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The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression

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  • Sichuan Provincial Center for Mental Health University of Electronic Science and Technology of China

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There is now evidence that major depression (MDD) is accompanied by an activation of the inflammatory response system (IRS) and that pro-inflammatory cytokines and lipopolysacharide (LPS) may induce depressive symptoms. The aim of the present study was to examine whether an increased gastrointestinal permeability with an increased translocation of LPS from gram negative bacteria may play a role in the pathophysiology of MDD. Toward this end, the present study examines the serum concentrations of IgM and IgA against LPS of the gram-negative enterobacteria, Hafnia Alvei, Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in MDD patients and normal controls. We found that the prevalences and median values for serum IgM and IgA against LPS of enterobacteria are significantly greater in patients with MDD than in normal volunteers. These differences are significant to the extent that a significant diagnostic performance is obtained, i.e. the area under the ROC curve is 90.1%. The symptom profiles of increased IgM and IgA levels are fatigue, autonomic and gastro-intestinal symptoms and a subjective feeling of infection. The results show that intestinal mucosal dysfunction characterized by an increased translocation of gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. It is suggested that the increased LPS translocation may mount an immune response and thus IRS activation in some patients with MDD and may induce specific "sickness behaviour" symptoms. It is suggested that patients with MDD should be checked for leaky gut by means of the IgM and IgA panel used in the present study and accordingly should be treated for leaky gut.
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Neuroendocrinol Lett 2008; 29(1): 117–124
ORIGINAL ARTICLE
Neuroendocrinology Letters Volume 29 No. 1 2008
The gut-brain barrier in major depression:
Intestinal mucosal dysfunction with an increased
translocation of LPS from gram negative
enterobacteria (leaky gut) plays a role in the
inflammatory pathophysiology of depression
Michael Maes 1, Marta Kubera 2 and Jean-Claude Leunis 3
MCare4U Outpatient Clinics, Belgium;
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of
Sciences, Krakow, Poland;
Laboratory Ategis, Waver, Belgium.
Correspondence to: Prof. Dr. M.Maes, M.D., Ph.D. Director: M-Care4U Outpatient Clinics,
Olmenlaan 9, 2610 Antwerp, Belgium. tel: +32-3-4809282 fax: +32-3-2889185
www.michaelmaes.com e-mail : crc.mh@telenet.be
Submitted: 2008-01-06 Accepted: 2008-01-27 Published online: 2008-02-22
Key words: major depression; chronic fatigue syndrome; inflammation; enterobacteria;
leaky gut; gut permeability; cytokines; LPS; oxidative stress
Neuroendocrinol Let t 2008; 29(1):117–124 PMID: 18283240 NEL290108A12 © 2008 Neuroendocrinology Letters www.nel.edu
Abstract
There is now evidence that major depression (MDD) is accompanied by an ac-
tivation of the inflammatory response system (IRS) and that pro-inflammatory
cytokines and lipopolysacharide (LPS) may induce depressive symptoms.
The aim of the present study was to examine whether an increased gastrointestinal
permeability with an increased translocation of LPS from gram negative bacteria
may play a role in the pathophysiology of MDD. Toward this end, the present study
examines the serum concentrations of IgM and IgA against LPS of the gram-nega-
tive enterobacteria, Hafnia Alvei, Pseudomonas Aeruginosa, Morganella Morganii,
Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in MDD
patients and normal controls.
We found that the prevalences and median values for serum IgM and IgA against
LPS of enterobacteria are significantly greater in patients with MDD than in nor-
mal volunteers. These differences are significant to the extent that a significant
diagnostic performance is obtained, i.e. the area under the ROC curve is 90.1%.
The symptom profiles of increased IgM and IgA levels are fatigue, autonomic and
gastro-intestinal symptoms and a subjective feeling of infection. The results show
that intestinal mucosal dysfunction characterized by an increased translocation of
gram-negative bacteria (leaky gut) plays a role in the inflammatory pathophysiol-
ogy of depression. It is suggested that the increased LPS translocation may mount
an immune response and thus IRS activation in some patients with MDD and may
induce specific “sickness behaviour” symptoms. It is suggested that patients with
MDD should be checked for leaky gut by means of the IgM and IgA panel used in
the present study and accordingly should be treated for leaky gut.
1.
2.
3.
