attract neutrophils to the damaged area (PMNs). Sympathetic afferents activate the locus coeruleus (central
nucleus of the sympathetic nervous system, SNS) and Noradrenaline (Norepinephrine, NE) is released. The released NE activates the adrenal
medulla inducing the production of systemic catecholamins that supports the activation of the PMN. Damaged blood vessels are a source of an
omega 3 rich edema (EPA and DHA). DHA and EPA inhibit LOX-5 directly and through conversion into resolvins and protectins. Both PGE2 and
PGD2, produced by the breakdown of AA by COX-2 activity, will now override the strong chemotaxic effect of LTB4. The combined action of
protectins, resolvins and lipoxins produced out of AA will put a hold on the pro-inflammatory activity of PMNs, which is supported by the
increased production of systemic cortisol. Cortisol further activates macrophages (M-Ph) to phagocytose issue debris and quiet PMN by releasing
substances such as LXA4, resolvin E1 (RvE1), prostanoid D1 (PD1), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and
epithelial growth factor (EGF) at the same time. Further edema leakage will be stopped, whereas angiogenesis and production of connective
tissue will take place, finishing the inflammatory reaction and starting the production of new tissue.
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
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Page 3 of 14
This terminationeffect of cortisol is normally sup-
ported by a compensatory anti-inflammatory response
through activation of the vagal anti-inflammatory loop
[27]. The resulting production of ACh inhibits the IS
through the alfa-7-nicotin-Acetylcholinergic Receptor
(a7nAChR) [28] (Figure 1).
The SNS (NE) increases the initial pro-inflammatory
immune response in the initiation phase, whereas
delayed cortisol response, induced by the HPA axis,
inhibits the pro-inflammatory response [29]. Integrity of
the SAM axis with its NE response/reaction is necessary
for an adequate initial inflammatory response [30]. At
the beginning of the initiation phase, there is resistance
to both cortisol and insulin in order to allow for the
activation of the IIS [12]. At the end of this phase, corti-
sol sensitivity and insulin sensitivity should be recovered
to facilitate the Eicosanoid Switch to the resolution
phase.
Chronic stress exposure reduces the capacity to mount
an acute stress response [31], resulting in an inadequate
pro-inflammatory response. Chronic (psycho-emotional)
stress situations can be responsible for the continuous
production of catecholamines by the SAM axis. People
suffering from perpetual stress, for example the parents
of a child with cancer, showed chronic, increased levels
of circulating pro-inflammatory cytokines [26]. This
situation requires a high level of energy expenditure. The
metabolic rate is increased to provide extra energy for
the brain (arousal of all senses), the heart muscle and the
locomotive system. The existing cells from the IIS are
activated and will proliferate (relatively low energy
expenditure), whereas proliferation of new immune cells
(much more costly energy expenditure) will be blocked.
Further consequences of chronic SAM activity are nar-
rowing of the cell spectrum of the IIS and complete loss
of activity of the Th1 section of the adaptive IS, leading
to an insufficient capability to fight viruses, (pre)neoplas-
tic cells and intracellularly presented pathogens [31].
An inflammatory response leading to solution depends
on the sensitivity of glucocorticoid receptors (GR) and
catecholamine receptors of the IIS [32]. Factors such as
stress endured early in life, trauma and polymorphisms
are possible risk factors for loss of GR and catecholamine
sensitivity [33-35].
Suboptimal inflammatory response as a consequence of
chronic stress prevents the Eicosanoid Switch from func-
tioning, since the switch to the resolution phase requires
recovered cortisol and insulin sensitivity. The initiation
phase should have a maximum duration of 8 to 12 hrs.
PMN number and activation levels should reach their
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Figure 2 Inflammation is a controlled process with an initiation, resolution and termination phase. After microbial invasion, lesion or
chemical injury, the initiation phase starts with the production of pro-inflammatory mediators like LTB4 and PG2. These mediators increase
inflammation until the Eicosanoid Switch, the end of the initiation phase, takes place. This occurs when the level of PGE2 plus PGD2 is equal to
the LTB4 level. The resolution phase is entered, triggering the generation of anti-inflammatory mediators like LK, resolvins, protectins, maresins,
PGD2 and PGF2a. When the total level of anti-inflammatory mediators exceeds the level of LTB4 the Stop Signal takes place. This is the last
phase, the inflammation will be terminated by clearing the affected area [11]. The stress hormones produced by the systemic stress axes have a
direct effect on the inflammation phases. A microbial invasion, lesion or injury sends off an alarm in the body, setting off the systemic stress
system which produces NE as response and tunes the system to insulin and cortisol resistance [12]. The Eicosanoids Switch to resolution can
only take place when NE is equal to the level of cortisol plus insulin and when cortisol sensitivity is recovered. The Stop Signal requires a low
level of NE and normalized cortisol sensitivity. The termination phase is entered when the stress axes are switched off.
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
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Page 4 of 14
maximum during this phase; longer duration caused by
chronic stress could produce secondary damage to neigh-
bouring tissues due to the strong cytotoxic effects of acti-
vated PMNs [11]. Supramaximal activation of PMNs
could sensitize the adapted IS if contact time between
self-antigens and the IS is significantly increased [11,29].
The crosstalk between the IS and stress axes is further
evidenced by the fact that acute production of high levels
of catecholamines activate the IIS strongly [23], whereas
eicosanoids produced from AA induce the production of
local and systemic catecholamines [36]. Long-term activa-
tion may lead to catecholamine resistance and lack of eico-
sanoid production. This situation, combined with the
aforementioned possibility of resistance to insulin and cor-
tisol, provokes a suboptimal inflammatory response and
consequently the perpetuation and development of low-
grade inflammation [26,37].
Nutritional factors and Resoleomics
Several dietary factors influence the activity of the IIS and
the function of a wide range of hormones, including cor-
tisol, insulin and catecholamines. The dramatic changes
in dietary composition since the agricultural revolution
(some 10,000 years ago) and, to a greater extent, since
the industrial revolution (some 200 years ago) have
turned the intake of food into a common daily danger
and therefore a cause of continuous systemic stress.
Some of these changes include an increase in the omega
6/omega 3 fatty acid ratio, a high intake of saturated fatty
acids (SFA) and refined carbohydrates, the introduction
of industrially produced trans fatty acids, a lower intake
of vitamins D and K, imbalanced intake of antioxidants,
high intake of anti-nutrients (eg lectines, saponins) and
an altered intake of dietary fibre [38].
The following section will discuss the impact of the
changed ratio of polyunsaturated fatty acids (PUFAs) and
the intake of food with a high glycemic load on Resoleo-
mics. The pro-inflammatory effects of anti-nutrients pre-
sent in cereals [39], potatoes [40], legumes [41], and
tomato have previously been extensively reviewed [7].
Role of PUFAs in inflammation
The intake ratio of a-linoleic acid (LA) (omega 6), a-lino-
lenic acid (ALA) (omega 3), docosahexaenoic acid (DHA)
and eicosapentaenoic acid (EPA) in the Western diet has
changed dramatically compared to the estimated intake
ratio of hunter-gatherer diets from 2-3:1 to 10-20:1 in the
contemporary diet [42,43]. All of these PUFAs are essen-
tial for normal Resoleomics response, as they function as
precursors for the special small mediators responsible for
the instigation and conclusion of the inflammatory
response. One of the toxic changes in fatty acid composi-
tion of food corresponds to the increased intake of LA
since the production of vegetable oils in 1913. Increased
LA levels affect the inflammation process in three ways
(Figure 3):
1. Increase of the omega 6/omega 3 fatty acid ratio
2. Altered AA level
3. Increases of inflammatory compounds, leukotoxins
(LK) production
Increased omega 6/omega 3 fatty acid ratio
The inflammatory effect of a high omega 6/omega 3 fatty
acid ratio during inflammation has been demonstrated in
recent human studies [44,45], in vitro studies [46,47] and
animal studies [48,49]. The higher LA levels in phospholi-
pids in plasma and cell membranes seem to be a major
factor responsible for incomplete Resoleomics reactions.
