Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky
gut) is accompanied by a remission of chronic fatigue syndrome: a case report.
Michael Maes, M.D. Ph.D, Francis Coucke, M.D., Jean-Claude Ategis, Ph. D.
Neuro Endocrinol Lett. 2007 Dec; 28(6): 739-44.
PMID: 18063928 [PubMed - indexed for MEDLINE]
There is now evidence that chronic fatigue syndrome (CFS) is accompanied by an increased
translocation of endotoxins from gram-negative enterobacteria through the gut wall, as demonstrated
by increased prevalences and median values for serum IgM and IgA against the endotoxins of gram-
negative enterobacteria. This condition can also be described as increased gut permeability or leaky
gut and indicates intestinal mucosal dysfunction (IMD). Here we report a case of a 13 year old girl
with CFS who showed very high values for serum IgM against the LPS of some enterobacteria and
signs of oxidative and nitrosative stress, activation of the inflammatory response system, and IgG3
subclass deficiency. Upon treatment with specific antioxidants and a “leaky gut diet”, which both aim
to treat increased gut permeability, and immunoglobins intravenously, the increased translocation of
the LPS of gram negative enterobacteria normalized and this normalization was accompanied by a
complete remission of the CFS symptoms.
Key words: chronic fatigue syndrome, intestinal mucosal dysfunction, leaky gut, leaky gut diet,
oxidative stress, immunoglobins intravenously, antioxidants.
Recently, we have shown that gram-negative enterobacteria may play a role in the etiology of
chronic fatigue syndrome (CFS) . We detected an increased IgM and IgA response to the
lipopolysaccharide (LPS) of different enterobacteria in CFS. These results were interpreted to indicate
an increased gut-intestinal permeability in CFS which in turn allows an increased translocation of LPS
from gram-negative enterobacteria through the gut wall. The latter, in turn, causes an immune response
directed against the translocated LPS. This condition is also described as leaky gut and indicates
intestinal mucosal dysfunction . Accordingly, we suggested that CFS patients should be treated for
leaky gut by specific antioxidants such as glutamine, N-acetyl cysteine and zinc .
Here we report a case of a 13 years old girl. November 10, 2006, she entered our consultation
room sitting in a wheel chair because she was unable to walk or stand due to muscle pain and
weakness. The symptoms had begun in January 2005 after a common pharyngitis. The symptoms did
not reside and she developed progressive muscle weakness, muscle hypotonia, abdominal bloating,
headache, and concentration and sleep disorders. There was a weight loss of 10 kg in a few months
(from 57 kg to 47 kg). Since a Belgian University Department of internal medicine detected a
mycoplasma infection, she was treated with Biclar. But, at the same time the internal specialists
suspected a strong “psychogenic component” and sent her to the Department of Psychiatry.
Fortunately, the parents did not follow this advice and went to another University Department
specialized in CFS. There, they found a number of inflammatory markers, such as: increased serum
IgM and increased leukocyte elastase activity, increased PKR activity, and RNAse activity and
lowered natural killer cell activity, which was as low as 8.4%. These are well-known biomarkers for
CFS . In addition, very low serum IgG3 levels (14 mg/dL) and a lactose intolerance could be
detected, as well as increased serum IgM levels to the LPS of gram negative bacteria (Table 1, 04-06-
2005). Consequently, the correct diagnosis of CFS due to gut dysbiosis was made. She then was
treated with Ciproxine 500 mg tid, for 10 days a month, to be repeated during several months.
However, due to further symptoms of muscle weakness, “paralysis” and a further weight loss of 4 kg
she was admitted into another hospital for nutritional treatment by the second co-author of this study.
The latter, found also a stomach paresis, another biomarker for CFS. When the nutritional parameters
were more or less normalized she was send to the Department of Neurology for further examination.
