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R E V I E W Leaky gut in chronic fatigue syndrome: A review

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Abstract

There is now evidence that the pathophysiology of chronic fatigue syndrome (CFS) is related to inflammation and oxidative & nitrosative stress (IO&NS) with a) signs of immune activation and a suppression of ex vivo cellular immune responses; and b) damage to membrane lipids, functional proteins and DNA by O&NS. The above disorders are mediated by intracellular inflammation as indicated by an increased production of nuclear factor kappa Βeta (NFκΒ), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS). The above inflammatory reactions may by activated by a number of etiological factors, e.g. psychological stress, strenuous exercise, viral and bacterial infections. The purpose of this paper is to review the evidence that an increased translocation of gram negative bacteria is another inflammatory pathway that is involved in CFS. The serum concentrations of IgM and IgA to lipopolysaccharide (LPS) of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae are significantly increased in patients with CFS. This suggests that in CFS there is an increased LPS translocation through a weakened tight junction barrier with subsequent gut-derived inflammation. This condition indicates an increased gut permeability or leaky gut. Treatment for 10-14 months with specific anti-inflammatory and-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, with or without immunoglobins intravenously (IVIg), significantly attenuates the initially increased IgA and IgM responses to LPS, showing that the gut-derived inflammation is attenuated and thus that the weakened tight junction barrier is partly restored. The attenuation of gut-derived inflammation predicts the clinical improvement 10-14 months after intake of NAIOSs. The above findings show that an increased translocation of gram negative bacteria with subsequent inflammation is a new pathway that contributes to the systemic IO&NS responses in CFS.
Act Nerv Super Rediviva 2009; 51(1-2): 21–28
REVIEW
Activitas Nervosa Superior Rediviva Volume 51 No. 1-2 2009
21
Leaky gut in chronic fatigue syndrome: A review
Michael M
CRC-MH, Antwerp, Belgium.
Correspondence to: Prof. Dr. M. Maes, M.D., Ph.D. Clinical Research Center for Mental Health (CRC-MH)
Groenenborgerlaan 206, 2610 Antwerp, Belgium.
: 32-3-4809282; : 32-3-2889185; www.michaelmaes.com
Submitted: 2009-01-12 Accepted: 2009-02-02
Key words:
chronic fatigue syndrome; leaky gut; gut permeability; bacterial translocation; LPS;
endotoxin; inflammation; IgA; cytokines; enterobacteria; oxidative stress
Act Nerv Super Rediviva 2009; 51(1-2): 21–28 PII: ANSR51129R03 © 2009 Act Nerv Super Rediviva
Abstract
There is now evidence that the pathophysiology of chronic fatigue syndrome (CFS)
is related to inflammation and oxidative & nitrosative stress (IO&NS) with a) signs of
immune activation and a suppression of ex vivo cellular immune responses; and b) dam-
age to membrane lipids, functional proteins and DNA by O&NS. The above disorders
are mediated by intracellular inflammation as indicated by an increased production of
nuclear factor kappa Βeta (NFκΒ), cyclo-oxygenase-2 (COX-2) and inducible NO synthase
(iNOS). The above inflammatory reactions may by activated by a number of etiological
factors, e.g. psychological stress, strenuous exercise, viral and bacterial infections.
The purpose of this paper is to review the evidence that an increased translocation of gram
negative bacteria is another inflammatory pathway that is involved in CFS. The serum con-
centrations of IgM and IgA to lipopolysaccharide (LPS) of gram-negative enterobacteria,
i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida,
Citrobacter Koseri, and Klebsielle Pneumoniae are significantly increased in patients with
CFS. This suggests that in CFS there is an increased LPS translocation through a weakened
tight junction barrier with subsequent gut-derived inflammation. This condition indicates
an increased gut permeability or leaky gut. Treatment for 10-14 months with specific anti-
inflammatory and -oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine
and zinc, with or without immunoglobins intravenously (IVIg), significantly attenuates the
initially increased IgA and IgM responses to LPS, showing that the gut-derived inflamma-
tion is attenuated and thus that the weakened tight junction barrier is partly restored. The
attenuation of gut-derived inflammation predicts the clinical improvement 10-14 months
after intake of NAIOSs. The above findings show that an increased translocation of gram
negative bacteria with subsequent inflammation is a new pathway that contributes to the
systemic IO&NS responses in CFS.