118
Copyright © 2008 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Michael Maes, Marta Kubera and Jean-Claude Leunis
INTRODUCTION
There is now evidence that activation of the inflamma-
tory response system (IRS) plays a role in the patho-
physiology of major depression (MDD). This theory
has been described as the “cytokine or “monocyte-T
lymphocyte hypothesis” of depression, although recent-
ly we described this newly discovered pathway as the
“IRS activation” theory [1–4] and now as the “inflam-
matory and neurodegenerative (I&ND) hypothesis” of
depression [5].
The IRS findings in MDD show: a) an increased pro-
duction of pro-inflammatory cytokines, such as inter-
leukin-6 (IL-6), IL-1β and tumor necrosis factor alpha
(TNFα); b) an increased expression of T lymphocyte
activation markers, such as HLA-DR+ and CD25+; c)
the presence of an acute phase response, with increased
serum levels of haptoglobin, decreased serum zinc levels
and increased serum concentrations of the alpha2 glob-
ulin fraction obtained by electrophoresis; d) and signs
of poor cellular immunity, such as lowered natural kill-
er cell cytotoxity and decreased mitogen–induced lym-
phocyte responses; and e) an increased induction of in-
doleamine oxidase (IDO) with consequent tryptophan
depletion and formation of TRYCATs (tryptophan cat-
abolites along the IDO pathway) [6].
Activation of the IRS is found in animal models of
MDD, such as the chronic mild stress and the olfac-
tory bulbectomized rat models of depression [7–10].
Newly generated rat models of depression are based
on induced inflammation, e.g. the LPS-induced model
[11] and sustained administration of IL-6 by infecting
healthy MRL +/+, C3H.SW and Balb/C mice with ad-
enovirus vector carrying cDNA for murine IL-6 or mice
infected with Ad5mIL6 adenovirus [12,13].
It is known that systemic LPS and administration of
pro-inflammatory cytokines cause chronic central neu-
roinflammation. For example, systemic LPS results in
rapid increases in brain TNFα levels, which may remain
elevated for 10 months [14]. Moreover, brain microglia
are activated to produce chronically elevated pro-in-
flammatory factors in the brain [14]. Central neuroin-
flammation and an increased production of pro-inflam-
matory cytokines, such as TNFα, IL-1β and IL-6, may
induce a behaviour complex, i.e. sickness behaviour,
characterized by the appearance of symptoms such as
anorexia, psychomotor retardation, malaise, loss of in-
terest, etc. [14]. This symptom complex is quite similar
to the symptoms of MDD [15].
External (psychological) as well as internal (organic
stressors) stressors, which induce IRS activation, are re-
lated to the appearance of depressive episodes. Exam-
ples are severe negative life events, some inflammato-
ry and autoimmune illnesses, the postnatal period, etc.
Maes et al. [16–18] were the first to show that – in hu-
mans – psychological stress induces IRS activation with
increased production of pro-inflammatory cytokines,
such as IFNγ and TNFα. In experimental animals in-
creased IL-1β and IL-6 levels have been detected in the
blood and various brain regions [19]. The IRS activa-
tion theory of MDD is fueled by the high comorbidity
of MDD with inflammatory disorders such as multiple
sclerosis (MS), coronary-heart disorder, HIV-infection,
inflammatory bowel disease and rheumatoid arthritis
[1,20]. For example, in MS, the depressive episodes are
preceded by increased IFNγ production [21], suggesting
that IRS activation may underpin depression in MS.
The aim of the present study is to examine anoth-
er immune pathway which may underpin MDD, i.e. an
immune response mounted against an increased trans-
location of LPS from gram-negative enterobacteria. Re-
cently, we published that the median values for serum
IgA and IgM against LPS of enterobacteria are signifi-
cantly greater in patients with chronic fatigue syndrome
(CFS) than in normal volunteers, suggesting that an in-
creased translocation of LPS from enterobacteria is a
new pathway underpinning CFS [22,23]. This condi-
tion can also be described as increased gut permeability
or leaky gut and indicates intestinal mucosal dysfunc-
tion (IMD). Since there is a strong degree of comorbid-
ity between MDD and CFS, and since fatigue is one of
the key symptoms of major depression and gastrointes-
tinal symptoms frequently occur in MDD [24,25], we
hypothesized that also MDD might be accompanied by
an increased translocation of LPS.
The specific aims of the present study are to examine
whether MDD is accompanied by increased serum lev-
els of IgM and IgA against the LPS of 6 enterobacteria,
i.e. Hafnei Alvei, Pseudomanes Aeruginosa, Morganel-
la Morganii, Pseudomanus Putida, Citrobacter Koseri,
and Klebsiella Pneumoniae indicating an immune re-
sponse directed to endotoxins secreted by gram-nega-
tive enterobacteria and which cannot be detected when
the gut-intestinal lining is intact.