The latter showed: normal EMG and MRI of the brain, and an aspecific type II muscle fiber atrophia
(muscle biopsy of the M. quadriceps femoris). Therefore, the neurologists posited that a mild axonal
type of Guilain-Barré syndrome might be present. Their main diagnosis, however, was “conversion
hysteria”. The latter was based on the symptom “la belle indifference”, established by the senior
neurologist. In their referral letter they stated that “the previous CFS specialist of course made the
diagnosis of CFS”, but in no way, they could even consider CFS as a possible diagnosis.
We could register the following symptoms: fatigue, muscle weakness, impossibility to walk or
to stand, muscle contractions, sore throat, tender lymph nodes, abdominal complaints (bloating),
malaise, nausea, vertigo, concentration difficulties and failing recent memory, sleep disorders and
unrefreshing sleep, headache, and repeated subjective experiences of infection. Thus, the patient
fulfilled the diagnosis of CFS according to the Centers for Disease Control and Prevention (CDC)
criteria . The first author of this paper, a psychiatrist, could not detect anything as “la belle
indifference”. What we saw was a young lady who was very ill and suffered from her illness and not
being able to go to school and meet with her friends.
Blood analyses revealed a number of immune disorders, i.e. with reference to the normal limits
as established for these analytes in accredited laboratories: low serum IgG3 (11 mg/dL), increased
serum immune complexes (C1Q = 25 ?g Eq/mL), increased serum IgM (392 mg/dL), complement C3
(148 mg/dL), and antibody levels against gangliosides (GT1b-IgM), and somewhat increased
microsomial TPO antibodies (68 IU/mL). There were signs of increased oxidative and nitrosative
stress (O&NS) and damage caused by O&NS to fatty acids, DNA and proteins, i.e. high oxydized
LDL-antibodies (> 1200 ?U/mL), increased excretion of 8-OH-desoxyguanosine (32.1 ?g/g creatinin),
and increased serum IgM levels directed against phosphatidyl inositol, nitro-cysteinyl, and serum
bovine albumin . A number of anti-oxidants were significantly decreased, i.e. plasma free carnitine
(14.5 ?mol/L), total carnitine (20.3 ?mol/L), acylcarnitine (5.8 ?mol/L) and coenzyme Q10 (CoQ10;
42.3 ?g/L). Finally, we found also decreased levels of the ?3-polyunsaturated fatty acids,
eicosapentanoiac acid (EPA) and docosahexaeenic acid (DHA), which constitute other biomarkers for
CFS . A repeated measurement of the IgM responses directed against the LPS of gram-negative
enterobacteria showed very high IgM responses (Table 2, 08-06-2005). These results show a very
severe translocation of the LPS of gram-negative enterobacteria and, thus, suggest a very severe IMD,
which was more pronounced than some months earlier. Our diagnosis was: chronic fatigue syndrome
(as far as this label is adequate: see further) caused by IMD, damage due to O&NS, a lowered
antioxidant status, and activation of the inflammatory response system (IRS) with an autoimmune
We started our treatment (10-11-2005) which consisted of: antioxidants, i.e. a mixture of L-
carnitine, CoQ10, lipoic acid, and taurine; and another supplement consisting of substances that are
known to treat gut permeability, consisting of L-glutamine, gamma oryzanol, zinc, etc. In addition, we
started a specific “leaky gut diet” (Maes, Van Nunen and Heynssens, unpublished data; the diet can be
requested from the corresponding author). We also started a treatment with intravenous
immunoglobulins (IVIg), i.e. sandoglobuline 6g/day during 1 month, and thereafter 6 g each two
weeks for the following months .
During the next few moths, i.e. from December 2005 to May 2006, no change in the clinical
picture could be detected. The IgM values against LPS remained very high but were already
significantly lower than before starting the treatment (Table 1, 13-01-2006 and 22-03-2006).
However, August 18, 2006 the patient walked in into our consultation room. She told us that
she regained strength, that her concentration was much better and could read books again, and that her
sleep disorders were much better. She had restarted her swimming classes. She still suffered from a
non-refreshing sleep and abdominal complaints. The IgM response against LPS again was improved
(Table 1, 18-08-2006).
