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Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: Effects of age, duration of illness and the translocation of LPS from gram-negative bacteria

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There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS). The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs. Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years). The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.
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Neuroendocrinol Lett 2008; 29(6):101–000
ORIGINAL ARTICLE
Neuroendocrinology Letters Volume 29 No. 6 2008
Normalization of leaky gut in chronic fatigue
syndrome (CFS) is accompanied by a clinical
improvement: effects of age, duration of illness
and the translocation of LPS from gram-negative
bacteria
Michael Maes 1,2, Jean-Claude Leunis 2
MCare4U Outpatient Clinics, Belgium; and
Laboratory Ategis, Waver, Belgium.
Correspondence to: Prof. Dr. M. Maes, M.D., Ph.D.
Clinical Research Center for Mental HealthOlmenlaan 9, 2610 Antwerp, Belgium.
: 32-3-4809282; : 32-3-2889185; www.michaelmaes.com
Submitted: 2008-10-28 Accepted: 2008-11-18 Published online: 2008-12-29
Key words: chronic fatigue syndrome; inflammation; immunity; IgA; cytokines;
enterobacteria; gut permeability; leaky gut; oxidative stressIntroduction
Neuroendocrinol Lett 2008; 29(6):101–000 PMID: 19112401 NEL290608A08 © 2008 Neuroendocrinology Letters www.nel.edu
Abstract
BACKGROUND: There is now evidence that an increased translocation of LPS from
gram negative bacteria with subsequent gut-derived inflammation, i.e. induction
of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new
pathway in chronic fatigue syndrome (CFS).
ME THOD S: The present study examines the serum concentrations of IgA and
IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas
Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and
Klebsielle Pneumoniae in CFS patients both before and after intake of natural
anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine,
N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14
months. We measured the above immune variables as well as the Fibromyalgia
and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and
10-14 months after intake of NAIOSs.
RES ULTS: Subchronic intake of those NAIOSs significantly attenuates the initially
increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24
patients showed a significant clinical improvement or remission 10-14 months
after intake of NAIOSs. A good clinical response is significantly predicted by at-
tenuated IgA and IgM responses to LPS, the younger age of the patients, and a
shorter duration of illness (< 5 years).
DISCUSSION: The results show that normalization of the IgA and IgM responses
to translocated LPS may predict clinical outcome in CFS. The results support the
view that a weakened tight junction barrier with subsequent gut-derived inflam-
mation is a novel pathway in CFS and that it is a new target for drug development
in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific
NAIOSs and a leaky gut diet.
1.
2.
102
Copyright © 2008 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Michael Maes, Jean-Claude Leunis
There is now evidence that activation of inflammatory
and oxidative & nitrosative stress (IO&NS) pathways
play a role in chronic fatigue syndrome (CFS) [1-3]. The
activated pathways include intracellular inflammation,
systemic inflammation with increased levels of pro-in-
flammatory cytokines, increased O&NS, and damage to
DNA, membrane lipids and functional proteins caused
by O&NS [3]. There is now also evidence that leaky gut
is a novel inflammatory pathway in CFS. Recently, we
found that CFS is accompanied by increased serum lev-
els of IgM and IgA directed against lipopolysaccharide
(LPS) of gram-negative enterobacteria and that the IgM
and IgA values are significantly correlated to specific
symptoms of CFS, such as fatigue, autonomic and gas-
tro-intestinal symptoms, and a subjective feeling of in-
fection [1]. This shows that the symptoms of CFS have
a genuine immune pathophysiology [1-3].
These results indicate that in CFS an IgM and IgA-
mediated immune response is raised against the LPS of
different gram negative enterobacteria. The latter indi-
cates that CFS is accompanied by an increased gut per-
meability or leaky gut . This condition is also labelled
intestinal mucosal dysfunction. This suggests that one
of the critical functions of the gut wall has been jeop-
ardized, ie. the integrity of the tight junction barrier,
which separates intestinal microorganisms from the
interstitium.
Disruptions of the permeability of the gut tight junc-
tion barrier may be caused by IO&NS pathways [4-6].
Pro-inflammatory cytokines, which are often increased
in CFS, i.e. and interleukin-1β (IL-1β), IL-6, tumor
necrosis factor-alpha (TNFα), and interferon-gamma
(IFNγ) [3] may cause a loss of the protective barrier
function by enlarging the spaces between the cells of
the gut wall, which results in an increased permeabil-
ity in the intestinal epithelial tight junction barrier [4-
10]. The IL-1β-induced increase in permeability is part-
ly mediated by the activation of nuclear factor kappa
beta (NFκβ) [7]. The TNFα-induced increase in intes-
tinal epithelial tight junction permeability is mediated
by NFκβ p50/p65 binding through activation of myosin
light chain kinase (MLCK) promoter which eventual-
ly leads to a MLCK-mediated opening of the intestinal
tight junction barrier [8,9]. Not only pro-inflammatory
cytokines, but also oxygen free radicals may cause in-
testinal barrier impairment, e.g. following ischaemia /
reperfusion [11]. Natural anti-inflammatory and anti-
oxidative substances (NAIOSs), such as N-acetyl-L-cys-
tine (NAC), glutamine and zinc, may improve the in-
tegrity of the gut barrier [11-17].