I
Chronic Fatigue Syndrome (CFS) is a medical illness
that is characterized by specific symptoms, such as
fatigue, pain, infectious and neuropsychiatric symp-
toms (Fukuda et al 1994). Typical symptoms are
substantial impairment in short–term memory or
concentration; sore throat; tender cervical and axillary
lymph nodes; muscle pain; multi–joint pain without
selling or redness; headache of new type; unrefresh-
ing sleep; post exertion malaise lasting more than 24
hours; and symptoms of irritable bowel syndrome
(IBS). The symptoms must have persisted for at least
six months (Fukuda et al 1994).
There is now evidence that CFS is an immune disor-
der characterized by an induction of inflammatory and
oxidative and nitrosative stress (IO&NS) pathways.
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Copyright © 2009 Activitas Nervosa Superior Rediviva ISSN 1337-933X
M. Maes
1. S    CFS
A systemic inflammatory response is indicated by a
number of findings. An increased production of pro-
inflammatory cytokines, such as interleukin-1 (IL-1),
IL-6 and tumor necrosis factor-α (TNFα). There is also
an increased expression of T cell activation markers,
such as CD26 and CD38, suggesting immune activa-
tion. Indicators of a peripheral inflammatory response
are increased plasma concentrations of alpha-2 globu-
lins, as obtained by electrophoresis, and decreased
serum zinc levels (Aoki et al 1993; Barker et al 1994;
Klimas et al 1990; Visser et al 1998; Patarca et al 1994;
Linde et al 1992; Lloyd et al 1992; Gerrity et al 2004;
Maes et al 2006a). Also, the suppression of ex vivo cel-
lular immune responses, such as decreased mitogen–
induced lymphocyte responses and mitogen-induced
expression of CD69 indicates the presence of an immune
response (Mihaylova et al 2007). It is also known that
viral infections, e.g. with Ebstein Barr Virus may induce
CFS. EBV viremia in CFS is accompanied by systemic
inflammation, as indicated by an increased degrada-
tion of tryptophan (Bellmann-Weiler et al 2008). The
catabolism of tryptophan is typically enhanced by pro-
inflammatory cytokines, such as interferon-γ (IFNγ)
and IFNα. Those cytokines can induce indoleamine
2,3-dioxygenase (IDO), the enzyme that converts tryp-
tophan into tryptophan catabolites along the IDO path-
way (TRYCATs) (Maes et al 2007a). In the former study,
the authors (Bellmann-Weiler et al 2008) found that
the serum concentrations of neopterin are positively
correlated to signs of tryptophan degradation, suggest-
ing that CFS patients due to EBV infection suffer from
IFNγ-induced activation of cell-mediated immunity.
These findings suggest that induction of IDO with an
activation of cellular immunity and decreased plasma
tryptophan are related to chronic fatigue following viral
infections.
Also experimental induced inflammation is accom-
panied by fatigue. Thus, IFNα-based immunotherapy
in HCV patients (hepatitis-C virus) has been shown to
induce fatigue and “psychosomatic symptoms”, includ-
ing pain (Wichers et al 2005; Martin et al 2007; Bull et al
2008). These symptoms appear soon after starting the
treatment. This indicates that fatigue, pain and psycho-
somatic symptoms are early signs of cytokine-induced
inflammation. It is also known that IFNα-based immu-
notherapy can induce depression and even full blown
major depression in a considerable number of HVC
patients. However, the depressive symptoms occur
some weeks after starting the treatment (Wichers et al
2005). Thus, it appears that fatigue/pain and depres-
sion are two different signs of inflammation: the former
appearing some days after starting treatment, the latter
appearing some weeks later. Also, the depressive reac-
tions are predicted by the degree of fatigue one week
after starting cytokine treatment (Wichers et al 2005).