SUBJECTS AND METHODS SUBJECTS
Fifty-one subjects participated in the present study, 23
controls (staff or their family members), and 28 MDD
patients admitted to the M-Care4U Outpatient Clinics,
Belgium. The patients were classified according to the
Diagnostic and Statistical Manual of Mental Disorders,
4th edition [26]. We have excluded:
a) subjects with life-time diagnosis of other psychiat-
ric DSM-IV-TR disorders, such as anxiety disor-
ders, schizophrenia, substance use disorders and
organic mental disorders;
b) subjects with CFS as diagnosed by the CDC criteria
[27]; c) subjects with other medical illness, such as
other inflammatory or autoimmune disorders;
d) subjects who ever had been treated with anti-psy-
chotic drugs or anticonvulsants and subjects who
had been taking psychotropic drugs during the last
year prior to the studies; e) subjects with abnor-
mal values for routine blood tests, such as alanine
119
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The gut-brain barrier in major depression: Intestinal mucosal dysfunction ...
aminotransferase (ALT), alkaline phosphatase
(ALP), blood urea nitrogen (BUN), calcium, cre-
atinine, electrolytes, thyroid stimulating hormone
(TSH), total protein, and iron or transferrin satu-
ration; and
f) subjects with acute inflammatory and allergic reac-
tions for at least 1 month prior to the study.
The total sum of the FibroFatigue (FF) scale, i.e. the
Fibromyalgia and Chronic Fatigue Syndrome Rating
Scale [28,29], was used in the MDD patients to com-
pute the severity of specific symptoms, some of which
have been shown to be correlated to the IgM and IgA
levels against LPS in CFS [22]. This scale measures 12
items reminiscent for CFS and fibromyalgia: pain, mus-
cular tension, fatigue, concentration difficulties, failing
memory, irritability, sadness, sleep disturbances, auto-
nomic disturbances, irritable bowel, headache, and sub-
jective experience of infection. Patients and controls
gave written informed consent after the study protocol
was fully explained. The study has been approved by
the local ethical committee.
METHODS
Blood was taken during the morning hours for the de-
termination of IgM and IgA against the LPS of 6 differ-
ent enterobacteria, i.e. Hafnei Alvei, Pseudomanes Aer-
uginosa, Morganella Morganii, Pseud omanus Putida,
Citrobacter Koseri and Klebsiella Pneumoniae. Serum
IgM and IgA levels were measured by means of an in-
direct ELISA method according to the methods out-
lined by the manufacturer (Gemacbio, The Ultimate
Biopharmaceuticals, France). Each serum sample was
measured in duplicate and tested simultaneously with
three standard 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
Group mean differences were assessed by means of
analysis of variance (ANOVA) or analysis of covariance
(ANCOVA). The diagnostic performance was checked
by means of ROC (receiver operating characteristics)
analysis with computation of the area under the ROC
curve, sensitivity, specificity and predictive value of a
positive test result (PV+) and with kappa statistics. Data
reduction was obtained by means of principal compo-
nent (PC) analyses. In order to assess the “total LPS
translocation load” we have employed three different
indices: a) the first PC of the 12 Ig (IgM and IgA) val-
ues; b) the total sum of the 12 Ig (IgM and IgA) levels;
and c) 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 first PCs of
the 6 IgM and 6 IgA data; the peak IgM and peak IgA
data; and the total sum of the 6 IgM and 6 IgA data. We
employed Pearsons product moment correlation coef-
ficients, Spearmans rank order correlations, and multi-
ple regression analyses in order to examine the relation-
ships between variables. The relationships between the
IgM / IgA values and the symptoms of the FF scale were
assessed by means of canonical correlation analyses and
by means of stepwise (F-to-enter p=0.05) linear discri-
minant analysis (LDA) with the 12 FF scale items as the
discriminatory variables and the dichotomized peak Ig
(IgM and IgA) data as grouping variable. The signifi-
cance was set at α=0.05 (two tailed).
RESULTS
There were no significant differences (F=1.6, df=4/49,
p=0.2) in age between normal controls (mean ±SD =
40.0 ± 12.9 years) and MDD patients (44.3 ±11.2 years).