Higher intake of omega 3 fatty acids in the form of DHA
and EPA regulate the production of pro-inflammatory
cytokines and decrease LA levels in phospholipids in
plasma and cell membranes [46,48]. The conversion of LA
and ALA into respectively AA, DHA and EPA depend on
the same enzymes in the desaturase and elongase cascade,
with δ-6-desaturase as the rate-limiting enzyme (Figure 4)
[50].
Human trials investigating the effects of omega 3 dietary
supplements showed significant improvements of symp-
toms in patients suffering from diseases such as RA,
inflammatory bowel disease, asthma, psoriasis, breast can-
cer and CVD. However, full remission of symptoms was
not achieved [43,51]. Our conclusion is that an increased
intake of omega 3 alone is not enough to restore Resoleo-
mics; the intake of LA must be decreased as well.
LA effect on AA level
Higher AA levels in plasma result in more adequate
inflammatory reactions, since AA is a precursor of pro-
and anti-inflammatory substances within the self-limiting
inflammatory process [52]. LA is the precursor for AA in
the desaturase/elongase conversion (Figure 4). Theoreti-
cally, LA could be the source of a sufficient level of endo-
genous AA. However, higher intake of LA does not deliver
increased levels of AA in comparison to low intake
[53,54]. To achieve the required AA level, AA should be
present in the regular diet [45]. The combined situation of
AA deficiency together with a reduced intake of omega 3
fatty acids such as DHA and EPA (necessary for the flip
flop reaction of LOX-5 and the Eicosanoid Switch [3]),
enable a perpetuation of the pro-inflammatory initiation
phase and therefore of chronic inflammation.
Increased production of leukotoxin
The third harmful effect of high LA intake is the possible
production of so-called leukotoxins (LK). High LA levels
are metabolized by CYP2C9 in the liver into biologically
active oxidation products known as LK and leukotoxin
diol (LTD). These metabolites promote oxidative stress
responses and the activation of NFkB and AP-1, increasing
the systemic release of pro-inflammatory cytokines [55].
LK and LTD are toxic for T cells, and can kill these cells
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
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Page 5 of 14
with pathways resembling necrosis and programmed cell
death [56].
Role of high glycemic food in Inflammation
An abundant intake of high glycemic food appears to be
related to an increased susceptibility to the development
of chronic inflammation, as has been demonstrated by sev-
eral research groups [57-59]. The consequences of a high
carbohydrate diet are complex and multiple. The pathways
leading to disturbances of normal inflammation are:
1. High glycemic food intake increases inflammation
markers
2. High glycemic food intake causes hyperglycemia
and hyperinsulinemia leading to disturbed balances in
insulin growth factor-1 (IGF-1) and androgens
3. Chronic intake of high glycemic food causes hypo-
glycemia, which triggers central stress axes
High Glycemic food increases inflammation markers
Various clinical trials have shown that an abundant intake
of high glycemic food increases inflammatory markers and
markers of metabolic syndrome such as postprandial NFkB
in mononuclear cells [57], high sensitive-C-Reactive Pro-
tein (hs-CRP)[58], interleukin (IL)-6, IL-7, IL-18 [60], levels
of free radicals [59], cholesterol, triglycerides [61] and even
blood pressure [62]. Changes incurred by following a low
glycemic diet include improved insulin sensitivity, lower
blood pressure and total cholesterol, which are all key mar-
kers of the metabolic syndrome [58,60,61]. The high glu-
cose-induced inflammatory response is accompanied by
hyperinsulinemia and insulin resistance, characteristic for
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Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
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Page 6 of 14
people suffering from obesity [57,59]. Increased hsCRP
values, hyperinsulinemia and insulin resistance are strongly
related to CVD risk [60]. Glycemic index (GI) and glycemic
load (GL) have therefore been proposed as biomarkers and
predictors for (chronic) inflammation [63].
Hyperglycemia and hyperinsulinemia
Cordain demonstrated that high glycemic food is a poten-
tial risk factor for inflammation through disturbed signal-
ling of mechanisms as a result of hyperglycemia and
hyperinsulinemia [64] (Figure 5b). Long exposure to high
glucose levels in blood, which leads to a slow recovery of
the homeostasis, makes tissues vulnerable to disease [65].
High plasma insulin can increase the production of IGF-1
and androgens. Both hormones are related to disorders
such as polycystic ovarian syndrome (PCOS) [66], epithe-
lial cell cancer (breast, prostate, colon) [67,68], acne [69],
androgenic alopecia [70], and acanthosis nigricans [71].
Several pathways in this respect have been previously
described in medical literature, but these go beyond the
scope of this article.
Hypoglycemia triggers the systemic stress system
As previously mentioned, intake of a high glycemic diet
can cause hyperglycemia and hyperinsulinemia. Hyper-
glycemia will push abundant glucose via insulin into
muscle and adipocytes at the instigation of the inflam-
matory process. However, continuous intake of high gly-
cemic food results in reactive hypoglycemia, ie an
energy-deficient situation which threatens the homeosta-
sis of the body. As a consequence, the brain will main-
tain its own energy supply aimed at the survival of the
organism (the selfish brain) [25]. To ensure sufficient
energy supply, the brain activates its systemic stress sys-
tem to induce gluconeogenesis (Figure 5a). Excreted
catecholamines and cortisol will mobilize extra energy,
which is allocated with priority to the brain and to the
activated IS, at the expense of other body tissues [72].
On the basis of the above information and other refer-
enced data, it seems plausible to state that aspects of the
Western diet, of the modern industrialised environment
and of their resultant lifestyles form a chronic danger to
the body, triggering both the central stress axes and the
IIS into a state of chronic activity. This state seems to be a
direct cause of the development of low-grade inflamma-
tion and consequently of chronic inflammatory diseases
(Figure 5a).
Impact of current medication on Resoleomics
The role of the IIS is to limit the damage of inflamma-
tion in acute situations. Anti-inflammatory medication
can be used to dampen the immune response. Nowa-
days, as a result of lifestyle changes, man is exposed to
chronic inflammation and consequently to the chronic
use of anti-inflammatory medication, much of which in
fact suppresses Resoleomics. Current medication used to
treat chronic inflammatory diseases does suppress the
symptoms of inflammation, but complete remission of
the disease is seldom realized [73]. Resoleomics is hin-
dered and complete resolution of the inflammation does
not take place. Modern chronic inflammatory diseases
are treated by several groups of medication. In this arti-
cle we focus on rheumatoid arthritis (RA) medication as
an example. Four groups of anti-inflammatory RA medi-
cation are taken into account: the prostaglandin inhibi-
tors [Nonsteroidal anti-inflammatory drugs [NSAIDs:
Aspirin (ASA) and COX-inhibitors], the Glucocorticoids
(GCs), the Disease Modifying Drugs [DMARDs: Metho-
trexate (MTX) and Sulfasalazine (SSZ)] and the cytokine
blockers [Biologicalagents:antiTNF-alpha and IL-1
blockers]. The mechanisms of action and possible effects
on the IIS and Resoleomics are summarized from litera-
ture (see Table 1). Most current therapies target the IIS
in an attempt to inhibit the production of pro-inflam-
matory chemical mediators (Table 1). However, an
equally important target is the active induction of pro-
resolution programs by stromal cells such as fibroblasts
within the inflamed tissues [74]. Inhibition of MIF [75]
and production of NO [76] are not addressed in this
article.