There is another argument showing that both symp-
tom clusters have a different pathophysiology. Thus,
the depressive symptoms respond well to serotonergic
antidepressants, whereas the fatigue / pain symptoms
do not (Martin et al 2007). Also translational research
shows that, in rats, intraperitoneal injections of polyri-
boinosinic : polyribocytidylic acid (PIC), which mimics
some of the effects of RNA viruses and which induces
IFN, causes profound fatigue (Katafuchi et al 2005). The
findings suggest that induction of inflammatory path-
ways may underpin fatigue.
2. I   ONS 
Inflammatory stimuli are also accompanied by
increased oxidative stress, that is an increased produc-
tion of oxygen radicals with increased levels of perox-
ides (H2O2) and superoxide (2O2-). Also, nitrosative
stress may be increased with an increased production of
nitric oxide (NO) and peroxynitrite (ONOO-) by acti-
vated neutrophils and monocytes. Oxidation and nitra-
tion may cause chemical modifications of membrane
fatty acids, functional proteins and DNA, which in turn
may cause functional defects. Moreover, the damage by
O&NS may cause the formation of neoepitopes which
are strongly immunogenic, e.g. nitro-tyrosine (Ohmori
& Kanayama 2005). There is now evidence that CFS
is accompanied by an induction of various O&NS
pathways.
The findings comprise: increased isoprostane levels;
increased oxidized low density lipoproteins (LDL),
increased protein carbonyl levels; and increased LDL
thiobarbituric acid reactive substances (TBARS) (Ken-
nedy et al 2005; Smirnova & Pall 2003; Vecchiet et al
2003). Translational research shows that in animal
models of stress-induced chronic fatigue O&NS plays
a key role (Singh et al 2002a; 2002b). Also, the anti-
oxidative defences are decreased in CFS, as indicated by
a) lower serum levels of zinc, a strong antioxidant; and
b) lowered plasma levels of dehydroepiendrosterone-
sulfate, a hormone with strong antioxidant properties
(Maes et al 2005; Maes et al 2006a;).
There is also evidence for severe damage caused
by O&NS in CFS. Thus, CFS is characterized by an
increased IgM-mediated response to neoepitopes
formed by damage to membrane fatty acids, e.g. oleic,
palmitic, and myristic acid; to byproducts of lipid
peroxidation, e.g. azelaic acid and malondialdehyde
(MDA) (Maes et al 2006b); to functional intracellular
fatty acids, such as phosphatidyl-inositol (Pi) (Maes
et al 2007b); to NO derivates, such as nitro-tyrosine,
nitro-phenylalanine, nitro-arginine, nitro-tryptophan
and nitro-cysteine (Maes et al 2006b) and NO-bovine
serum albumin (Maes et al 2008). Thus, these findings
show that CFS is characterized by an IgM-mediated
inflammatory response directed against fatty acids
and proteins which are modified by oxygen radicals,
NO and peroxynitrite. CFS is also characterized by an
increased oxidative damage to the membrane of the red
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Act Nerv Super Rediviva Vol. 51 No. 1-2 2009
Leaky gut in chronic fatigue syndrome
blood cells (RBC) and to hemoglobin (Richards et al
2007). The latter may indicate that the RBC membrane
of patients with CFS are damaged and that the peroxy-
dized membrane bilayer has become more rigid (Rich-
ards et al 2007).