There were no significant differences (χ2 Yates = 0.1,
df=1, p=0.7) in the female / male ratio between normal
controls (16 / 7) and MDD patients (17 / 11). There
were no significant correlations between age and any
of the serum IgM or IgA levels directed against the LPS
of the different enterobacteria and no significant differ-
ences in the serum IgM or IgA values between males
and females. The FF score was not significantly differ-
ent between men and women (F=0.06, df=1/26, p=0.8)
and there was no significant correlation between age
and the FF score (r=–0.33, p=0.08).
Table 1 shows the serum IgM values in the MDD
patients and controls. ANOVAs showed that the IgM
levels directed against the LPS from Pseudomonas Aer-
uginosa and Putida were significantly greater in MDD
that in the normal controls. Table 1 shows that there
were significant differences between the study groups
in the 6 IgA levels against LPS except against Pseu-
domonas Aeruginosa. Covarying for age and sex did
not change any of the above results. By means of Fish-
er’s exact probability test we found a significantly (ψ =
0.50, p=0.0002) greater number of MDD patients (12 /
28) with abnormally increased IgM levels (i.e. anyone
of the 6 IgM values > 2 Z values) than in controls (0 /
23). Also, the prevalences of MDD patients (11 / 28)
with abnormally increased IgA levels (i.e. anyone of the
6 IgA > 2 Z values) were significantly (ψ = 0.35, p=0.01)
higher than in normal controls (2 / 23).
Table 2 gives the peak serum Ig values (IgM or IgA,
alone and together), the total sum of the Ig data (IgM or
IgA, alone and together) and the first PC of the IgM and
the IgA data. However, we were unable to find that one
PC could reflect the 12 Ig (IgM and IgA) data: indeed,
the first PC of the 12 Ig data explained only 38.2% of
the variance, while the 6 IgM variables loaded highly on
the first PC and the 6 IgA data on the second PC even
120
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Michael Maes, Marta Kubera and Jean-Claude Leunis
without performing a rotation. Thus, there is no com-
mon PC which can reflect the 12 Ig variables. The peak
IgM and IgA values and the total sum of all 6 IgM and
IgA values as well as the first PC subtracted from the 6
IgM and IgA values were significantly higher in MDD
patients than in normal controls. The peak Ig (either
IgM or IgA) values and the sum of the 12 Ig values were
both significantly higher in MDD patients than in nor-
mal controls. Covarying for age and sex in ANCOVAs
did not change any of these results. ROC analysis per-
formed on the peak IgM or IgA values showed that the
area under the ROC curve (AUC) was highly significant
(AUC=90.8%). Accordingly, the diagnostic perform-
ance computed was highly significant; at a cut off value
for the peak IgM or IgA values > 2.2 Z, the diagnostic
performance was: sensitivity=67.9%, specificity=95.6%,
and PV+=95.0% (κ=0.62, t=5.66, p=0.00002).
By means of Spearman’s rank order correlation coef-
ficients we found a significant positive correlation be-
tween the peak IgM-IgA data and the total sum on the
FF scale (r=0.49, p=0.007). Two items of the FF scale
were significantly related to the peak IgM-IgA data, i.e
fatigue (r=0.54, p=0.003) and irritable bowel (r=0.56,
p=0.002). Table 3 shows the results of a canonical cor-
relation analysis with peak IgM and peak IgA values as
explanatory variables and the 12 items of the FF scale as
dependent variables. We found that the symptom pro-
files of increased IgM and IgA were fatigue, autonomic
disturbances, irritable bowel and a subjective feeling of
infection. In order to further examine the relationships
between serum IgM and IgA levels and the severity of
the FF scale, we carried out stepwise LDA with the 12
FF scale symptoms as the explanatory variables and the
dichotomized peak IgM (higher versus lower than 2 Z
values) and peak IgA (higher versus lower 2 Z values)
as groups. We found that sadness (loading=0.71), irri-
table bowel (loading=0.58) and muscular tension (load-
ing=0.40) were significant discriminatory variables for
the dichotomized peak IgM values (F=18.5, df=1/26,
p=0.0004). The dichotomized peak IgA groups were
best discriminated (F=5.7, df=1/26, p=0.02) using fa-
tigue (loading = 0.86) and irritable bowel (loading =
0.77) as discriminatory variables. Finally, the dichot-
omized peak IgM or IgA values were best predicted by
fatigue (loading = 0.87), irritable bowel (loading = 0.75)
and a subjective feeling of infection (loading = 0.65)
(F=18.2, df=1/26, p=0.0004).