Increased gut permeability is a driver of systemic in-
flammation [16]. For example, in abdominal postopera-
tive patients the gut is an important source of systemic
inflammation and decreases in intestinal permeabil-
ity may attenuate the systemic inflammatory response
[17]. The pathway which plays a decisive role in gut-
derived inflammation is translocation of gram negative
enterobacteria (bacterial translocation) or transloca-
tion of LPS from gram negative bacteria from the gut
to the blood through the intestinal barrier failure. Thus,
a leaky gut allows normally poorly invasive enterobac-
teria or the LPS from gram negative bacteria to exploit
the enlarged spaces or lipid raft-mediated transcytotic
pathways to cross the gut epithelium [1-4]. This causes
systemic increases in LPS or infections in the peripheral
blood. Depletion of NAIOSs, such as glutamine, may
increase the risk towards cytokine-mediated bacterial
translocation, while supplementation with glutamine
may reduce bacterial translocation [18].
Bacterial or LPS translocation, in turn, may induce
activation of NFκβ, the major upstream, intracellu-
lar mechanism which regulates the IO&NS pathways
[19,20], such as cyclo-oxygenase (COX-2) and induc-
ible NO synthase (iNOS) [19-21]. Previously, we have
shown that CFS is accompanied by an increased pro-
duction of NFκβ, iNOS and COX-2 by white blood
cells, and other sings of activation of O&NS pathways
[1-3,19,21-25]. As discussed above, pro-inflammatory
cytokine-induced weakening of the tight junction bar-
rier is mediated by NFκβ [7-9]. Consequently, NFκβ ac-
tivation may be not only the cause, but also the conse-
quence of the opening of the tight junction barrier and
thus could perpetuate a vicious circle between NFκβ ac-
tivation and weakening of the tight junction barrier.
Systemic activation of the IO&NS pathways by in-
creased LPS translocation is accompanied by a central
neuroinflammation and increased levels of pro-inflam-
matory cytokines and activation of microglia in the
brain [26]. The latter two central pathways may remain
activated for several months and are accompanied by
a chronically activated production of pro-inflammato-
ry cytokines, such as TNFα [26]. We have previously
discussed that increased intracellular inflammation, in-
duction of the O&NS pathways and the increased pro-
duction of pro-inflammatory cytokines, such as IL-1β,
IL-6, IFNγ, and TNFα, may induce many symptoms of
CFS, such as fatigue, muscle pain, muscle tension, ma-
laise, depressive feelings, and cognitive disorders [3].
Systemic LPS may provoke comparable symptoms in
animal models [27,28].
By inference, the increased LPS translocation with
subsequent gut-derived inflammation is a novel path-
way which may explain the activated IO&NS pathways
in CFS and the symptoms of CFS as well. It is also in-
teresting to note that an increased gut permeability is
induced by the established trigger factors of CFS, e.g.
psychological stress [29,30], sustained strenuous exer-
cise [31]; and inflammatory conditions, such as surgery,
trauma and infections [32,33]. Moreover, the intestinal
barrier may be compromised by other conditions which
are known to be accompanied by chronic fatigue, but
because of the CDC (Centers for Disease Control and
Prevention) criterion no other medical condition may
explain the chronic fatigue cannot be diagnosed as CFS
[34]. The symptoms and pathophysiology, however, of
both CFS according to the CDC and secondary CFS due
103
Neuroendocrinology Letters Vol. 29 No. 6 2008 Article available online: http://node.nel.edu
Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration ...
to other organic illnesses are quite similar [3]. These lat-
ter comprise - amongst others - the use of chemothera-
peutic agents [35], prolonged use of antibiotics [36,37],
radiation [38], AIDS/HIV [39], autoimmune disorders
[40] and inflammatory bowel disorder [41].
In a case report, we have shown that normaliza-
tion of the IgM and IgA response directed against LPS
predicts a gradual remission to treatment with intra-
venous immunoglobins (IVIg), specific NAIOSs, e.g.
glutamine, NAC and zinc, and a milk allergic, gluten-
free and low-carb diet, labelled the leaky gut diet [2].
This gradual normalization of the translocation of LPS
during this treatment regime was also accompanied by
a normalization of most IO&NS variables.
The present study has been carried out in order to
examine the relationships between the translocation of
LPS from gram negative bacteria and the clinical out-
come in CFS.
SUBJECTS AND METHODS
Subjects
Forty-one patients participated in the present study.
They were consecutively admitted to the M-Care4U
Outpatient Clinics, Belgium and selected on the basis
of initial increases in the IgM and / or IgA responses to
LPS [1,2]. The diagnosis CFS was made by means of the
CDC criteria [34]. That is: i) the patient must have a se-
vere chronic fatigue of six months or longer, while there
is no other known medical condition which can explain
the fatigue; and ii) the patient must have four or more
of the following symptoms: substantial impairment in
short-term memory or concentration, sore throat, ten-
der lymph nodes, muscle pain, multi-joint pain with-
out swelling or redness, headache of a new type, pat-
tern or severity, unrefreshing sleep, and post-exertional
malaise lasting more than 24 hours. We employed the
Fibromyalgia and Chronic Fatigue Syndrome Rating
Scale (FF scale) [42,43] in order to measure severity of
illness. This scale measures 12 symptoms of CFS and
fibromyalgia, that is pain, muscular tension, fatigue,
concentration difficulties, failing memory, irritability,
sadness, sleep disturbances, autonomic disturbances,
irritable bowel, headache, and subjective experience of
infection.