3. I 
Recently, we detected that there is an intracellu-
lar inflammation in CFS. A major finding is that the
production of nuclear factor kappa beta (NFκΒ), and
the inducible enzymes cyclo-oxygenase-2 (COX-2)
and inducible NO synthase (iNOS) are significantly
increased in CFS (Maes et al 2007c; 2007d). These find-
ings are also corroborated by gene expression studies
which observed an increased NFκΒ gene expression
in CFS (Kerr et al 2008). NFκΒ is the major intracel-
lular mechanism that regulates and induces the IO&NS
pathways (Brasier 2006). Once induced, NFκΒ will be
translocated from the cytoplasma to the nucleus of
the cell. In the nuclues NFκΒ binds with DNA pro-
moter sequences to induce transcriptional activation
of IO&NS pathways, such as COX-2, iNOS, and pro-
inflammatory cytokines, such as IL-1β, IL-6, and TNFα
(Brasier 2006). COX-2 is another key enzyme that is
induced during inflammation. COX-2 is involved in
the synthesis of prostaglandins and prostacyclins (Feng
et al 1995). Upon stimulation, iNOS will generate nitric
oxide (NO) by macrophages and neutrophils (Lipton
1996; Brown 1999). As explained above NO plays an
important role in generating damage caused by O&NS.
We found that - in CFS - the production of NFκΒ was
significantly related to the production rates of both
iNOS and COX-2 which shows that the increased pro-
duction of NFκΒ drives the higher production rates of
iNOS and COX-2 (Maes et al 2007c).
Therefore, we have argued that the peripheral signs
of systemic IO&NS, as discussed above, should be
attributed to intracellular inflammation. Indeed, NFκΒ
may induce the production of the IO&NS pathways,
such as that of the pro-inflammatory cytokines, which
in turn can induce signs of systemic inflammation, such
as decreased zinc and changes in acute phase proteins
(Maes et al 2007c; 2007d). Moreover, the induction of
COX-2 and iNOS is responsible for further induction
of more IO&NS pathways, with causes an increased
production of prostaglandins, NO, superoxide, perox-
ynitrite and eventually to the damage to proteins and
fatty acids with the formation of neoepitopes which
in turn will induce greater and more responses in the
IO&NS pathways (Maes et al 2007c; 2007d).
4. S   
    CFS
Systemic inflammation is often accompanied by central
neuroinflammation. For example, challenge with LPS
induces an activation of brain microglia with a chroni-
cally elevated production of pro-inflammatory media-
tors, such as TNFα (Qin et al 2007). The latter may
remain elevated during 10 months (Qin et al 2007).
Peripheral or central administration of LPS thus may
cause brain neuroinflammation and an increased pro-
duction of pro-inflammatory cytokines, such as IL-1β,
IL-6 and TNFα, which in turn may induce specific
symptoms, labeled as the sickness behavior syndrome
(Qin et al 2007). As explained (Maes et al 1993; 2009),
there is a strong similarity between the symptoms of
sickness behavior, on the one hand, and those of depres-
sion (anorexia, weight loss, psychomotor retardation,
anhedonia) and CFS (fatigue, pain, sleep disorders,
soporific effects, cognitive disorders), on the other. In
both disorders, there are highly significant correlations
between sings of inflammation and the key symptoms of
depression or CFS, which indicates that the symptoma-
tology of both disorders is related to IO&NS. Thus, in
depression, there is a strong correlation between serum
haptoglobin levels (an acute phase protein) and the
“psychosomatic” depressive symptoms, e.g. anorexia,
weight loss, middle insomnia, psychomotor retarda-
tion, and loss of interest (Maes et al 1993; 2009). In CFS,
we detected significant correlations between sings of
IO&NS activation and specific symptoms: a) the serum
IgM levels directed against fatty acids, MDA and azelaic
acid are significantly related to aches and pain, muscu-
lar tension and fatigue (Maes et al 2006b); the serum
IgM levels directed against Pi are significantly related
to fatigue and depression (Maes et al 2007b); the IgM
antibodies directed against the nitro-derivates of the
amino-acids are significantly related to aches and pain,
muscular tension and fatigue (Maes et al 2006b); and
increased NFκΒ is significantly correlated to aches and
pain, muscular tension, fatigue, irritability, sadness, and
the subjective feeling of infection (Maes et al 2007c).