DISCUSSION
The findings of the present study show that MDD is ac-
companied by increased serum levels of IgM and IgA
directed against LPS of gram-negative enterobacteria
and that the IgM-IgA values are related to symptoms
reminiscent of MDD and CFS, e.g. fatigue, autonomic
and gastro-intestinal symptoms, and a subjective feel-
ing of infection.
The results of our study show that there is an IgM
and IgA-related immune response raised to the LPS
of enterobacteria in MDD. Increments in serum IgM
levels can be seen in immune activation and mucosal
immunity. B1 lymphocytes are a significant source of
natural serum IgM and they constitute a first line of
defence against systemic viral and bacterial infections
[30]. Moreover, B1 cells migrate to the intestinal lamina
propria to differentiate into IgA-producing serum cells,
which in turn play a role in mucosal immunity [30].
The increased serum IgM and IgA levels against LPS
in MDD indicate that MDD is accompanied by an in-
creased gut permeability and that there is an immune
response directed against LPS of enterobacteria. Indeed,
the intestinal epithelial barrier has critical functions,
such as a) the formation of a barrier, which separates
the luminal contents from the interstitium, and which
protects against micro-organisms including gram neg-
ative bacteria, larger toxic and antigenic molecules; b)
the transportation of fluids, electrolytes and nutrients
across the intestinal wall; and c) the secretion of IgA
to bind to bacteria thus preventing their attachment to
epithelial cells.
The function of the intestinal barrier may be com-
promised by IRS activation. The latter may cause a
loss of the protective barrier function [31–33], which
in turn causes enlarged spaces between the cells of the
gut wall [31–33]. In this respect, the important inflam-
matory mediators which induce “leaky gut”, IFNγ and
IL-6, are both significantly increased in MDD [34,35].
These disruptions of the intestinal epithelium allow
normally poorly invasive enterobacteria to exploit lipid
raft-mediated transcytotic pathways or the enlarged
spaces to cross the gut wall [31–33]. Thus, IRS activa-
tion – through an increased production of IFNγ and
IL-6 – is an essential factor in the loss of the epithelial
barrier function [31,33]. The former may induce an in-
creased translocation of LPS and thus cause increased
serum concentrations of LPS which, in turn, may trig-
ger an IgM or IgA-mediated immune response to LPS
[22,23].
Systemic increases in LPS not only cause a system-
ic inflammation, but also a central neuroinflammation;
increased brain tumor necrosis factor-α (TNFα) activi-
ties, which may remain elevated for 10 months; and ac-
tivation of brain microglia with a chronically elevated
production of pro-inflammatory mediators [14]. It is
well-known that an increased production of pro-in-
flammatory cytokines, such as IL-1, IL-6 and TNFα, ei-
ther peripheral or central, and brain neuroinflammation
may induce the sickness behaviour complex [14]. Also
systemic LPS may provoke sickness behaviour [36,37].
As explained previously, symptoms of sickness behav-
iour, such as anorexia, soporific effects, disturbances of
locomotor activity and exploration, and anhedonia bear
a strong similarity with those of MDD [15].
Increased LPS translocation may play a role in the
O&NS, which occurs in MDD. Indeed, MDD is ac-
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The gut-brain barrier in major depression: Intestinal mucosal dysfunction ...
Table 1. Measurements of serum IgM levels against the LPS of Hafnia Alvei, Pseudomonas Aeruginosa, Morganella
Morganii, Pseudomonas Putida, Citrobacter Koseri and Klebsiella Pneumoniae in normal controls and MDD patients.
Variables normal controls MDD p
Hafnei Alvei IgM
IgA
–0.41 (0.98)
–0.85 (0.71)
0.33 (2.03)
0.32 (2.13)
0.1
0.01
Pseudomonas Aeruginosa IgM
IgA
– 0.28 (1.00)
–0.40 (1.14)
0.68 (1.83)
0.27 (1.83)
0.02
0.13
Morganella Morganii IgM
IgA
–0.10 (0.91)
–0.88 (0.58)
0.98 (2.51)
1.00 (2.73)
0.052
0.002
Pseudomonas Putida IgM
IgA
–0.15 (0.85)
–0.56 (0.94)
1.19 (2.40)
0.26 (1.44)
0.01
0.02
Citrobacter Koseri IgM
IgA
–0.18 (1.05)
–0.60 (0.62)
0.61 (1.81)
1.09 (3.16)
0.07
0.01
Klebsiella Pneumoniae IgM
IgA
–0.46 (0.76)
–0.93 (1.39)
0.07 (1.67)
0.99 (1.90)
0.17
0.0004
All results are shown as mean (±SD). All results of ANOVAs (df=1/49)
Table 2. Measurements of peak IgM or IgA values, total sum of the 6 IgM or 6 IgA data, the first principal component
(PC) of the 6 IgM and 6 IgA data, as well as the peak, total sum and the first PC of the 12 Ig (IgM and IgA) data.