In the present study the following patients were ex-
cluded: those who had suffered from a life-time diag-
nosis of psychiatric DSM IV disorders, such as bipolar
depression, anxiety disorders, schizophrenia, substance
use disorders and organic mental disorders and patients
with abnormal values for routine blood tests, such as
alanine aminotransferase (ALT), alkaline phospha-
tase (ALP), blood urea nitrogen (BUN), calcium, cre-
atinine, electrolytes, and thyroid stimulating hormone
(TSH). Also, patients with other medical illnesses, such
as epilepsia, diabetes, inflammatory bowel disease, etc.
were excluded. Patients gave written informed consent
after the study was explained. The study has been ap-
proved by the local ethical committee. This is a non-
interventional study. We did not intend to examine
the effects of a specific treatment, but rather the IgM /
IgA responses to LPS translocation in relation to clini-
cal variables both in CFS patients without a treatment
(baseline) and in the CFS patients who had been tak-
ing specific NAIOSs and had a leaky gut diet for 10-12
months (endpoint). All patients followed the leaky gut
diet and took glutamine, zinc and NAC, in combina-
tion with other NAIOSs, which were given according
to the immune and biochemical status of the patients,
i.e. L-carnitine, coenzyme Q10, taurine and lipoic acid
(in case of carnitine and/or coenzyme Q10 shortage);
or curcumine and quercitine (in case of systemic or in-
tracellular inflammation).
Methods
Fasting blood samples were taken during the morning
hours for the assays of the serum IgM and IgA values
against the LPS of 6 different enterobacteria, i.e. Hafnei
Alvei, Pseudomanes Aeruginosa, Morganella Morganii,
Pseudomanus Putida, Citrobacter Koseri and Klebsi-
ella Pneumoniae. The analyses were performed as ex-
plained before [1,44,45]. In short we used an indirect
ELISA method according to the methods outlined by
the manufacturer (Gemacbio, The Ultimate Biophar-
maceuticals, France). Each serum sample was measured
in duplicate and tested simultaneously with three stan-
dard solutions. The optical densities (OD) of the three
standards are expressed as Z values and from this the
reference linear curve is calculated as Z = f(OD) with
Z = a OD + b. Thus, the Z value of the lowest standard
can be negative. This curve allows to deduce the mean
values of the duplicate measurements of the OD values.
The biological interassay CV values were < 10%.
Statistics
Relationships between variables were assessed by means
of Pearson’s product moment correlation coefficients
and multiple regression analyses. Group mean differ-
ences were checked by means of the analysis of variance
(ANOVA) and by means of linear discriminant analy-
sis. Repeated measurements analyses of variance (RM
ANOVAs) were used to compare basal and endpoint
measurements. When the interaction between time X
groups was significant, analyses of simple effects were
employed to examine the interaction pattern. The in-
dependence of classification systems was ascertained
by means of analysis of contingence tables (χ2-test). In
order to assess the “total LPS translocation load” we
have employed two different indices: a) the total sum
of the 12 Ig (IgM and IgA) levels; and b) the peak Ig
(IgM or IgA) levels, i.e. the highest of the 12 Ig values.
The same indices were also employed to assess the IgM-
versus the IgA-related translocation loads. Toward this
end, we computed the peak IgM and peak IgA data; and
the total sum of the 6 IgM and 6 IgA data. The signifi-
cance was set at α=0.05 (two tailed).
104
Copyright © 2008 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Michael Maes, Jean-Claude Leunis
RESULTS
The mean age of the patients was 37.9 (±11.1) years.
The male / female ratio was 7/34. The mean duration
of illness was 7.9 (±6.6) years and the mean age at onset
was 30.1 (±10.4) years.
Table 1 shows the measurements of the different
IgM and IgA values both basal and at endpoint. RM
design ANOVAs showed that the end point values of
all 6 IgM values were significantly lower than the basal
values. RM design ANOVAs showed that there were no
significant differences in serum IgA to the 6 LPS val-
ues between basal and endpoint. RM design ANOVAs
showed that the end point values of peak IgM and IgA
were significantly lower than the basal peak IgM and
IgA values, respectively. RM design ANOVA showed
that the end point values of the peak Ig values, either
IgA or IgM, were significantly lower than the basal peak
Ig values.
The mean basal FF score was 38.8 (±7.5) and the
endpoint FF score was 14.0 (±11.1). The variability in
the basal FF data was 19.5% and in the endpoint FF data
was 79.4%. We have divided the groups into patients
who showed a good clinical response and those who
did not. Towards this end, we have made the regression
of the endpoint FF values on the basal FF values. Both
values were strongly correlated (R2=23.8%, r=0.49,
p=0.001). The residualized values were consequently di-
chotomized to yield two groups, labelled as responders
(greater reduction in the FF score) versus non-respond-
ers. Table 1 shows the measurements of the FF values
both basal and endpoint in the responders and the non-
responders. RM design ANOVA showed significant dif-
ferences in the FF values between responders and non-
responders (F=18.4, df=1/39, p=0.0002); significant
effects of treatment (F=105, df=1/39, p<10E-4) and a
significant interaction between groups X time (F=12.3,
df=1/39, p=0.001). Analyses of simple effects showed
that at baseline, there were no significant differences
between the FF values between responders and non-re-
sponders (F=0.47, df=1/78, p=0.5) and that at endpoint
there were significant differences between both groups
(F=49.5, df=1/78, p<10E-4). Overall, 26 (that is 63.5%)
of the patients showed a good clinical response, where-
as 15 (that is 36.5%) showed less clinical improvement,
although still statistically significant.