Recently, we have discussed that LPS administration
and activation of the systemic IO&NS pathways are
accompanied by increased levels of pro-inflammatory
cytokines in the brain with activation of microglia and,
thus, with neuroinflammation (Qin et al 2007). Pre-
viously we have discussed that the symptoms of CFS
may be induced by a) intracellular inflammation with
increased COX-2 and iNOS levels, which may induce
pain, muscle pain, inflammatory malaise, neurocogni-
tive disorders (Maes et al 2007c; 2007d); b) increased
production of pro-inflammatory cytokines, which may
induce fatigue, depression, and inflammatory malaise
(Maes et al 2009); and c) damage caused by O&NS,
which may induce fatigue, muscle pain, and muscle
tension (Maes et al 2006b; Maes 2009). Administration
of LPS may provoke comparable symptoms in animal
models (Borowski et al 1998; Lacosta et al 1999). The
above findings suggest that IO&NS may have induced
the symptoms of CFS.
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Copyright © 2009 Activitas Nervosa Superior Rediviva ISSN 1337-933X
M. Maes
5. T   
  CFS  
We have explained previously that CFS may be induced
by a number of trigger factors, such as viral infections,
psychological stress and sustained strenuous exercise
(Maes 2009). Increased serum antibodies to Epstein-
Barr virus (Lerner et al 2004), human cytomegalovirus
(Beqaj et al 2008), herpes VI virus (Patnaik 1995), and
human parvovirus B19 (Seishima et al 2008) are pres-
ent in CFS. Enterovirus VP1, RNA and non-cytopathic
viruses are significantly more detected in the stomach
of patients with CFS (Chia & Chia 2008). Therefore,
it has been suggested that CFS may be due to persis-
tent viral infections (Dowsett et al 1990). These find-
ings are corroborated by recent findings that treatment
with valacyclovir for six months shows a significant
efficacy in treating CFS by increasing energy levels
(Lerner et al 2007). Also, psychological stress is known
to induce the IO&NS pathways, such as the production
of pro-inflammatory cytokines (Maes et al 1998); lipid
peroxidation and oxidative/nitrosative DNA damage
(Aleksandrovskii et al 1988; Pertsov et al 1995; Sivon-
ova et al 2004; Irie et al 2001); and LPS-induced NFκΒ
activation in the frontal cortex and the hippocampus
(Munhoz et al 2006). Sustained strenuous exercise
throughout childhood and early adult life can increase
the risk to develop CFS and to generate IO&NS (Orhan
et al 2004; Klapcinska et al 2005), including increased
NFκΒ in muscles (Kramer & Goodyear 2007). Thus, the
various factors which are known trigger factors of CFS
also induce the IO&NS pathways including the produc-
tion of NFκΒ. Recently, we detected a new pathway that
may induce systemic inflammation and that is related
to CFS, i.e. an increased translocation of LPS with con-
sequent gut-induced inflammation.
6. I   LPS 
  
We found that the prevalences and median values for
the plasma IgA and IgM levels directed against LPS of
various enterobacteria (Hafnia Alvei; Pseudomonas
Aeruginosa, Morganella Morganii, Proteus Mirabilis,
Pseudomonas Putida, Citrobacter Koseri, and Kleb-
sielle Pneumoniae) are significantly greater in patients
with CFS than in normal controls (Maes et al 2007e).
This suggests that there is a systemic inflammation
directed against LPS, which is induced by the presence
of increased intestinal permeability (leaky gut) with
enlarged spaces between the cells of the gut wall and
a loss of the protective barrier. Such a phenomenon is
known to cause an increased bacterial translocation
and an increased translocation of LPS (endotoxin),
which both cause increased LPS circulating levels in
the peripheral blood and consequently an increased
production of NFκΒ, which in turn can induce the
IO&NS pathways (Maes et al 2007e). Phrased differ-
ently, the increased plasma IgA and IgM levels against
the LPS of gram negative enterobacteria in CFS indi-
cate the presence of an increased gut permeability and a
mounted immune response directed against LPS of the
enterobacteria.