Variables normal controls MDD F value p
Peak IgM
Sum of the 6 IgM
First PC of the 6 IgM data
–0.48 (0.83)
–1.57 (4.48)
2.39 (1.09)
2.09 (2.67)
3.87 (10.63)
3.68 (2.56)
7.7
5.2
5.1
0.007
0.02
0.03
Peak IgA
Sum of the 6 IgA
First PC of the 6 IgA data
0.13 (1.12)
–4.22 (3.81)
–0.95 (085)
2.59 (3.09)
3.90 (10.79)
0.78 (2.32)
13.2
11.8
11.5
0.0009
0.002
0.002
Peak Ig (IgM and IgA) data
Sum of the 12 Ig (IgM and IgA) data
0.13 (1.12)
–5.79 (6.41)
2.59 (3.09)
7.77 (13.89)
27.5
18.6
0.00003
0.0002
All results are shown as mean (±SD). All results of ANOVAs (df=1/49)
Table 3. Results of canonical correlation analysis with the regression of the first principal
component (PC) of the IgM and the first PC of the IgA data directed against the LPS of Hafnia Alvei,
Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and
Klebsiella Pneumoniae on the one hand and the symptoms of the FibroFatigue scale, on the other.
IgM 0.78
IgA 0.54
Aches & pain 0.24
Muscular tension 0.10
Fatigue 0.36
Concentration difficulties 0.21
Failing memory 0.28
Irritability 0.28
Sadness 0.24
Sleep disturbances –0.13
Autonomic disturbances 0.59
Irritable bowel 0.86
Headache 0.18
Subjective experience of infection 0.47
Canonical correlation coefficient r=0.67
Shown are the significant loadings (> 0.35) of the canonical regressions of the
IgM / IgA data on the different symptoms of the FibroFatigue scale.
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Michael Maes, Marta Kubera and Jean-Claude Leunis
companied by O&NS as indicated by increased levels of
malondialdehyde (MDA), a byproduct of polyunsatu-
rated fatty acid peroxidation and arachidonic acid, 8-
hydroxy-2-deoxyguanosine, indicating damage to DNA
by oxygen radicals [38–40]; increased catalase and
MDA levels [41,42], increased peroxidase and catalase
activities in blood and saliva [43]; and increased IgM
levels directed against nitro-BSA (bovine serum albu-
min), indicating increased nitrosative stress [44]. It is
well known that LPS causes induction of nuclear factor
kappa beta (NFκβ), the major upstream, intracellular
mechanism which regulates inflammatory and O&NS
mediators, such as cyclo-oxygenase (COX-2) and in-
ducible NO synthase (iNOS) [45,46].
Based on the above, we may conclude that an in-
creased translocation of LPS is another pathway which
may explain the inflammatory pathophysiology of
MDD and which underpins the link between IMD and
MDD. For example, external stressors (psychological
stress) may compromise the intestinal barrier [47,48]
as well as inducing the cytokine network causing in-
creased IFNγ and IL-6 production [16], which in turn
may further endanger the mucosal gut barrier.
Increased LPS translocation offers also an explana-
tion for the increased incidence of MDD during alco-
hol dependence. Thus, alcoholism is known to induce
an increased translocation of LPS [49] and is accom-
panied by activation of the IRS with an increased ca-
tabolism of tryptophan [50,51]. Internal (organic) stres-
sors, such as infections (AIDS/HIV) [52], autoimmune
disorders [53] and inflammatory bowel disease [54]
– which all show some degree of comorbidity with de-
pression – may endanger gut mucosal function and may
increase gut barrier permeability. Thus, the LPS path-
way may either primarily (an increased translocation of
LPS inducing inflammation) or secondarily (a primary
inflammation may induce LPS translocation through
increased IL-6 and IFNγ production) be involved in
the inflammatory pathophysiology of MDD. Conse-
quently, the intertwined systemic inflammation and the
IgM and IgA-mediated immune response following LPS
translocation may further aggravate the depressogenic
effects of IRS activation.