The next consultation, December 8, 2006, learned that her clinical condition was again much
better: she could study and could concentrate just as before her illness. Her sleep became refreshing
and the abdominal complaints including bloating were better although sometimes she had diarrhea and
nausea. During one week she had suffered from sore throat and tender lymph nodes. The IgM
responses to LPS were considerably attenuated (Table 1, 15-11-2006), indicating less severe IMD.
Blood analyses showed that the immune complexes and serum IgM levels and other inflammatory
markers had normalized. Also, plasma L-carnitine and CoQ10 levels and the urinary excretion of 8-
OH-desoxyguanosine had normalized, although plasma oxidized LDL antibodies were still increased.
February 1, 2007 she told us that in January she had returned to school and took part in
swimming and fitness classes. She ascertained that all her symptoms had disappeared and that she felt
just as good as before her illness. We then stopped IVIg but continued the antioxidants and the leaky
gut diet, although we had to motivate the patient to continue with it.
July 13, 2007 she was very proud to tell us that she finished the school year with a very good
score (> 80%). Table 1 (26-06-2007) shows that the IgM responses were normalized. By now -
November, 2007 - all CFS symptoms are still in remission.
This patient fulfilled the diagnostic symptomatic criteria for CFS , i.e. the patient had a
severe chronic fatigue of longer than six months; and suffered from more than four symptoms, i.e.
substantial impairment in short-term memory or concentration, sore throat, tender lymph nodes,
muscle pain, headache of a new type, pattern or severity, unrefreshing sleep, and post-exertional
malaise lasting more than 24 hours. Although these diagnostic criteria are now well established, many
specialists - neurology and internal medicine in this case report - still miss and dismiss this diagnosis.
They rather conclude that patients with this medical disorder suffer - in accordance with Freud’s non-
scientific theories - from “conversion symptoms with a strong psychogenic component”, a symptom
complex which could not be detected by the first author, a skilled psychiatrist. It is common practice in
our Benelux countries that those patients then are referred to a psychiatrist to undergo the mainstream
treatment for that condition, i.e. psychodynamic therapies. This means that patients with severe
medical disorders are being treated as having a mental illness with "a nonsense treatment" that does
not treat anything. Even worse, in Belgium, some doctors who treat CFS are prosecuted by the national
health care insurances, e.g. by the Christian Mutualiteit (CM). In another Benelux country, the
Netherlands, scientists and professors who work on psychoneuroimmune disorders in CFS are called
quacks by an anti-quack organization, which is officially supported by the Ministery of Health - since
previous ministers or their deputies directly took part in this organization. Phrased differently, the
Dutch Ministery of Health supports anti-quacks to blame academicians of being quacks because they
consider CFS (and other medical illnesses such as postnatal depression) as a medical disorder. The
above are indeed organized attempts of the political world to try to eliminate the scientific view that
CFS is a medical disorder. The official acceptance of the latter obviously would mean that the national
health care systems are obliged to financially support those patients who now are considered
hypochondriacs and, therefore, may easily be suspended from the national health care systems.
One of the above diagnostic criteria implies that the patient has to have a severe chronic fatigue
of longer than six months while no other known medical condition could explain the CFS. However,
using specific biomarkers, which we described above, a specific organic disorder may be observed,
characterized by intracellular inflammation, O&NS and damage due to O&NS, and an increased
translocation of the LPS of gram-negative bacteria and sometimes auto-immunity. This means that the
diagnosis CFS according to the CDC criteria cannot be used when the known biomarkers described
above are measured. Therefore, the diagnostic criteria should be adapted to meet the new findings that
CFS has a specific organic pathophysiology.