Leaky gut is known to be a driver of systemic inflam-
mation (Wischmeyer 2006). For example, in abdomi-
nal postoperative patients increased gut permeability
is a cause of systemic inflammation, while an attenu-
ation of leaky gut is accompanied by a reduced sys-
temic inflammation (Quan et al 2004). The pathway
which causes gut-derived inflammation is bacterial
translocation or translocation of LPS from gram nega-
tive bacteria, whereby bacteria or LPS are increasingly
translocated from the gut into the blood (Wischmeyer
2006; Quan et al 2004). Phrased differently, “increased
intestinal permeability” allows normally poorly inva-
sive enterobacteria or the LPS from those bacteria to
exploit the enlarged spaces to cross the gut epithelium
(Wischmeyer 2006). The increased translocation of
LPS or bacteria causes infections or induces the IO&NS
pathways in the peripheral blood and liver through a
primary induction of NFκΒ, which eventually induces
central neuroinflammation.
We also detected significant correlations between
the increased IgA-mediated immune response directed
against LPS and muscular tension, fatigue, concentration
difficulties, failing memory, autonomic disturbances,
the subjective experience of infection and symptoms of
IBS (Wischmeyer 2006). Thus, the relationship between
the increased plasma IgA levels directed against LPS and
IBS reflects gut-induced inflammation and not “mental
stress” or “something in the mind” as most psychiatrists
would posit. In our clinical experience IBS may pre-
cede CFS, while in other patients IBS develops together
with the fatigue and pain symptoms or develops later
in the course of illness. This suggests that “gut-derived
inflammation” caused by increased LPS translocation
may be a primary cause of CFS or may be a secondary
phenomenon which may further aggravate the existing
IO&NS. In any case, these results show that gram nega-
tive enterobacteria may be one of the etiological factors
which can trigger CFS (Wischmeyer 2006).
7. C    

The intestinal barrier may be compromised by various
etiological factors which are also known to induce CFS
or chronic fatigue due to an organic disorder or con-
dition. These are amongst others: psychological stress
(Meddings & Swain 2000; Cameron & Perdue 2005);
sustained strenuous exercise (Davis et al 2005); surgery
and trauma (Riddington et al 1996; Pape et al 1994),
alcoholism (Bjarnason et al 1984), the use of non-ster-
oid anti-inflammatory drugs (NSAIDs) (Bjarnason et
al 1986), chemotherapeutic agents (Coltart et al 1988),
prolonged use of antibiotics (Berg 1992; Viljoen et al
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Leaky gut in chronic fatigue syndrome
2003), radiation (Coltart et al 1988), AIDS/HIV (Lim et
al 1993), autoimmune disorders (Sundqvist et al 1982)
and inflammatory bowel disease (Shanahan 1994).
But also activation of the systemic IO&NS pathways
induces disruptions of gut permeability. a) Pro-inflam-
matory cytokines, such as IL-1β, IL-6, TNFα, and IFNγ
are known to induce leaky gut by causing a loss of the
gut tight junction barrier (Clark et al 2005; Chavez et al
1999; Yang et al 2003; Al-Sadi & Ma 2007). This phe-
nomenon entails an enlarging of the spaces between
the epithelial cells surrounding the gut wall, causing
an increased permeability of the gut (Clark et al 2005;
Chavez et al 1999; Yang et al 2003; Al-Sadi & Ma 2007).
NFκΒ is essential in the loosening of the intestinal epi-
thelial tight junction barrier. Thus, the IL-1β-induced
leaky gut is mediated by NFκΒ activation (Al-Sadi &
Ma 2007). Also, the TNFα-induced opening of the tight
junction barrier is mediated by NFκΒ p50/p65 binding
( Ye et al 2006; Ma et al 2005). Oxygen free radicals also
cause a disruption of the tight junctions and thus of
the intestinal barrier (Sun et al 2002). It is interesting
to note that a depletion in certain natural anti-inflam-
matory and anti-oxidative substances (NAIOSs), e.g.
glutamine, increases the risk to develop bacterial trans-
location (Wu et al 2004).