The symptom profiles of increased IgM and IgA lev-
els to LPS of enterobacteria in MDD are fatigue, sad-
ness, autonomic and gastro-intestinal symptoms, mus-
cular tension, and a subjective feeling of infection.
These findings corroborate our previous report that, in
CFS, there are significant positive correlations between
the IgA responses to LPS of enterobacteria and symp-
toms of the FibroFatigue scale, such as muscular ten-
sion, fatigue, concentration difficulties, failing memory,
autonomic disturbances, irritable bowel and the subjec-
tive experience of infection [22]. These correlations
probably reflect causal relationships between IRS acti-
vation and O&NS inducing the abovementioned symp-
toms occurring in CFS and MDD. As discussed above,
LPS and pro-inflammatory cytokines are depressogen-
ic and induce sickness behaviour, e.g. fatigue, anorex-
ia, weight loss, sleep disorders, psychomoror retarda-
tion, etc. Also, O&NS is implicated in the production
of musceloskeletal pain, muscle fatigue resistance, re-
duced responses to aerobic exercise and reduced maxi-
mal exercise time [55–59]. The significant correlation
between gastro-intestinal symptoms and the Ig-me-
diated immune response against LPS in MDD and in
CFS indicates that the gastro-intestinal symptoms in
some patients with MDD (and in CFS) reflect – in part
– disorders in gut-intestinal permeability and cannot be
considered as a symptom of mental stress as most psy-
chiatrists tend to confirm. The significant positive cor-
relation between the IgM and IgA-mediated immune
response against LPS and the subjective experience of
infection in MDD indicates that the latter is an index of
the inflammation from which the patients are suffering.
The canonical correlation analysis which was carried
out showed also a significant correlation between the
Ig-mediated immune response against LPS and auto-
nomic disturbances, such as gastroparesis, neuropathy,
vascular neuropathy, and dysautonomia. This may be
explained since LPS as well as IRS activation and O&NS
have multivarious and profound effects on the autono-
mous nervous system [60–66].
Increased gut permeability may be another factor
explaining the occurrence of autoimmunity in MDD.
There are many reports that MDD is accompanied
by autoimmune responses, such as against phopholi-
pids [67]. Indeed, enterobacteria may act as superan-
tigens for T lymphocytes or may induce autoimmu-
nity through a mechanism called molecular mimicry
[68,69]. This may be explained since enterobacteria
have antigenic sites which are very similar to those of
the lipid structures of neuronal tissue. These antigens
will go into various tissues and trigger inflammation
and once autoantibodies are formed the inflammation
may become more chronic. Thus, systemic LPS caused
by an increased translocation not only induces periph-
eral inflammation and O&NS, but also induces a cen-
tral neuroinflammation and eventually an autoimmune
responses directed against neuronal tissues.
The results of the present study show that patients
with MDD should be checked for the presence of leaky
gut by the measurements of IgM and IgA against the
LPS of gram-negative bacteria. The results of the present
study suggest that MDD patients who have a leaky gut
should be treated with specific antioxidants with an ef-
ficacity for leaky-gut and a leaky gut diet [23].
Acknowledgments
The research reported was supported by a NARSAD
Distinguished researcher award to M.Maes and by M-
CARE4U and CRC-MH, Antwerp, Belgium. The secre-
tarial assistance of Indra Corten is greatly appreciated.
123
Neuroendocrinology Letters Vol. 29 No. 1 2008 Article available online: http://node.nel.edu
The gut-brain barrier in major depression: Intestinal mucosal dysfunction ...
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... Another significant mechanism of immunosuppression during prolonged sympathetic activation is the disruption of tissue barrier functions, such as those of the mucosal membranes, which play a critical role in protecting the body from pathogens. Under the adrenaline and noradrenaline influence, immunoglobulin production, particularly immunoglobulin A (IgA), decreases, weakening the barrier function of mucosa and increasing the risk of pathogenic microorganisms entering the body [5,65]. ...
... Sympathetic activation is also associated with the increased expression of adhesion molecules on the endothelium, facilitating the leukocyte migration into tissues. However, under chronic stress, this process becomes impaired, and immune cells respond less effectively to inflammatory signals, subsequently weakening the innate immune response [8,65]. This mechanism further underscores the negative adrenaline and noradrenaline impact on the immune system under chronic stress, explaining the increased susceptibility to infectious and chronic diseases [66][67][68][69][70]. Noradrenaline also affects the gut microbiota, disrupting the balance between various bacterial species. ...