Table 2 shows the FF measurements in groups di-
vided according to duration of illness (longer versus
shorter than 5 years). The FF score was significant-
ly higher in patients with a longer duration of illness
as compared with those with a shorter duration of ill-
ness (F=7.5, df=1/39, p=0.009); the interaction time x
groups was significant (F=17.4, df=1/39, p=0.0003).
Simple effects showed that in baseline conditions, there
were no significant differences between the FF values in
both groups (F=0.4, df=1/78, p=0.5), but at endpoint,
patients who suffered from CFS for more than 5 years
showed significantly higher FF values than those who
did not (F=16.9, df=1/78, p=0.0002).
Table 2 shows the measurements of the basal and
endpoint FF values in patients dichotomized accord-
ing to their age (<38.0 years versus > 38 years). RM de-
sign ANOVA did not show significant differences in the
FF values between older and younger subjects (F=1.5,
df=1/39, p=0.2) but there was a significant interaction
between age groups X time (F=6.9, df=1/39, p=0.01).
Analyses of simple effects showed that at baseline there
were no significant differences between the FF values
Table 1. The measurements of serum IgM and IgA levels against LPS of Hafnia Alvei, Pseudomonas
Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri and Klebsiella Pneumoniae
in basal conditions and at endpoint in 41 patients with chronic fatigue syndrome.
Variables basal endpoint F value* p value (df=1/39)
Hafnei Alvei IgM
IgA
1.82 (2.26)
0.71 (2.60)
0.61 (2.03)
0.53 (1.72)
9.0
0.2
0.005
0.7
Pseudomonas Aeruginosa IgM
IgA
2.38 (1.90)
0.80 (2.12)
0.77 (1.60)
0.97 (1.93)
21.9
0.4
0.01
0.6
Morganella Morganii IgM
IgA
2.51 (2.40)
0.76 (2.80)
1.24 (1.82)
0.62 (1.80)
9.7
0.5
0.004
0.5
Pseudomonas Putida IgM
IgA
2.77 (2.78)
1.68 (4.40)
1.27 (2.19)
0.96 (2.41)
12.7
3.3
0.001
0.07
Citrobacter Koseri IgM
IgA
2.12 (2.11)
1.05 (2.95)
0.90 (1.99)
0.49 (1.63)
13.4
1.37
0.001
0.2
Klebsiella Pneumoniae IgM
IgA
2.24 (4.23)
1.73 (3.96)
1.10 (1.84)
0.55 (1.56)
6.0
3.6
0.02
0.06
Peak IgM
Peak IgA
Peak
IgM
IgA
IgM or IgA
4.22 (3.31)
4.07 (4.55)
6.83 (3.67)
2.06 (2.31)
2.15 (2.51)
3.20 (2.55)
19.6
13.7
57.2
0.0002
0.0009
<10E-5
All results are shown as mean (±SD).
*All results of RM design ANOVAs.
105
Neuroendocrinology Letters Vol. 29 No. 6 2008 Article available online: http://node.nel.edu
Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration ...
between older and younger patients (F=0.07, df=1/78,
p=0.8) and that at endpoint older subject had higher FF
values than younger ones (F=5.9, df=1/78, p=0.02).
We have also computed the differences between the
responders and the non-responders as defined above.
Responders tended to be younger that non-respond-
ers (F=3.3, df=1/39, p=0.07). The duration of illness
was significantly (F=20.2, df=1/39, p=0.0001) higher
in non-responders (mean=12.9 ±5.9 years) than in re-
sponders (mean=4.9 ±5.2 years). There were no signifi-
cant differences between responders and non-respond-
ers in gender distribution, age at onset, baseline IgM or
IgA values, and the endpoint IgM values. Non-respond-
ers (3.29 ±2.33 SD) had significantly (F=5.4, df=1/39,
p=0.02) higher peak IgA values at endpoint than re-
sponders (1.50 ±2.41 SD). Also the residual sum of the
6 IgA values (obtained by the regression from endpoint
IgA on baseline IgA values) was significantly (F=5.2,
df=1/39, p=0.02) higher in non-responders (2.34 ±6.34
SD) than in responders (-1.35 ±3.98 SD). We found that
some of the endpoint IgM or IgA values against LPS
were significantly higher in non-responders than in re-
sponders, i.e. IgM against Pseudomonas Aeruginosa
(F=5.2, df=1/39, p=0.02); Pseudomanas Putida (F=4.7,
df=1/39, p=0.03) and Hafnia Alvei (F=4.1, df=1/39,
p=0.047); and IgA against Citrobacter Koseri (F=4.3,
df=1/39, p=0.04); and Klebsiella Pneumoniae (F=4.5,
df=1/39, p=0.04). By means of linear discriminant
analysis a significant discrimination of non-responders
from responders was obtained by means of two signifi-
cant discriminatory variables, i.e. IgM against Pseudo-
monas Aeruginosa and IgA against Citrobacter Koseri
(F=6.7, df=2/38, p=0.003).
We have also examined the correlations between
the residualized FF values (endpoind FF value with the
baseline FF values covaried out) and various predictors.
We found significant correlations between the residual-
ized FF values and age (r=0.32, p=0.03), duration of ill-
ness (r=0.61, p<10E-4) and the residualized IgA values
(r=0.34, p=0.02), but not with the age at onset (r=-0.05,
p=0.7). We found that 46.7% of the variance in the re-
sidualized FF values could be explained by the regres-
sion on age (F=24.4, df=1/37, p=0.00008), age of onset
(F=16.2, df=1/37, p=0.0005) and the residualized sum
of the IgA values (F=5.8, df=1/37, p=0.01). Age at onset
was negatively loaded, the other explanatory variables
were positively loaded.