Positive effect of ASA and GCs on Resoleomics
Medical intervention should stimulate the endogenous
pathways of resolution and two drugs already known to
possess these qualities are central to contemporary
medicine: glucocorticoids (GCs) [77] and aspirin (ASA)
[106,107]. It is apparent that ASA and GCs have a
positive effect on Resoleomics, while other medications
prolong the initiation phase, tempering and/or blocking
the resolution and termination phase of Resoleomics in
various ways (Table 1). The positive effect of ASA on
Resoleomics can be ascribed to its ability to produce
ASA-triggered lipoxins (ATLs) through acetylation
(and not through an irreversible inhibition) of the
COX-2 enzymes [78]. These ATLs show many pro-
resolving properties, which are essential in the resolu-
tion and termination phase of the inflammation pro-
cess [79,108]. Long-term intake of high doses of ASA
blocks PGE2 production and initiates the resolution
phase without affecting the biosynthesis of other pro-
resolving mediators [108]. Low and high doses of ASA
increase the production of lipoxin A4 (LXA4) and 15-
epi-LXA4 in the rat brain, suggesting that ASA could
protect against neuroinflammation [109]. However,
because of its side effects, ASA is no longer the treat-
ment of choice for RA. In high doses, inhibition of the
COX-1enzymebyASAisresponsiblefordamageto
the stomach lining.
ASA and also GCs activate the ALX/FRP2 receptor,
making them the ideal collaborator in the resolution
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
Page 7 of 14
process [77]. GCs-induced annexin-1 protein (ANXA1)
[110,111] as well as ASA-induced ATLs act on the same
ALX/FPR2 receptor and dampen PMN infiltration
[77,80]. ANXA1 also inhibits the phospholipids A2
enzyme (PLA2). Reduced PLA2 activity appears to
reduce AA release from the cell membrane [32,112],
which possibly leads to decreased levels of both PGs
and LTs and to the delay of resolution. Besides their
anti-inflammatory effects, GCs have a positive influence
on resolution by enhancing macrophage migration and
phagocytosis [11,113].
Adverse effects of medication on Resoleomics
The use of anti-inflammatory medication without the
capacity to induce (complete) resolution should be con-
sidered solution-toxic, ie hindering Resoleomics. NSAIDs
are strong inhibitors of COX-2 and less of COX-1
enzymes [114]. Almost complete COX-2 inhibition
decreases the PGs synthesis, and consequently leads to a
higher production of LTs via LOX-5 in PMNs [115].
PGE2 and PgD2 decrease the activity of LOX-5, decreas-
ing neutrophil activity and facilitating the end of the
inflammatory phase and the instigation of resolution.
Immune-suppressors such as SSZ (and less powerful
GCs) almost completely block NF-kB transcription,
leading to insufficient cytokine production and subopti-
mal inflammation [86]. Again the resolution process will
not be completed, with perpetuation of inflammation as
the logical consequence.
Perhaps the most deleterious drugs, interfering nega-
tively with resolution, are TNF-alpha inhibitors such as
anti TNF-alpha and MTX. MTX inhibits the proliferation
of the IIS cells, decreasing the production and accumula-
tion of adenosine within the IS cells [88,116]. These effects
lead to rapid anti-inflammatory effects and symptom
release. However, because of its side effects and incom-
plete resolution, this medication is qualified as solution-
toxic. This conclusion is supported by many patients who
have discontinued this treatment [73].
Another group of possible solution-toxic drugs are biolo-
gical agents with an inhibiting effect on TNF-alpha and IL-
1. Biological agents together with DMARDS (Table 1) are
strong anti-inflammatory compounds, decreasing the pro-
duction of pro-inflammatory cytokines. The absence or
insufficient activity of pro-inflammatory cytokines
decreases cell communication and induction of COX-2 in
activated neutrophils. This can lead to less production of
resolution substances such as PgE2, PgD2 and lipoxins
[54,103]. Furthermore, DMARDs and biological agents
appear to reduce the functioning and number of IIS cells,
Hyperglycemia
Hyperinsulinemia
Reactive
Hypoglycemia
Stress
Limbic system
Glutamate command
SAM HPA
NE Cortisol
NFʃB
IʃB
Chronic stress
TH1 TH2
Long term chronic stress:
Immune suppression
¾>ŽǁŐƌĂĚĞŝŶĨůĂŵŵĂƚŝŽŶј
¾sƵůŶĞƌĂďŝůŝƚLJĞdžĐĞƐƐŝǀĞŝŶĨůĂŵŵĂƚŝŽŶј
¾ŚƌŽŶŝĐŝŶĨůĂŵŵĂƚŽƌLJĚŝƐĞĂƐĞƐј
Advanced
glycation end
products
IGF-ϭј
',љ
ZyZĂĐƚŝǀŝƚLJљ
Glucose to
adipocytes
ŶĚƌŽŐĞŶƐј
^,'љ
Aromatase blocked
Hepatatic synthese
/'&Wљ
'ůƵĐŽƐĞї'ůLJĐŽŐĞĞŶ
IGF-ϭј
Metabolic
programming
Prenatal
¾ŽůůĂŐĞŶј
¾Inflamed Legs
¾PCOS
¾Androgenic alopecia
¾ŶĚŽƚŚĞůŝĂůĐĞůůĂ ĐƚŝǀĂƚŝŽŶј
¾Beard, lower voice, hirsutism
¾&ĞƌƚŝůŝƚLJљ
¾Myopia
¾Acne
¾Early menarche/puberty
¾dŝƐƐƵĞŐƌŽǁƚŚј
¾^ƚĂƚƵƌĞј
¾Acanthosis nigracans
¾ƉŝƚŚĞůŝĂůĐĞůůĐĂŶĐ Ğƌј
¾ZŝƐŬŝĂďĞƚĞƐ//ј
¾Cellular dysfunction
¾Oxidative stress
¾Nerve damage
¾Blindness
¾RĞŶĂůĨƵŶĐƚŝŽŶљ
Hepatatic synthese
^,'љ
dŚĞĐĂĐĞůůƐĂĐƚŝǀ ŝƚLJј
Figure 5 High glycemic food intake could cause inflammation and diseases as a result of hyperinsulinemia. The pathways in the shaded
area have been extensively described by Cordain [64] (part B). Part A: The consequential reactive hyperglycemia is another deleterious pathway.
Hyperglycemia is a danger signal, which activates the systemic stress system. Chronic activation will suppress the IIS, resulting in low grade
inflammation and an increased vulnerability for excessive inflammation.
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
Page 8 of 14
causing suboptimal inflammation and possibly inflamma-
tion perpetuation [104].
Discussion
Long-term activity of the IIS results in low-grade
inflammation and chronic disease. Over the past years,
ideas regarding the treatment of inflammation have
started to change as evidence accumulates which shows
that, although the targeting of infiltrating immune cells
can control the inflammatory response, it does not lead
to its complete resolution and a return to homeostasis,
which is essential for healthy tissue and good health in
general.