There is now some evidence that CFS is accompanied by an activation of the IRS, including
signs of poor cellular immunity; and by increased O&NS [review: 4, 7, 8]. Also, this patient showed
signs of activation of the IRS, such as: increased serum IgM; immune complexes; complement C3;
microsomial TPO antibodies; anti ganglioside GT1b IgM antibodies; leukocyte elastase activity, PKR
activity, and RNAse activity and lowered natural killer cell activity. She also showed signs of O&NS
and a lowered antioxidant status, such as increased oxydized LDL-antibodies; 8-OH-desoxyguanosine;
and serum IgM levels directed against phosphatidyl inositol, nitro-cysteinyl, and serum bovine
albumin; and decreased plasma free L-carnitine; total carnitine; acylcarnitine and CoQ10.
As previously discussed by us, the different immune findings in CFS, e.g. activation of the IRS,
intracellular inflammation, O&NS, autoimmunity, etc. may be related to the increased translocation of
LPS of gram-negative bacteria . Thus, the trigger factors of CFS, e.g. infections - in this case report
a mycoplasma infection -, psychological stress, and physical exhaustion may have induced IRS
activation and O&NS . Inflammation may - through an increased production of interferon-gamma
(IFN?) and interleukin-6 (IL-6) - cause a loss of the epithelial barrier function [9-11]. This in turn may
cause normally poorly invasive enterobacteria to exploit lipid raft-mediated transcytotic pathways to
cross the intestinal epithelium, and these effects may precede cytokine-induced disruption of tight
junctions [9-11]. This increased translocation of the LPS of enterobacteria may then mount an immune
response against the LPS of gram-negative enterobacteria thereby aggravating preexisting
inflammation and O&NS in CFS or - when primary - induce inflammation and consequently CFS. We
have discussed previously, that different trigger factors, such as psychological stress, viral and
bacterial infections, physical exhaustion and leaky gut, may cause induction of nuclear factor kappa
beta (NF??), the major upstream, intracellular mechanism which regulates inflammatory and O&NS
mediators , such as cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS). Indeed, we
found that the production of NF??, COX-2 and iNOS is significantly higher in patients with CFS than
in normal controls [12, 13]. The translocated LPS of the gram-negative enterobacteria may induce a)
NF??, COX-2 and iNOS, and consequently, the IRS and O&NS; and b) TOLL-like receptors, which
may activate the PKR pathway . These mechanism could explain the occurrence of IRS activation
and the increased PKR activity in this patient. It is also known that systemic LPS causes chronic
central neuroinflammation. Thus, systemic LPS results in rapid brain tumor necrosis factor-? (TNF?)
increases, which remain elevated for 10 months, and activates brain microglia to produce chronically
elevated pro-inflammatory factors . It is well-known that a central neuroinflammation with
increased production of pro-inflammatory cytokines, such as TNF?, is accompanied by the sickness
behaviour complex . This mechanism could also explain the sleep disorders, cognitive disorders,
anorexia and frank weight loss in this patient. Moreover, increased gut permeability may also explain
the occurrence of autoimmunity in CFS, such as against gangliosides, as found in this case report [1,
17, 18]. Enterobacteria may act as superantigens for T lymphocytes or may induce autoimmunity
through a mechanism called molecular mimicry [19, 20]. Indeed, these enterobacteria have antigenic
sites very similar to those of neuronal tissue and its lipid structures. These antigens will go into various
tissues and trigger inflammation and once autoantibodies are formed the inflammation may become
more chronic. Similar causal mechanisms have been presented to occur in Guillain-Barré syndrome
, a diagnosis which was considered by the neurologist in this case report, although he did not
measure ganglioside antibodies. Thus, systemic LPS caused by an increased translocation not only
induces peripheral inflammation and O&NS, but may also induce a longstanding central
neuroinflammation and an autoimmune responses directed against neurons.
This patient also had an IgG3 subclass deficiency, a condition which is over-represented in
patients with CFS (Maes et al. in preparation) and is related to recurrent infections, environmental
allergies, and autoimmune responses [21, 22]. Therefore, it may be hypothesized that the IgG3
subclass deficiency had increased the risk to develop CFS since it induces an increased propensity
towards infections, IRS activation and autoimmune responses.