By means of regression analyses with the various
endpoint FF symptoms as dependent variables and the
basal FF symptom values, duration of illness and the
residualized IgA or IgM values as explanatory variables
we found that 58.9% of the variance in endpoint values
of the FF item aches and pain was explained by the re-
gression on basal FF values of aches and pain (F=23.8,
p=0.00009), duration of illness (F=16.3, p=0.0004) and
the residualized IgA values (F=5.1, p=0.02). 60.2% of
the variance in endpoint muscle tension was explained
by the regression on baseline muscle tension (F=19.4,
p=0.0002), duration of illness (F=11.2, p=0.002) and
the residualized IgA values (F=10.1, p=0.003). 41.0%
of the variance in memory disturbances could be ex-
plained by the regression on duration of illness (F=17.3,
p=0.0003) and the residualized IgA values (F=7.0,
p=0.01). 52.9% of the variance in gastro-intestinal
symptoms was explained by the regression on the base-
line symptom values (F=10.7, p=0.002), duration of ill-
ness (F=10.5, p=0.003) and the residualized IgA values
(F=11.2, p=0.002).
DISCUSSION
This study shows that normalization of the IgA and IgM
responses to translocated LPS may predict the clinical
outcome in CFS. A younger age at onset, a shorter du-
ration of illness and a younger age of the patient are sig-
nificantly predict a better outcome in CFS.
The first major finding of this study is that the intake
of specific NAIOSs may attenuate the initially increased
IgM and IgA responses to LPS, which indicates that
those NAIOSs may reduce gut-derived inflammation
and by inference may tighten the opened tight junction
barrier. However, the normalization of the IgM values
was more pronounced than that of the IgA values. This
may be explained since increases in serum IgA indicate
the more chronic pathogenic conditions [1]. Different
pathways may be involved in this improvement of gut
permeability.
Table 2. Measurements of the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF
scale) both at baseline and at endpoint according to different dichotomies.
criterion FF basal FF endpoint n
responders
non responders
38.2 (7.8)
39.9 (7.3)
7.7 (5.7)
24.9 (9.7)
26
15
duration of illness < 5 years
duration of illness > 5 years
37.8 (7.3)
39.5 (7.8)
7.3 (4.8)
18.7 (11.9)
17
24
age < 38 years
age > 38 years
39.2 (7.5)
38.4 (7.8)
10.6 (8.2)
17.6 (12.7)
21
20
All results are shown as mean (±SD).
See text for results of statistical analyses.
106
Copyright © 2008 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Michael Maes, Jean-Claude Leunis
a) NAIOSs, such as glutamine [12], NAC [13], and
zinc [14,15], have been shown to have a significant ef-
ficacity in the treatment of increased gut permeabil-
ity. In a recent review article it was discussed that in
laboratory and clinical settings, glutamine can atten-
uate gut permeability and enhance the protection of
the gut epithelial barrier through its ability to induce
the cellular protective stress response in the gut. Thus,
glutamine may attenuate gut injuries and may attenu-
ate the subsequent gut-derived systemic inflammato-
ry responses [16]. Foitzik et al. [46], using an animal
model of acute necrotizing pancreatitis, examined the
effects of total parental nutrition (TPN) or TPN com-
bined with glutamine. They found that glutamine sig-
nificantly increased transmucosal resistance, and de-
creased the mannitol flux through the epithelium and
the prevalence of pancreatic infections. Ann et al. [47]
showed that glutamine might effectively reduce non-
steroid anti-inflammatory drugs (NSAID)-induced gut
damage and bacterial translocation in the rat. Thus,
diclofenac causes an increase in gut damage, enteric
bacterial numbers and bacterial translocation, where-
as glutamine may reduce the above changes induced
by diclofenac. In another study, glutamine adminis-
tration was compared to placebo in patients undergo-
ing abdominal surgery [17]. It was found that in the
glutamine treated group, there were significant reduc-
tions in gut permeability, serum endotoxin concentra-
tions, serum malondialdehyde and WBC counts [17].
Similar findings were reported by Zhou et al. [48]: en-
teral glutamine supplementation improved gut perme-
ability and decreased plasma endotoxin concentrations
in thermally injured patients. In Caco-2 cells, TNFα
induces a translocation of E. Coli when there is a si-
multaneous depletion of glutamine [18]. Addition of
glutamine significantly inhibits the bacterial translo-
cation [18]. This indicates that in inflammatory condi-
tions, the availability of glutamine is essential for the
preservation of a functional barrier to microorganisms
[18]. The above results show that glutamine reduces
the permeability of the colon; the opening of the tight
junction barrier; and bacterial translocation by stabiliz-
ing the intestinal mucosal barrier; and that glutamine
attenuates gut-derived inflammation. These effects of
glutamine may be obtained through the augmentation
of small bowel villus morphology; the maintenance of
intestinal functions; intestinal permeability and im-
mune function; and prevention of clinical infection re-
lated to bacterial translocation [49].