Hotamisligil describes how low-grade, chronic inflam-
mation (meta-inflammation) induced by a nutritional
and metabolic surplus, is accompanied by disturbed
metabolic pathways and chronic metabolic disorders. He
states that this inflammatory response differs from the
classical inflammation response caused by injury [117].
However, others have shown that the classical response
of the IIS dealing with injuries can be linked to activation
of the central stress axes [26,28]. This article specifically
discusses the relationship between the over-activated sys-
temic stress system and the self-limited process of
inflammation, known as Resoleomics, executed and con-
trolled by the innate immune system (IIS).
Table 1 Current RA treatments and their effect on immune system cells and predicted effect on Resoleomics
Medication Mechanism of action Current RA treatment effects on
Immune System Cells
Predicted effects on
ResoleomicsPhase 1: initiation, Phase
2: resolution, Phase 3: termination
Aspirin (ASA)
[11,14,32,77-83]
COX-1 inhibition, COX-2 acetylationPGE2
ATLs (15-epi-LX) Activation of the
ALX/FPR2 receptor PLA2 : free AA,
PGE & LT
PMN infiltration , PGEs , chemokines
Leucocyte accumulation Neutrophil
recruitment Vascular permeability
Nonphlogistic phagocytosis of
apoptoticneutrophils
Negative: PG < LT levels: Phase 1
Positive: PG not completely : switch
from phase 1 to phase 2 Positive: ATLs
: phase 2 and 3
NSAIDs:COX-
inhibitors [84,85]
COX-2 inhibition > COX-1 inhibitionPGE2
, LTB4 PGF2a, PGD2
COX-2 expression macrophages :
Chemotaxis of neutrophils, eosinophils
and monocytes into synovium
Negative: PG < LTB4 levels: Phase 1
Switch from phase 1 to 2 Switch from
phase 2 to 3
Glucocorticosteroid
(GCs)[32,80,86,87]
Transcription of IKB : NFkB
Transcription by GCR &CREB-binding
protein (CBP) PLA2 : free AA, PGE & LT
Annexin-1 Activation of the ALX/FPR2
receptor
PMN infiltration , PGEs , chemokines
Leucocyte accumulation Neutrophil
recruitment NFkB - transcription
Expression of inflammatory genes
Macrophage migration and
phagocytosis
Negative: PGE, LT : switch from phase 1
to 2 Cortisol resistance: switch from
phase 1 to phase 2 or no
switchLipoxins : switch from phase 2 to
3
DMARDs:
Methotrexate MTX
[88-102]
Folate analogs:1. Folate-dependent
enzymes :1a. Thymidylate synthetase1b.
AICAR transformylase1c. Dihydrofolate
reductase2. Cytosol peroxide (ROS)
Ad 1a. Synthesis of DNA & RNA T-cell-
proliferation & protein- & cytokine-
expression by T-cells , LT & IL-1 Ad 1b.
Adenosine : NK-cell, monocytes &
macrophages functioning, Cytokine
synthesis of TNF-a, IL-1, IL-6 & IL-8
1c. THF : purine &
pyrimidine Ad 2.
T-cell apoptosis
Negative: cytokines, T-cell activity ,LT:
switch from phase 1 to 2 or no switch
DMARDs:
Sulphasalazine (SSZ)
[86]
SSZ: strong and potent inhibitor of
NFkB-activation5-amino acytelate (5-
ASA): PG sulpha-pyridine
Less NFkB activation : IL-2 of activated
T-cells , TNF alfa & IL-1 macro-phages ,
Antibody in plasma cells , Neutrophils,
monocytes, macrohages, granulocyte
activation , IKB : NFkB translocation
& transcription of cytokines, adhesion
molecules, chemokines : COX-2 & PG
Negative: Immune cell activity : switch
from phase 1 to 2
Biological agents:
Anti TNF-alpha
[54,103-105]
TNF-alfa signalling of monos, PMNs, T-
cells, endothelial cells, synovial fibroblasts
& adipocytes COX-2 induction
Monocyte activation, cytokine & PG
release PMN priming, apoptosis and
oxidative burst; T-cell apoptosis, clonal
regulation & T-cell receptor Endothelial-
cell adhesion molecule expression,
cytokine release synovial fibroblast
proliferation, collagen synthesis, MMP &
cytokine release Adipocyte FFA release
Negative: Immune cell activity : switch
from phase 1 to 2
Biological agents:IL-
1 blocker
[54,103-105]
IL-1 signalling of monocytes, B-cells,
endothelial cell, synovial fibroblasts,
chrondrocytes COX-2 induction
Synovial fibroblast cytokine, chemokine,
MMP, iNOS & PG release Monos
cytokine, ROI & PG release Osteoclast
activity GAG synthesis , iNOS , MMP
& aggrecanaseEndothelial-cell adhesion
molecule expression
Negative: Immune cell activity : switch
from phase 1 to 2
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
Page 9 of 14
Changes in lifestyle which are new to our evolutionary
process should be consideredamajortriggerincausing
chronic activation of the IS and consequently of the cen-
tral stress axes and vice versa, thereby leading to chronic
diseases such as cardiovascular diseases (CVD), diabetes,
respiratory diseases, mental disorders, auto-immune dis-
eases (AID) and cancers. This article evaluates two of the
lifestyle changes which contribute to long-term activity of
the ISS, namely, nutrition and continuous psycho-emo-
tional stress. Other risk factors such as physical inactivity
[6], genetic susceptibility [118], smoking, environmental
toxicity and shift work [119] fall beyond the scope of this
article but should not be ruled out.
Nutrition is an important factor in understanding the
development of chronic inflammation. The current Wes-
tern diet can disturb the resolution response in various
ways (Figure 6). In the Ancestral human diet, foodstuffs
with an increased risk of inflammation were virtually
unknown, while nutrients able to activate the IIS are now
abundant in our diet [38,120]. Cordains research has
focused on relating these anti-nutrients in food (eg lec-
tines, saponines) to the development of chronic inflamma-
tion and autoimmune diseases (AID) [7,39]. Fortunately, it
seems that the human body possesses a strong capacity to
recover from illness. If our genes are exposed to their ori-
ginalenvironment by intake of an ancestral human diet,
their function can recover rapidly. Research has shown
that obese persons improve their blood markers after just
10 days following a paleolithic diet consisting of fish, lean
meat, fruit, vegetables and nuts [121]. Similar results have
been found in a study with aboriginals suffering from
Diabetes II, who showed normalized blood markers after
returning to their traditional lifestyle for seven weeks
[122].
People suffering from chronic inflammatory disease
demonstrate over-activated central stress axes, which then
lead to catecholamines, cortisol and insulin resistance.
McGowan et al [123] show the impact of childhood abuse
on the epigenetic pattern of different genes including the
gene for GR in the hippocampus. They found a decreased
level of GR and an increased methylation pattern of the
GR gene, giving rise to a situation of lower cortisol sensi-
bility and altered HPA stress responses. This could make
people more vulnerable to developing diseases. An altered
sensitivity to cortisol has been linked to diseases such as
rheumatoid arthritis (RA) [124], post-traumatic stress syn-
drome [125], chronic fatigue syndrome [126], inflamma-
tory diseases and AID in general [127].