In conclusion, leaky gut may activate IO&NS path-
ways through increased bacterial and LPS translocation
but the activation of the IO&NS pathways may also
cause an opening of the tight junction barrier. Thus,
leaky gut may be a primary causative factor in CFS or
may be a secondary factor which further aggravates an
existing activation of the IO&NS pathways, thus induc-
ing a vicious circle between IO&NS activation and
weakening of the tight junction barrier.
8. T     CFS
There is now evidence that NAIOSs, such as glutamine,
NAC, and zinc, have significant effects in treating leaky
gut (Wu et al 2004; Olanders et al 2003; Sturniolo et al
2001; Chen et al 2003). Glutamine administration a)
may repair the openings of the tight junction barrier
and may decrease bacterial LPS translocation (Wu et
al 2004); b) attenuates gut injuries and therefore may
decrease gut-derived inflammation (Wischmeyer 2006);
c) increases transmucosal resistance and decreases the
mannitol flux through the epithelium and the prevalence
of systemic infections (Foitzik et al 1997); d) reduces gut
damage caused by NSAIDs and the consequent bacte-
rial translocation in the rat (Ann et al 2004); e) reduces
gut permeability, serum LPS concentrations and sings
of systemic IO&NS (Quan et al 2004); f ) improves gut
permeability and decreases plasma LPS concentrations
in injured patients (Zhou et al 2003); and g) signifi-
cantly inhibits TNFα-induced bacterial translocation
in caco-2 cells (Clark et al 2003). The abovementioned
results show that glutamine is not only essential for the
preservation of the functional tight junction barrier to
microorganisms, but also that glutamine administration
reduces leaky gut, the loosening of the tight junction
barrier; bacterial LPS translocation, and gut-derived
inflammation (Clark et al 2003; Buchman 1999). Zinc
administration improves damaged rat intestines and
stimulates gut repair and results in improved barrier
integrity (Tran et al 1999; 2003; Di Leo et al 2001). Also,
NAC administration tightens leaky gut and ameliorates
gut-derived inflammation (Sun et al 2002).
Therefore, we have examined the effects of the above
NAIOSs which had been taking during 12-14 months
on the initially increased IgA and IgM responses to
translocated LPS in patients with CFS (Maes et al 2007f;
Maes & Leunis 2008). We found that the intake of those
NAIOSs attenuates the increased IgM and IgA responses
directed to LPS. This shows that these NAIOSs reduce
gut-derived inflammation. By inference it may be
deduced that these NAIOSs restore the loosened tight
junction barrier. We found that the attenuation of the
IgM responses directed to LPS was more pronounced
than those in the IgA responses. We have explained this
phenomenon because serum IgA responses indicate the
more chronic pathogenic conditions (Maes & Leunis
2008).
Moreover, we found that the normalization of the
IgA and IgM responses directed to LPS may in part pre-
dict the clinical outcome in CFS. Other predictors for
a good outcome are: a younger age at onset of the CFS,
the younger age of the patient and a shorter duration of
the CFS (< 5 years). Thus, the attenuation of the trans-
location of LPS and consequently of the gut-derived
inflammation predicts a better clinical outcome. These
results support the view that restoration of the weak-
ened tight junction barrier with reduced translocation
of LPS by treatment with NAIOSs is accompanied by
an improvement in some patients or with a total clini-
cal remission in others. Thus, although improvement
of gut-derived inflammation by NAIOSs is accompa-
nied by a clinical improvement it is certainly not always
accompanied by clinical remission. The above and
the fact that the longer duration of illness is another
risk factor for a worse clinical response indicates that
other pathophysiogical factors are involved. These
may constitute: damage by O&NS to membrane fatty
acids, functional proteins and DNA and autoimmune
responses, which frequently occur in CFS.