Dietary supplementation with zinc improves meth-
otrexate-damaged rat intestine and in particular stim-
ulates gut repair [50,51]. In Crohn’s disease, zinc sup-
plementation tightens “leaky gut. Thus, the lactulose
/ mannitol ratio was significantly higher before zinc
supplementation than after, whereas during follow-up,
most of the patients had normal intestinal permeability
and did not relapse. This indicates that zinc can resolve
permeability alterations and improves intestinal barrier
function, which in turn contributes to a reduction of
relapses in Crohns disease [14,52]. Zinc-carnosine at
concentrations that are found in the gut lumen stabi-
lises the gut mucosa. Thus, in volunteers, indomethacin
caused a threefold increase in gut permeability, whereas
no significant increase in permeability was seen when
zinc carnosine was co-administered [53]. NAC pre-
treatment results in improved barrier integrity and less
pronounced reticuloendothelial system activation, in-
dicating that NAC ameliorates gut-derived inflamma-
tion through an increased gut barrier function [11].
b) The other NAIOSs employed in this study, e.g. a)
carnitine, coenzyme Q10, and lipoic acid; and curcu-
mine and quercetine, may normalize the activation of
the IO&NS pathways, e.g. through inhibition of oxygen
radical formation; protecting tissues and mitochondria
from O&NS damage; inhibiting the production of NFκβ,
iNOS and COX-2 by white blood cells; and decreasing
the production of pro-inflammatory cytokines [54-56].
For example, curcumine significantly reduces the pro-
duction of TNFα in colon mucosa cells, and can atten-
uate the production of COX-2 and iNOS immunosig-
nals and nitrite production as well [57]. Curcumine is
also a specific inhibitor of NFκβ [58]. In intimal cells,
propionyl-carnitine has been shown to be an inhibitor
of NFκβ [59]. In MonoMac6 cells (a human monocytic
cell line) stimulated with TNFα, lipoic acid significant-
ly suppresses the activity of NFκβ [60]. Lipoic acid and
NAC reduce the oxidative stress associated with zinc
deficiency and the subsequent triggering of NFκβ-acti-
vation in neuronal cells [61]. Quercetin inhibits the ac-
tivation of NFκβ and iNOS protein and mRNA expres-
sion and inhibits NO production in a dose-dependent
manner [62].
In our case report [2], the patient had been treat-
ed with NAIOSs in conjunction with IVIg. In this pa-
tient, IVIg was used primarily as an immunomodulator
because IVIg shows an efficacy in treating inflamma-
tory and autoimmune responses, the patient suffered
from. Indeed, IVIg may attenuate cytokine-induced
NFκβ production; the production of pro-inflamma-
tory cytokines; T-cell activation; and LPS-stimulated
cytokine production; IVIg may favour fagocytosis and
neutralize infectious agents; and IVIg contains antiidi-
otypic antibodies against human autoantibodies [63-
68]. Importantly, IVIg decreases bacterial translocation
beyond the mesenteric lymph nodes and decreases the
number of translocated bacteria thus preventing bacte-
rial translocation spread [69]. However, none of the pa-
tients in the present study has been treated with IVIg.
Since the patients took only NAIOSs, we may conclude
that NAIOSs in conjunction with the leaky gut diet may
tighten the weakened tight junction barrier in CFS.
The second major finding of this study is that the
abovementioned normalization of the IgA and IgM val-
ues in CFS predicts a better clinical outcome. These re-
sults support the view that an increased translocation
107
Neuroendocrinology Letters Vol. 29 No. 6 2008 Article available online: http://node.nel.edu
Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration ...
of LPS of gram-negative bacteria is a novel pathway in
CFS. Indeed, previously, we reported that the IgM and
IgA levels against LPS are significantly increased in pa-
tients with CFS as compared with normal controls [1].
In the abovementioned case report, we found that a
gradual normalization of the translocation of LPS was
accompanied by a gradual clinical improvement and
eventually remission of CFS [2]. In the present study,
we found that the normalization in serum IgA and
IgM directed against LPS predicts the clinical outcome
in patients with CFS. This indicates that a normaliza-
tion of the immune responses to LPS and thus of leaky
gut is accompanied by an improvement in the sever-
ity of CFS and in some patients to a clinical remission.
As explained, the NAIOSs which had been taken by
the patients are known to restore the openings of the
tight junction barrier which likewise is followed by an
attenuation of gut-derived activation of the IO&NS
pathways and thus a decrease in the symptoms of CFS.
Phrased differently, NAIOSs may have a clinical util-
ity in CFS because they attenuate the IO&NS pathways
and restore the gut barrier as well.
The third major finding of this study is that a lon-
ger duration of illness and older age are factors that in-
crease the probability towards a worse clinical outcome
in CFS. This may be explained since a longer duration
of illness may have allowed the IO&NS pathways to be
activated for longer times, thus resulting in more dam-
age caused by O&NS, such as lipid peroxidation, dam-
age to DNA and proteins, and consequently a higher
probability of autoimmune responses, which frequently
occur in severe CFS (Maes et al., in preparation). Also,
older age is a predisposing factor toward increased
IO&NS responses. Thus, increasing age is accompanied
by increased inflammatory [70] and oxidative processes
[71].
In conclusion, in this study we report that the nor-
malization of the increased LPS translocation during
treatment with specific NAIOSs and the leaky gut diet
is accompanied by a clinical improvement or remis-
sion of CFS. The results of the present support the view
that leaky gut is a novel pathway in CFS. At this point,
this condition may be treated by some NAIOSs and the
leaky gut diet. However, treatment with these NAIOSs
may take a long time (around 1 year) and is rather ex-
pensive. Therefore, future drug development in CFS
should target the weakening of the tight junction bar-
rier and the subsequent gut-derived inflammation.