The key priority in the treatment of people with
chronic inflammation is to induce the Eicosanoid Switch
to the anti-inflammatory resolution phase. Long-lasting
cortisol resistance and insulin resistance will definitely
delay or block complete resolution. The combination of
local factors (ie DHA deficiency, low levels of protectins)
disturbing the process of complete resolution (ie Resoleo-
mics) and the absence of adequate NE and cortisol
Nutrition and inflammation
Workin g
mechanism
Ratio ј͕>ј͗
-Lipoxins/resolvins/
ƉƌŽƚĞĐƚŝŶƐљ
-Pro-ŝŶĨůĂŵ͘ĐLJƚŽŬŝŶĞƐј
ůŝŬĞ/>ϲ͕dE&ɲ͕ZW
- via P450 Æleukotoxins
/diols їZK^ј͕W-ϭј
-Ğůů wall W͕,љ
-ĞƐĂƚƵƌĂƐĞͬĞůŽŶŐĂƐĞљ
,LJƉŽŐůLJĐĂĞŵŝĂ͕ stress
ǀŝĂ^Dͬ,Wјј
Low grade
inflammation
Immune suppression
,LJƉĞƌŝŶƐƵůŝŶĞŵŝĂ-
AŶĚƌŽŐĞŶƐј͕/'&ј
',љ͕/>-ϲјĞƚĐ
Empty calories
ŽĚLJĨĂƚ;sd͕^dͿј
Insulin ƌĞƐŝ ƐƚĂŶĐĞј
ZK^ј
/>ϲј
ZWј
>ĞƉƚŝŶј
ZĞƐŝƐƚŝŶ ј
ŝŶĚƚŽŐƵƚ͕
gut permeability ј
-IMS activation
-Low grade
inflammation
-Auto-ŝŵŵƵŶĞĚŝƐĞĂƐĞƐ͕
via molecular mimicry
Nutrition Vegetable oils (not
ŽůŝǀĞ͕ĐŽĐŽƐ͕ĐŽĐŽĂͿ
DĂƌŐĂƌŝŶĞ͕
ĂŝƌLJ͕
ĞƌĞĂůƐ͕
Meat ;ŶŽƚǁŝůĚͿ
EƵƚƐ͗ƉĞĂŶƵƚƐ͕ĐĂƐŚĞǁ
Refined carbs
(bread͕ƉŽƚĂƚŽĞƐ͕ƌŝĐĞ͕
ĞƚĐͿ
^ƵŐĂƌ;ƐǁĞĞƚŝĞƐ͕
ĐŽŽŬŝĞƐͿ
,ŝŐŚĐĂůŽƌŝĞĚŝĞƚ͗
ĂůŽƌŝĞŝŶƚĂŬĞх
Energy expenditure
,ĂƌŵĨƵů^ĂƉŽŶŝŶƐ
;ůĞŐƵŵĞƐ͕ĐĞƌĞĂůƐ͕ƐŽLJ͕
ƚŽŵĂƚŽĞƐ͕ĞƚĐͿ
>ĞĐƚŝŶƐ;ĐĞƌĞĂůƐ͕
ůĞŐƵŵĞƐͿ
'ůŝĂĚŝŶ;ŐůƵƚĞŶͿ
&ĂĐƚŽƌƐ Ratio ɏϲ͗ɏ3'ůLJĐĞŵŝĐ
index/load
ĂůŽƌŝĞƐ Anti-nutrients
Nutrition &ŝƐŚ
Walnuts
&ůĂdžƐĞĞĚ
ŚůŽƌŽƉůĂƐƚ–green leaves
vegetables
^ůŽǁĐĂƌďƐ͗ǀĞŐĞƚĂďůĞƐ ͕
nuts
'>љ͗ĨƌƵŝƚ
&ŝďĞƌƐј
>ŽǁĐĂůŽƌŝĞĚŝĞƚ͗
ĂůŽƌŝĞŝŶƚĂŬĞф
Energy expenditure
ǀŽŝĚŚĂƌŵĨƵůƐĂƉŽŶŝŶƐ͕
lectins and gliadin
Workin g
mechanism
ZĂƚŝŽљ͕>ј͗
-Lipoxins/resolvins/
protectinsј
-Block pro-inflammatory
cytokines production
-ĞůůǁĂůůW͕,ј
-Regulation of blood
sugar and insulin
ůĞǀĞůƐ͗
Inflammation
ŵĂƌŬĞƌƐљ
-DŝĐƌŽŶƵƚƌŝĞŶƚƐј
ŽĚLJĨĂƚ;sd͕^dͿљ
Insulin resistance љ
ZK^љ
/>ϲљ
ZWљ
>ĞƉƚŝŶљ
ZĞƐŝƐƚŝŶ љ
ZĞƉĂŝƌŐƵƚ͕ĂǀŽŝĚ
ŝŶƚĞƐƚŝŶƉĞƌŵĞĂďŝůŝƚLJ͗
&ŽƌĞŝŐŶƉƌŽƚĞŝŶƐŝŶ
ƉĞƌŝĨĞƌLJљ͕/D^љ
INFLAMMATIONRESOLUTION
Figure 6 Reflection of the working mechanism demonstrating how several nutritional factors could induce and inhibit inflammation.
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
Page 10 of 14
signalling can be responsible for perpetuatual inflamma-
tion by delaying the resolution phase of the inflammatory
response (Figure 7).
Current anti-inflammatory medication used in RA treat-
ment is aimed at the suppression of the IIS and its inflam-
matory response and thus hinders Resoleomics. In
addition, these medication interventions do not solve
underlying catecholamine, cortisol and insulin resistance,
and consequently making it impossible to achieve full
recovery of the chronic inflammation. This suggests that
chronic use of anti-inflammatory medication in fact
impedes the body from making a full recovery. Further-
more, the ongoing low-grade inflammation will continu-
ously trigger the activity of the systemic stress system [28].
Health care should focus on early detection of silent,
ongoing and low-grade inflammation in order to avoid the
development of many chronic diseases. Further research is
needed to validate a questionnaire which addresses early
symptoms of chronic low-grade inflammation, ie avoid-
ance of exercise, fatigue, emotional flatness, social isola-
tion, decreased libido, hyper or hyposomnia, obsessive
behaviour or sensitivity to addiction [6,128].
We have made an effort to demonstrate that the
science of Resoleomics can help to find new ways to treat
people suffering from diseases based on chronic inflam-
mation. Since over-activated central stress axes directly
delay Resoleomics, and thereby delay the resolution of
inflammation, treatment should focus on restoring the
central stress system to its default, healthy homeostasis.
Dietary changes, psycho-emotional stress release and
physical activity should always be included in treatment
of all chronic inflammatory diseases.