In our published case report (Maes et al 2007f), the
patient was treated with NAIOSs together with immu-
noglobins intravenously (IVIg). IVIg is used since it is
effective in reducing IO&NS reactions: this treatment
reduces NFκΒ production; pro-inflammatory cytokine
production; T-cell activation; and autoimmune reac-
tions (since it contains antiidiotypic antibodies against
human autoantibodies) (Garcia et al 2007; Skansen-
Saphir et al 1998; Menezes et al 1997; Wu et al 2006;
Makata et al 2006; Rossi & Kazatchkine 1989). Interest-
ingly, IVIg also decreases bacterial translocation (Herek
et al 2000). Thus, CFS patients with very severe leaky
26
Copyright © 2009 Activitas Nervosa Superior Rediviva ISSN 1337-933X
M. Maes
gut together with severe IO&NS activation and autoim-
mune reactions can best be treated with the abovemen-
tioned NAIOSs together with IVIg.
In conclusion, gut-derived inflammation due to
increased LPS translocation is a novel pathway in CFS.
Leaky gut can be a primary cause of CFS or may develop
during the course of CFS because the activated IO&NS
pathways with increased cytokine and NFκΒ produc-
tion induce a loosening of the tight junction barrier.
The latter can be treated by specific NAIOSs with or
without IVIg which in turn may have a clinical effi-
cacy in patients with CFS who suffer from leaky gut.
However, this treatment is rather expensive and takes
10-14 months. Therefore, leaky gut is a new drug target
to develop novel drugs useful in treating leaky gut and
CFS.
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... It is a combination of various compromised mucosal defenses that leads to bacterial translocation. When the influx of gut microbes and toxins is particularly abundant, it is often referred to as a "leaky gut" (Maes, 2009;Fasano, 2012;Quigley, 2016;Mu et al., 2017;Kell and Pretorius, 2018) and is due to severely compromised epithelial tight junctions (Fasano, 2012). ...
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... When this influx is particularly great, it is sometimes referred to as a 'leaky gut ' (e.g. Fasano, 2012;Kato et al., 2017;Li & Atkinson, 2015;Luettig et al., 2015;Maes, 2009;Maes et al., 2007;Mu et al., 2017;Quigley, 2016;Shukla et al., 2015;Thevaranjan et al., 2017;Wallace et al., 2014). The result of this, and of the two other main sources that we cover in Sections II.2 and III.3, is the existence of a standing crop of microbes that have entered the bloodstream Potgieter et al., 2015). ...
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... Moreover, many causes of increased gut permeability mayin theoryinduce "secondary depression", e.g. alcoholism, chemotherapeutic agents, radiation, surgery, trauma, use of non-steroid anti-inflammatory drugs, prolonged use of antibiotics, etc. (Maes, 2009b). ...
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The aim of this paper is to review recent findings on inflammatory and oxidative and nitrosative stress (IO&NS) pathways in chronic fatigue and somatization disorder. Activation of IO&NS pathways is the key phenomenon underpinning chronic fatigue syndrome (CFS): intracellular inflammation, with an increased production of nuclear factor kappa beta (NFkappabeta), cyclo-oxygenase-2 (COX-2) and inducible NO synthase (iNOS); and damage caused by O&NS to membrane fatty acids and functional proteins. These IO&NS pathways are induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-bacteria (leaky gut). The 'psychosomatic' symptoms experienced by CFS patients are caused by intracellular inflammation (aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection); damage caused by O&NS (aches and pain, muscular tension and fatigue); and gut-derived inflammation (complaints of irritable bowel). Inflammatory pathways (monocytic activation) are also detected in somatizing disorder. 'Functional' symptoms, as occurring in CFS and somatization, have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. The development of new drugs, aimed at treating those disorders, should target these IO&NS pathways.
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