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... Systemic and chronic activation of those IO&NS pathways may explain peripheral and central fatigue symptoms as well as other symptoms of ME/CFS [1,[3][4][5][6]. In addition, there is some evidence that some of these IO&NS biomarkers are associated with duration of illness, as for example the IgM/IgA responses to Gram-negative bacteria [7]. Nevertheless, there were no attempts to build data-driven models of ME/CFS based on the above-mentioned causome (increased bacterial translocation), protectome (lowered coQ10), adverse outcome pathways (AOP, increased activity of IO&NS pathways) and phenome data. ...
... Second, these individualized feature scores may be used to target specific aberrations in risk-resilience features and/or AOPs thereby allowing for a more personalized treatment. For example, high values on the IgA LPS latent vector score would indicate that customized treatments should target increased bacterial translocation [7,12]. ...
... This is important as based on ANOVAs one would conclude that ME/CFS is a unitary disease entity which is characterized by aberrations in all those pathways, whereas in fact ME/CFS comprises three distinct classes. The first cluster was externally validated by a longer duration of illness indicating that longer duration is accompanied by increased translocation of Gram-negative bacteria and especially by increased IgM-mediated autoimmune responses [7]. ...
Article
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The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.
... Does not cross blood-brain barrier [51][52][53] Serotonin ( Crosses blood-brain barrier [68][69][70][71][72][73][74][75][76][77][78][79][80][81] * Short chain fatty acids are not neurotransmitters. However, as they may modulate the levels of neurotransmitters, they are included here. ...
... Furthermore, the "leaky gut" phenomenon resulting from disrupted gut barrier function is proposed to contribute to MDD. In this context, MDD patients show elevated serum concentrations of immunoglobulin (Ig)-M and IgA against lipopolysaccharides of Gram-negative bacteria compared to healthy controls [75], suggesting an increase in bacterial translocation from the gut and subsequent inflammatory response, potentially contributing to an MDD phenotype. ...
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The microbiota–gut–brain axis is a bidirectional communication pathway that enables the gut microbiota to communicate with the brain through direct and indirect signaling pathways to influence brain physiology, function, and even behavior. Research has shown that probiotics can improve several aspects of health by changing the environment within the gut, and several lines of evidence now indicate a beneficial effect of probiotics on mental and brain health. Such evidence has prompted the arrival of a new term to the world of biotics research: psychobiotics, defined as any exogenous influence whose effect on mental health is bacterially mediated. Several taxonomic changes in the gut microbiota have been reported in neurodevelopmental disorders, mood disorders such as anxiety and depression, and neurodegenerative disorders such as Alzheimer’s disease. While clinical evidence supporting the role of the gut microbiota in mental and brain health, and indeed demonstrating the beneficial effects of probiotics is rapidly accumulating, most of the evidence to date has emerged from preclinical studies employing different animal models. The purpose of this review is to focus on the role of probiotics and the microbiota–gut–brain axis in relation to mood disorders and to review the current translational challenges from preclinical to clinical research.
... Moreover, increased commensal bacterial translocation and enhanced gut inflammation have been found in ME/CFS cases compared to controls, as discussed in more detail in Section 2.2 [60,74,75] (Figure 1). Although the exact mechanism behind this phenomenon largely remains unknown, one hypothesis is that the rise in Enterobacteriaceae found in dysbiosis may mediate intestinal inflammation and permeability, as increased levels of lipopolysaccharide derived from these bacteria is detected in ME/CFS [74,76,77] (Figure 1). However, it should be noted that this is far from being proven, and more research is needed to address this point. ...
... Likewise, raised IgA response to commensal bacteria and enhanced inflammation have been reported in 128 ME/CFS cases when compared to healthy volunteers [76]. Remarkably, significant improvement was obtained if a leaky gut diet was combined with anti-inflammatory and anti-oxidative substances, thus suggesting a new therapeutic approach in ME/CFS treatment [77]. Similar results were also obtained in depressed patients, suggesting that gut permeability and consequently enhanced immune response might explain overlap between major depressive disorder (MDD) and ME/CFS cognitive symptom [87,88]. ...
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The well-known symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic pain, cognitive dysfunction, post-exertional malaise and severe fatigue. Another class of symptoms commonly reported in the context of ME/CFS are gastrointestinal (GI) problems. These may occur due to comorbidities such as Crohn’s disease or irritable bowel syndrome (IBS), or as a symptom of ME/CFS itself due to an interruption of the complex interplay between the gut microbiota (GM) and the host GI tract. An altered composition and overall decrease in diversity of GM has been observed in ME/CFS cases compared to controls. In this review, we reflect on genetics, infections, and other influences that may factor into the alterations seen in the GM of ME/CFS individuals, we discuss consequences arising from these changes, and we contemplate the therapeutic potential of treating the gut to alleviate ME/CFS symptoms holistically.
... A low-carbohydrate diet has also been proposed in case of leaky gut disfunction and PCOS [339,372]. However, the central principles of a "leaky gut diet" are low carbohydrates, no/low milk and dairy products, and no/low gluten, as they all represent the main factors triggering LPS-induced immune-inflammatory response [376]. ...
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Increasing evidence on the significance of nutrition in reproduction is emerging from both animal and human studies, suggesting a mutual association between nutrition and female fertility. Different “fertile” dietary patterns have been studied; however, in humans, conflicting results or weak correlations are often reported, probably because of the individual variations in genome, proteome, metabolome, and microbiome and the extent of exposure to different environmental conditions. In this scenario, “precision nutrition”, namely personalized dietary patterns based on deep phenotyping and on metabolomics, microbiome, and nutrigenetics of each case, might be more efficient for infertile patients than applying a generic nutritional approach. In this review, we report on new insights into the nutritional management of infertile patients, discussing the main nutrigenetic, nutrigenomic, and microbiomic aspects that should be investigated to achieve effective personalized nutritional interventions. Specifically, we will focus on the management of low-grade chronic inflammation, which is associated with several infertility-related diseases.