Abbreviations
AA: Arachidonic acid; Ach: Acetylcholine; AID: Autoimmune diseases; ALA: α-
linolenic acid; ALX/FPR2: Lipoxin A(4) receptor; ANXA 1: Annexin 1 protein;
AP-1: Activator protein 1; ASA: Aspirin; ATLs: Stable aspirin-triggered lipoxin;
COX: Cyclo-oygenase; CRP: High sensitive-C- Reactive Protein; CVD:
Cardiovascular diseases; DHA: Docosahexaenoic acid; DMARDs: Disease
Modifying Drugs; EPA: Eicosapentaenoic acid; GI, Glycemic index; GL:
Glycemic load; GCs: Glucocorticoids; HPA: Hypothalamus-pituitary-adrenal;
IGF-1: Insulin growth factor-1; IS: Immune system; IIS: Innate immune system;
IL: Interleukin; LA: α-linoleic acid; LC: Locus Coeruleus; LOX: Lipoxygenase; LK:
Leukotoxins; LTs: Leukotrienes; LTD: Leukotoxin diol; LXs: Lipoxins; MTX:
Methotrexate; NE: Norepinephrine (ie noradrenaline); NF-kB: Nuclear factor-
KappaB; NSAIDs: Nonsteroidal anti-inflammatory drugs; PCOS: Polycystic
ovarian syndrome; PGs/PGE2/PGD2/PGF2a: Prostaglandins/prostaglandin E2,
D2, F2a; PLA2: Phospholipase A2 enzyme; PMNs: Polymorphonuclear
leukocytes; PUFAs: Polyunsaturated fatty acids; RA: Rheumatoid arthritis; SAM:
Sympathetic-adrenal-medulla; SFA: Saturated fatty acids; SNS: Sympathetic
nervous system; TNF: Tumour necrosis factor.
Authorscontributions
MMB executed an analysis and review of the relationship between chronic
inflammatory pathways and the central stress systems, Resoleomics and
nutrition. MMB also drafted the manuscript. MLvW reviewed the MOA of
currently used anti-inflammatory medication and its effect on Resoleomics.
LP played a central role in integrating the results of various stressors on
chronic inflammation pathways and also acted as lead reviewer. All authors
have approved the final manuscript.
Authorsinformation
MMB and MLvW, MD treat patients with chronic diseases in a private
practice. LP, a practising psychoneuroimmunologist and associate Professor
at the University of Gerona, Spain, has developed valuable insights into the
Chronic Overactivation
Systemic Stress system
Suppression Resoleomics
- Immune system
Chronic Low Grade Inflammation
sƵůŶĞƌĂďŝůŝƚLJdžĐĞƐƐŝǀĞ/ŶĨůĂŵŵĂƚŝŽŶј
Reactive
Hypoglycemia
Current medication
for chronic inflammation ZĂƚŝŽ>͗>
ј
‘Newenvironmental
stressors
>ј
Anti-nutrients
Hyperglycaemia
Hyperinsulinemia
High glycemic food
DƵƐůĞͬĨĂƚљ
džĞƌĐŝƐĞљ
High calorie diet
‘Newenvironmental
Immuun system
activation
essors
DĞŶƚĂůƐƚƌĞƐƐј
džŝĐƐƚƌĞƐƐј
džĞƌĐŝƐĞљ
sŝƚĂŵŝŶͬDŝŶĞƌĂůƐљ
New Food
Medication
Etc
Figure 7 Chronic over-activation of the systemic stress system as a result of external stressors plays a central role in the development
of chronic inflammatory diseases. Current intervention with anti-inflammatory medication suppresses Resoleomics and the IIS and so enhance
the over-activation of the systemic stress system.
Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
Page 11 of 14
metabolic pathways of chronic diseases, which he has applied in the
treatment of numerous patients.
Competing interests
The authors declare that they have no competing interests.
Received: 14 November 2011 Accepted: 17 April 2012
Published: 17 April 2012
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doi:10.1186/1743-7075-9-32
Cite this article as: Bosma-den Boer et al.: Chronic inflammatory
diseases are stimulated by current lifestyle: how diet, stress levels and
medication prevent our body from recovering. Nutrition & Metabolism
2012 9:32.
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Bosma-den Boer et al.Nutrition & Metabolism 2012, 9:32
http://www.nutritionandmetabolism.com/content/9/1/32
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... As reported, high intakes of starch and sugars can lead to hypoglycaemia because of an acute response to insulin; thus, this could induce central dysfunction and depressive disorder by influencing hormone levels [6]. Moreover, high intakes of starch and sugars and subsequent insulin secretion could increase the levels of circulating inflammatory markers, which may be associated with the risk of depression [7][8][9][10]. Circulating inflammatory markers reduce the expression of serum brain-derived neurotrophic factor [11], the lower level of which is suggested to reduce neurogenesis and lead to hippocampal atrophy in depression [12]. ...
... Meanwhile, the associations of starch intake (negative), lactose (no significant associations), and total fructose (positive) with depressive symptoms in the present population of young Japanese women differed from those in the US prospective study on menopausal women with no significant associations for starch and fructose and a negative association for lactose [21]. The associations of total and free sugars, sucrose, and glucose intakes with depressive symptoms could be a result of insulin secretion induced by an elevated blood glucose level and subsequent changes in hormone [6] and circulating inflammatory marker [7][8][9][10] levels, as well as the expression of serum brain-derived neurotrophic factor [11,12]. For total fructose, the association with depressive symptoms could be due to the increase in basal corticosterone concentration via hypothalamic-pituitary-adrenal axis stimulation [13]. ...
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The relationship between the intakes of saccharide subtypes and depressive symptoms is unclear in Asian countries. This cross-sectional study aimed to investigate this association among 3963 young (age of 18 years) and 3826 middle-aged (mean age of 47.8 years) Japanese women. The intakes of starch, total sugars, free sugars, sucrose, lactose, glucose, and total fructose were assessed using a validated diet history questionnaire. The prevalence of depressive symptoms was 22.0% and 16.8% among young and middle-aged women, assessed using the Center for Epidemiologic Studies Depression (CES-D) score. After adjusting for potential confounding factors, higher starch intake was associated with a lower prevalence of depressive symptoms in young women with an odds ratio (OR) of the fourth to the first quintiles of 0.75 (95% confidence interval (CI): 0.57, 0.99). Moreover, higher intakes of sugars (except for lactose) were associated with a higher prevalence of depressive symptoms in young women, with ORs (95% CI) of the fifth to the first quintiles ranging from 1.30 (0.995, 1.69) for glucose to 1.47 (1.12, 1.93) for sucrose. These associations were not observed in middle-aged women. Future prospective studies are needed to confirm these findings.
... These dramatic changes in diet were also accompanied by several "new" risk factors such as smoking, increasing psychological stress, decreased physical inactivity, and antibacterial strategies (such as disinfection and the use of antibiotics) resulting in a loss of important commensal bacteria for immune system development (like Bifidobacterium spp., Prevotella spp., Xylanibacter spp., Faecalibacter spp.) and the increase of autoimmune diseases and allergies [80,[88][89][90][91]. ...
... Certainly, the presented intrinsic and extrinsic motivation to continue a Western-style diet and the introduction of (historically seen) rather "new" risk factors, It can only be speculated why researchers primarily investigated symptomatic treatments and preventive concepts against caries and periodontitis such as the use of fluorides and oral hygiene. Certainly, the presented intrinsic and extrinsic motivation to continue a Western-style diet and the introduction of (historically seen) rather "new" risk factors, which were either addictive (like smoking), too elaborate (like physical activity), or contradictory to health changes (like chronic stress), played a major role [90,91,93,94]. Although the investigated symptomatic treatments such as fluoridation and plaque control showed a certain degree of efficacy, they were also shown to be unable to fully prevent oral diseases in the presence of persisting risk factors: A recent systematic review showed that oral plaque control on its own (without the use of fluorides) was not able to prevent caries [20]. ...