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We will pre-publish a set of preprints and posts that will look at different examples of American, Anglo-Saxon, and European research groups and societies that have silenced and/or plagiarized the pioneering findings of Maes et al. These include the link between depression and immune activation, abnormal lipid-immune interactions, oxidative and nitrosative stress, omega-3 PUFAs, leaky gut, and other findings in depression. These groundbreaking findings were not only silenced but also attributed to Westerns who later or never before examined these pathways in depression. Some American authors assert that I did not even exist in the 1990s. The primary message will be that those Western authors lag 20-30 years behind, specifically the period when I published the first studies on immune activation in depression (since 1990), lipid-immune interactions (1994–1997), oxidative stress (1994-2000), and leaky gut (2007). This pioneering research is frequently silenced by Western research groups, especially Americans, and our recent discoveries derived from precision nomothetic psychiatry experience a similar fate. The aforementioned nomothetic methodologies are employed to examine the intricate phenome of depression and the analysis of the immune system in subdomains, along with their connections with metabolic variables and oxidative stress. Most importantly, my groundbreaking discoveries are erroneously and inaccurately interpreted, sometimes attributed to themselves and their Western associates as incorrect hypotheses. Consequently, there exists a plethora of unfounded beliefs about “inflammation” in depression, the gut-brain axis, lipid-immune linkages, oxidative stress, and unvalidated depression clusters. This is due to the Western world’s decision between 2008 and 2024 to silence my findings to the greatest extent feasible. The current rejection rate based on inadequate Western comments in Anglo-Saxon (especially American) and European journals for my new findings is astonishing. This has significant ramifications for mental health, as treatments are being promoted based on erroneous interpretations of my pioneering research without accounting for my precision nomothetic results. The proposed repurposed drugs, such as anti-inflammatories, may likely demonstrate more adverse effects than the standard therapy, which is largely ineffective. I will therefore pre-publish letters to editors, publishers, authors, and presidents of psychiatric societies. These will show how often plagiarism by omission happens, why and how this Western silencing started, and what effects it will have on future research and new drug treatments. My pioneering findings and advancements in precision nomothetic psychiatry should be accurately cited and interpreted. Western scientists should stop publishing inaccurate deductions of my primary findings.
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In the present paper, we propose a concise immune-activation model of depression. The hypothesis is based on the following findings. 1) There is now some evidence that there is activation of the inflammatory response system (IRS) in major depression: increased numbers of leukocytes, monocytes, neutrophils, activated T-lymphocytes, and increased production of interleukin-1 (IL-1), IL-2, IL-6 and interferon- (IFN). 2) There is evidence that an acute phase response, with increased plasma concentrations of positive acute phase proteins, occurs in depression. 3) IRS activation in depression is related to and may explain neuroendocrine disorders occurring in the illness, such as activation of the hypothalamic-pituitary-adrenal- axis and reduced availability of plasma tryptophan, the precursor of serotonin. 4) Proinflammatory cytokines given to humans or animals produce depressive symptoms and depression. 5) Depression is a stress-induced disease: external (psychosocial stressors) and internal (organic stressors) stressors are emphasised. Psychological stress in humans and experimental animals results in increased production of proinflammatory cytokines, such as IL-6, IFN and TNF. Internal stressors, such as infections, stroke, autoimmune disorders and conditions, such as the postpartum period, are well established causes of depression and IRS activation. 6) Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, suppress the production of IL-6, IL-1β and IFN and increase the production of IL-10. This suggests that antidepressants have anti-inflammatory effects.
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Background: The aim of the present study was to examine the production of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), IL-10, IL-4, IL-5, IL-1 receptor antagonist (IL-1RA), and prostaglandin E2 in relation to the number of leukocytes in the blood of detoxified, chronic alcoholic patients without apparent liver disease (AWLD). Methods: Phytohemagglutinin + lipopolysaccharide-induced production of the above variables as well as the number of white blood cells and differentials were determined in detoxified AWLD patients and normal volunteers. Results: Detoxified AWLD patients have a significantly higher production of IL-6, IL-10, TNF-alpha, GM-CSF, and IL-1RA and significantly increased numbers of leukocytes and neutrophils compared to normal volunteers. Conclusions: Detoxified AWLD patients show an increased production of proinflammatory cytokines, i.e., IL-6, TNF-alpha, and GM-CSF, as well as negative immunoregulatory proteins, such as IL-10 and IL-1RA.
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