... We propose that the sequence during critical illness-from splanchnic hypoperfusion to hypoxia, redox imbalance, altered gut microbiome, intestinal injury, gut-related endotoxemia, pro-inflammatory cytokines and systemic inflammatorymay also contribute to explain the emergence of ME/CFS following a physiological insult. Our proposal is in alignment with others' findings that intestinal injury and resulting inflammation are central to ME/CFS (73)(74)(75)(76)(77)(78)(79)(80)(81) and consistent with findings linking the gut microbiome to inflammation (82)(83)(84)(85) and to fatigue symptoms in ME/CFS (86). If verified, the existence of a vicious inflammatory cycle centered around intestinal injury could contribute to explain the perpetuation of ME/CFS. ...
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We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS. Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.
... Moreover, researchers have induced fatigue in mice through the administration of LPS (69). Finally, studies have shown that the normalization of leaky gut in ME/CFS by administration of natural antiinflammatory and antioxidative substances is accompanied by a clinical improvement (70). Readers are referred to the reviews for a detailed discussion on the implication of gut permeability on the immune system and mitochondrial function in ME/CFS (7, 71). ...
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... [143,[145][146][147][148]. Therapeutic interventions aimed at re-establishing eubiosis and reducing intestinal permeability may be helpful in this respect. It has been demonstrated that a leaky gut diet, together with anti-inflammatory and anti-oxidative substances, is able to significantly improve CFS conditions, [149]. Moreover, the use of probiotics and/or prebiotics should also be considered, and preliminary studies in mice and rats show promising results [150][151][152][153]. Finally, positive outcomes were reported using fecal microbiota transplantation (FMT) in CFS patients [154], but further evidence is needed. ...
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient. In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.
... This will lead to depletion of monodeoxyribonucleotide building blocks that are equally much needed both for DNA repair as for de novo synthesis of DNA molecules. Simultaneous GSH depletion and TrxR inhibition must therefore be expected to lead to inhibition of DNA synthesis, which will be especially unfavorable for fast-replicating cells, such as leukocytes (or leukocyte progenitors) and enterocyteswhich may not only lead to immunosuppression (which might be potentially significant in the etiopathogenesis of chronic fatigue syndrome), but also to various pathological disturbances of intestinal function -with potential consequences also for other parts of the body, including the brain [71][72][73]. However, it must also be expected to cause inhibition of DNA repair, leading to abnormal enhancement of the rate of mitochondrial DNA aging as well as enhancing the risk of cancer. ...
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... It is a disruption in the gut barrier, where the epithelium is compromised as a result of stress and it becomes permeable [22]. It causes a translocation of lipopolysaccharide (LPS) of Gram-negative bacteria which results in activation of the immune system (Toll-like receptors -TLRs) and production of pro-inflammatory cytokines (IL-6, IFN-γ, CRP, TNF-α) [1,5,44]. ...
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Emerging evidence indicates that the gut microbiota play a crucial role in the bidirectional communication between the gut and the brain suggesting that gut microbes may shape neural development, modulate neurotransmission and affect behavior, and thereby contribute to the pathogenesis and/or progression of many neurodevelopmental, neuropsychiatric, and neurological conditions. This review summarizes recent data on the role of microbiota–gut–brain axis in the pathophysiology of neuropsychiatric and neurological disorders including depression, anxiety, schizophrenia, autism spectrum disorders, Parkinson’s disease, migraine, and epilepsy. Also, the involvement of microbiota in gut disorders co-existing with neuropsychiatric conditions is highlighted. We discuss data from both in vivo preclinical experiments and clinical reports including: (1) studies in germ-free animals, (2) studies exploring the gut microbiota composition in animal models of diseases or in humans, (3) studies evaluating the effects of probiotics, prebiotics or antibiotics treatment as well as (4) the effects of fecal microbiota transplantation.
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• The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, system­ atic, and integrated approach to the evaluation, classi­ fication, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.
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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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A prospective study was conducted to study the effect of radiotherapy (RT) and regional pelvic hyperthermia (HT) on intestinal permeability in three groups of patients. Fifteen acted as cancer controls, receiving RT away from the peritoneal cavity, 21 patients received radical pelvic or abdominopelvic RT and 13 patients pelvic RT followed by pelvic HT using a BSD 1000 phased array applicator. Small bowel permeability was measured by oral administration of a mixture of [51Cr]EDTA, [14C]mannitol and lactulose before and after a course of treatment. The absorption of each marker was calculated by measuring the urinary excretion over 0-6 and 0-12 hours. The 6 hour collection gave results similar to the 12 hour collection, but had logistical advantages. The EDTA absorption rose and the mannitol absorption fell during a course of treatment, but the best index of permeability change was the EDTA/mannitol ratio (E/M). The E/M ratio rose by a factor of 2.4 (P less than 0.001) and 1.82 (P = 0.05) following RT and RT/HT respectively. There was no significant difference between the RT and RT/HT groups but the thermal dose to the RT/HT group was low (23 min./equiv 43 degrees C over three or four fractions in 4 weeks). There was no correlation between small bowel permeability and bowel frequency. The E/M permeability test is a useful simple functional assay for assessing small bowel damage after RT and RT/HT.