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Plaque control is one of the most recommended approaches in the prevention and therapy of caries and periodontal diseases. However, although most individuals in industrialized countries already perform daily oral hygiene, caries and periodontal diseases still are the most common diseases of mankind. This raises the question of whether plaque control is really a causative and effective approach to the prevention of these diseases. From an evolutionary, biological, and nutritional perspective, dental biofilms have to be considered a natural phenomenon, whereas several changes in human lifestyle factors during modern evolution are not "natural". These lifestyle factors include the modern "Western diet" (rich in sugar and saturated fats and low in micronutrients), smoking, sedentary behavior, and continuous stress. This review hypothesizes that not plaque itself but rather these modern, unnatural lifestyle factors are the real causes of the high prevalence of caries and periodontal diseases besides several other non-communicable diseases. Accordingly, applying evolutionary and lifestyle medicine in dentistry would offer a causative approach against oral and common diseases, which would not be possible with oral hygiene approaches used on their own.
... AA and its metabolites are strongly associated with the development and regression of inflammation (Calder, 2009;Yao et al., 2009;Legler et al., 2010;Bosma-den Boer et al., 2012). Under catalyzation of cyclooxygenase, AA can generate unstable PGG2, and rapidly convert to PGH2, which is finally converted to biologically active PGD2 by various enzymes (Hamberg et al., 1975;Cha et al., 2006). ...
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Qing-Wen-Jie-Re mixture (QWJR) has been used in the treatment of the coronavirus disease 2019 (COVID-19) in China. However, the protective mechanisms of QWJR on viral pneumonia remain unclear. In the present study, we first investigated the therapeutic effects of QWJR on a rat viral pneumonia model established by using polyinosinic-polycytidylic acid (poly (I:C)). The results indicated that QWJR could relieve the destruction of alveolar-capillary barrier in viral pneumonia rats, as represented by the decreased wet/dry weight (W/D) ratio in lung, total cell count and total protein concentration in bronchoalveolar lavage fluid (BALF). Besides, QWJR could also down-regulate the expression of inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. More M1-type macrophage polarization was detected by calculating CD86+ cells and CD206+ cells and validated by the decline of inducible nitric oxide synthase (iNOS) and elevated arginase-1 (Arg-1) in lung. Finally, serum untargeted metabolomics analysis demonstrated that QWJR might take effect through regulating arginine metabolism, arachidonic acid (AA) metabolism, tricarboxylic acid (TCA) cycle, nicotinate and nicotinamide metabolism processes.
... Nevertheless, some studies showed that mental disorders are associated with circulating inflammation markers [39,40]. Pro-inflammatory nutrients may activate the innate immune system that can lead to chronic low-grade inflammation [41,42]. On the other hand, dietary factors can affect the markers of neuronal function [43,44]. ...
Article
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The potential modifiable role of diet in common psychological disorders, including depression and anxiety, has attracted growing interest. Diet may influence the occurrence of mental disorders through its inflammatory characteristics. The purpose of this meta-analysis was to explore whether dietary inflammatory potential is associated with the risk of depression and anxiety. A systematic literature search was conducted in PubMed, Web of Science, and Embase databases up to February 2021. Articles related to dietary inflammatory potential and risk of depression or anxiety were included. After the elimination of repetitive and irrelevant literature, we conducted quality assessment, publication bias, and sensitivity analysis. In total, 17 studies with a total of 157,409 participants were included in the final analysis. Compared with the lowest inflammatory diet group, the highest group was significantly associated with the incidence of depression and anxiety, with the following pooled odds ratios (ORs) and 95% confidence intervals (95% CIs): 1.45 (1.30 ~ 1.62) for depression and 1.66 (1.41 ~ 1.96) for anxiety. A subgroup analysis by gender showed that this association was more prominent in women. For depression, the increased risk was 49% in women (OR 1.49, 95% CI 1.28 ~ 1.74) and 27% in men (OR 1.27, 95% CI 1.06 ~ 1.52). As for anxiety, the increased risk was 80% in women (OR 1.80, 95% CI 1.30 ~ 2.49) and 47% in men (OR 1.53, 95% CI 0.81 ~ 2.89). As a result, long-term anti-inflammatory eating patterns may prevent depression and anxiety, whereas pro-inflammatory eating patterns may promote these conditions. People should add more fish, fish oil, fresh fruit, walnuts, and brown rice to their diet.
... An optimal way to reduce inflammation involves life-long adoption of a diet high in anti-inflammatory products (Giugliano et al., 2006). Regularly including anti-inflammatory foods in the diet reduces the risk of developing inflammation-related diseases (Olendzki et al., 2014), whereas, adopting a diet low in anti-inflammatory foods may accelerate inflammatory disease processes (Bosma-den Boer et al., 2012). Foods that cause inflammation in the Western diet include refined carbohydrates, french fries, soda, red meat, margarine, food high in saturated fats etc (Cordain et al., 2005). ...
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Parkinson’s disease (PD) is the second most common age-associated neurodegenerative disorder and is characterized by progressive loss of dopamine neurons in the substantia nigra. Peripheral immune cell infiltration and activation of microglia and astrocytes are observed in PD, a process called neuroinflammation. Neuroinflammation is a fundamental response to protect the brain but, when chronic, it triggers neuronal damage. In the last decade, central and peripheral inflammation were suggested to occur at the prodromal stage of PD, sustained throughout disease progression, and may play a significant role in the pathology. Understanding the pathological mechanisms of PD has been a high priority in research, primarily to find effective treatments once symptoms are present. Evidence indicates that early life exposure to neuroinflammation as a consequence of life events, environmental or behaviour factors such as exposure to infections, pollution or a high fat diet increase the risk of developing PD. Many studies show healthy habits and products that decrease neuroinflammation also reduce the risk of PD. Here, we aim to stimulate discussion about the role of neuroinflammation in PD onset and progression. We highlight that reducing neuroinflammation throughout the lifespan is critical for preventing idiopathic PD, and present epidemiological studies that detail risk and protective factors. It is possible that introducing lifestyle changes that reduce neuroinflammation at the time of PD diagnosis may slow symptom progression. Finally, we discuss compounds and therapeutics to treat the neuroinflammation associated with PD.
... Numerous studies have correlated hyperglycemia with an increased risk of cancer [68,69]. Hyperglycemia also causes inflammation [70] via increasing obesity [71] gut permeability [72] and LDL levels in humans [73,74]. Hyperglycemia may be caused by a number of factors including aggressive insulin reduction, insulin omission, or carbohydrate overconsumption for fear of hypoglycemia [75]. ...