During the combined treatment with antioxidants, the “leaky gut diet”, and IVIg, the
translocation of LPS from gram negative bacteria decreased and normalized which was accompanied
by an attenuation of most of the IRS and O&NS variables measured by us. There is now some
evidence that specific antioxidants, e.g. glutamine , N-acetyl-cysteine , and zinc [25, 26], show
a significant efficacity in the treatment of increased gut permeability. Since our patient showed signs
of O&NS and damage due to O&NS, such as lipid peroxidation, damage to DNA and proteins, and
decreased antioxidant defences, we administered a specific antioxidant mixture based on L-carnitine,
CoQ10, lipoic acid and taurine. These substances are known to: inhibit oxygen radical formation; help
protect tissues from O&NS damage; protect mitochondria from oxidative damage; improve
mitochondrial function; increase energy levels in the mitochondria through ?-oxidation and, thus,
function as mitochondrial nutrients; modulate immune function; and have cyto- and neuroprotective
activities [27-30]. It is our expertise that - in order to restore IMD - the above antioxidants should be
combined with a “leaky gut diet” consisting of a milk allergic, gluten-free and low-carb diet. The latter
sometimes should be combined with an exclusion diet, based on the elimination of dietary allergens.
This is comparable with rheumatoid arthritis patients who sometimes show leaky gut and may develop
aggravation of the symptoms as a result of allergens in their diet . In this respect, we should also
point toward the finding of a lactose-intolerance in our patient.
Since our patient had also lowered IgG3 serum levels and signs of inflammatory and
autoimmune reactions, we also started a treatment with IVIg. Indeed, IVIg have usually been
administered for replacement therapy of humoral immunodeficiencies, including common variable
hypogammaglobulinemia and IgG subclass deficiencies . IVIg shows a significant efficacy in
preventing respiratory symptoms and in treating recurrent bronchitis and asthma in
hypogammaglobulinemic patients . Moreover, IVIg are now also widely used as
immunomodulators because of their efficacy in treating inflammatory and autoimmune disorders. The
exact mechanism of action by which IVIg are of benefit in these immune disorders is only partly
understood. There is now some evidence that IVIg may attenuate cytokine-induced NF?? production;
inflammation and the production of IFN? and IL-6; may exhibit immunomodulatory effects on T-cell
activation; modulate and promote the immune response; neutralize infectious agents; favour
phagocytosis; and inhibit LPS-stimulated cytokine production [33-37]. Secondly, IVIg contain
antiidiotypic antibodies against human autoantibodies, which may explain its efficacy in treating
autoimmune disorders . Last but not least, IVIg may decrease bacterial translocation beyond the
mesenteric lymph nodes, i.e. IVIg protects the intestinal ecological equilibrium by decreasing bacteria
overgrowth in the intestinal microflora; decreases the number of translocated bacteria; and prevents
bacterial translocation spread . Thus, IVIg may be useful to treat IMD because IVIg decrease
bacterial translocation beyond the mesenteric lymph nodes; have anti-inflammatory effects; and
attenuate the production of pro-inflammatory cytokines that may induce IMD, i.e. IFN? and IL-6;
neutralize microorganisms; favour phagocytosis; and inhibit LPS-stimulated cytokine production. The
above working mechanisms may explain why our treatment with antioxidants, the “leaky gut diet” and
IVIg is able to attenuate IRS activation, reverse O&NS and damage due to O&NS, and may decrease
LPS translocation, which all together have lead to a normalization of the IMD after some months of
In conclusion, in this case report, we show that the normalization of the increased translocation
of gram-negative enterobacteria - obtained with a specific diet, specific antioxidants and IVIg - is
accompanied by an attenuation or normalization of IRS activation and O&NS and by a clinical
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