Article
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Sedentary behavior refers to certain activities in a reclining, seated, or lying position requiring very low energy expenditure. High prevalence of sedentary behaviors in today's society is a growing public health concern. Sedentary behavior and physical inactivity are among the leading modifiable risk factors worldwide for cardiovascular disease and all-cause mortality. Excessive sedentary time increases the risk of cardiometabolic diseases (CD), such as obesity, hyperglycemia, dyslipidemia and hypertension. Physical activity (PA) and exercise have established protective effects on health, and its potential benefits span across the prevention, management, and treatment of cardiometabolic disease. In this review study, the relationships between physical activity and cardiometabolic diseases and the effects of physical activity on cardiometabolic diseases were examined. Sedentary Behavior and Health Sedentary behavior (SB) style one of the biggest public health problems in the 21st century and physical inactivity and light physical activities-has been described as an "unhealthy and costly lifestyle" [1,2]. SB is often described as "any waking behavior characterized by an energy expenditure ≤1.5 metabolic equivalents (METs), while in a sitting, reclining or lying posture" [3,4] and includes activities such as television watching, driving, seated electronic play game and computer use, reading, and study time arts and crafts, listening to music, social interactions and personal care [5,6]. Generally, these habits are considered different from practicing small amounts of PA, a behavior in which the individual also fails to engage in moderate or vigorous PA that would require energy expenditure above 3 metabolic equivalents [7,8]. There is strong evidence that sedentary behavior is independently related to a greater risk for all cause chronic disease and premature death [9-11]. Low physical activity is decreases resistance to various diseases, increases risk of many diseases such as; type 2 diabetes and obesity, cardiovascular disease, hypertension, [12,13] abnormal glucose metabolism and some types of cancers are among the most important causes of death and disability [8,14]. On the other hand, various studies have shown that PA, particularly when performed within the domain of leisure time, is inversely associated with cardiometabolic diseases (CD) including obesity, hyperglycemia, dyslipidemia and hypertension [8, 15-17]. Nowadays, health guidelines and most research is emphasized in this area have focused on regular PA order to maintain a healthy life and to have both preventive and improving effects for many diseases [18,19]. Physical Activity and Exercise Physical activity (PA) and exercise are often used interchangeably, but these terms are not synonymous. PA is defined "movement that increases heart rate and breathing any bodily movement produced by the contraction of skeletal muscles that results in a substantial increase in caloric requirements over resting energy expenditure [20,21]. Exercise is a type of physical activity consisting of planned, structured, and repetitive bodily movement done to improve and/or maintain one or more components of physical fitness [20,22,23]. Regular PA is very important part of wellbeing and health living. Generally active people are live longer and have more low risk of adverse health condition [24]. In addition, PA is primary and secondary prevention of chronic diseases and the decrease in all-cause mortality is compelling [25-27]. PA showed that many positive health effects for people such as, decreased risk of Type 2 diabetes, osteoarthritis, osteoporosis, obesity, some cancers types, cardiovascular diseases, dementia, depression, stress and anxiety [22, 28, 29]. In addition, PA can improve blood parameters, aerobic capacity, balance, flexibility, posture, and mobility and there is evidence to suggest the benefits of PA may also extend to greater job satisfaction and improved cognitive functioning [30-33]. Exercise training has been shown to significantly reduce cardiometabolic risk factors [34]. In particular, the combination of aerobic and resistance
... Inflammation is the self-limited defense mechanism of innate immune system, employed against the antigen to circumvent the associated damage (Bosma-den Boer et al., 2012). It is reported that inflammation is upregulated by increased consumption of unhealthy diet and diverse environmental stress factors (Calder, 2010). ...
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Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.
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It is described how an unhealthy lifestyle, via causation of chronic systemic low grade inflammation leads to insulin resistance, the metabolic syndrome and eventually its associated diseases, such as diabetes mellitus type 2, cardiovascular disease, certain cancers, neurodegenerative diseases, pregnancy complications and fertility problems. Homo sapiens' sensitivity for the development of insulin resistance traces back to our rapid brain growth in the past 2.5 million years. Our brain ranks high in the energetic hierarchy. When threatened by a glucose deficit, such as during pregnancy and infection, we respond with an inflammatory reaction that causes insulin resistance and is followed by, amongst others, a functional reallocation of energy-rich nutrients and a change in the serum lipoprotein composition. During inflammation the latter aims at the redistribution of lipids, modulation of the immune response and active inhibition of reverse cholesterol transport for damage repair. With the advent of the agricultural revolution and with increasing paste since the industrial revolution, we have introduced numerous false inflammatory triggers in our lifestyle that took us into a state of chronic systemic low grade inflammation. Eventually, this condition leads to the above mentioned typically Western diseases via an evolutionary conserved interaction between our immune system and metabolism. The triggers can roughly be subdivided into an abnormal dietary composition, abnormal microbial flora, insufficient physical activity, stress, insufficient sleep and environmental pollution. The current decrease of the number of life years without chronic disease is rather due to 'nurture' than 'nature', since less than 5% of our chronic diseases are directly attributable to heritable genetic factors. Resolution of the conflict between environment and our ancient genome is the only effective manner to arrive at 'healthy aging' and for this we should return to the balance of the Paleolithic era, as translated to the culture of the 21 st century. Clinical chemists are pre-eminently capable to play an important role in the increasing attention for 'lifestyle', because lifestyle factors can at least in part be mapped by analyses of markers in blood and urine.
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Lipoxins (LX), a series of anti-inflammatory mediators, are short lived endogenously produced nonclassic eicosanoids, whose appearance in inflammation signals the resolution of inflammation. Cell-cell interactions and transcellular biosynthesis of mediators are well recognized as important means of generating new signals during multicellular processes in vivo. Lipoxins are generated by two main routes. The first described involves initial lipoxygenation by 15-LO that inserts molecular oxygen in predominantly the S configuration at carbon 15, followed by 5-LO based transformation. A second route, which occurs predominantly as a major intravascular origin within blood vessels when, for example, platelet intracellular glutathione is depleted, involves the conversion of 5-LO-derived LTA4 that is released from leukocytes and subsequently converted to lipoxins. Human platelets do not generate LXs, but become a major intravascular source of LXs when they interact with leukocytes. They are potent signals that counteract the pro-inflammatory mediators which evoke the cardinal signs of inflammation, and as specialized signals generated in the resolution phase they are dual acting signals promoting the important non-phlogistic steps in resolution. Inappropriate control of inflammation and its resolution is now recognized to contribute to many chronic inflammatory diseases as well as those not previously recognized to have inflammation as a basis of their pathophysiology.
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1. Glucocorticoids are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases, all of which are associated with increased expression of inflammatory genes. The molecular mechanisms involved in this antiinflammatory action of glucocorticoids is discussed, particularly in asthma, which accounts for the highest clinical use of these agents. 2. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which then dimerize and translocate to the nucleus, where they bind to glucocorticoid response elements (GRE) on glucocorticoid-responsive genes, resulting in increased transcription. Glucocorticoids may increase the transcription of genes coding for antiinflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase, but this is unlikely to account for all of the widespread anti-inflammatory actions of glucocorticoids. 3. The most striking effect of glucocorticoids is to inhibit the expression of multiple inflammatory genes (cytokines, enzymes, receptors and adhesion molecules). This cannot be due to a direct interaction between glucocorticoid receptors and GRE, as these binding sites are absent from the promoter regions of most inflammatory genes. It is more likely to be due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors, such as nuclear factor-κB and activator protein-1, which regulate the inflammatory gene expression. 4. It is increasingly recognized that glucocorticoids change the chromatin structure. Glucocorticoid receptors also interact with CREB-binding protein (CBP), which acts as a co-activator of transcription, binding several other transcription factors that compete for binding sites on this molecule. Increased transcription is associated with uncoiling of DNA wound around histone and this is secondary to acetylation of the histone residues by the enzymic action of CBP. Glucocorticoids may lead to deacetylation of histone, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing gene expression. 5. Rarely patients with chronic inflammatory diseases fail to respond to glucocorticoids, although endocrine function of steroids is preserved. This may be due to excessive formation of activator protein-1 at the inflammatory site, which consumes activated glucocorticoid receptors so that they are not available for suppressing inflammatory genes. 6. This new understanding of glucocorticoid mechanisms may lead to the development of novel steroids with less risk of side effects (which are due to the endocrine and metabolic actions of steroids). ‘Dissociated’ steroids which are more active in transrepression (interaction with transcription factors) than transactivation (GRE binding) have now been developed. Some of the transcription factors that are inhibited by glucocorticoid, such as nuclear factor-κB, are also targets for novel anti-inflammatory therapies.
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