- Vincent van Gogh
- "At Eternity's Gate"1890,
A Man with MDD Major Depressive Disorder Caused by Leaky Gut
A
52 year old male came to see me in the office. He is a successful
business man with a string of lucrative stores. He is currently under
the care of a psychiatrist who prescribes two different anti-depressant
drugs for chronic depression, an SSRI drug and Lithium Carbonate. In
spite of the medications, the patient complains of continued symptoms of
depression, chronic fatigue, vague body aches and pains and arthritis.
Upper
left image: Painting by Vincent van Gogh (1853–1890) entitled "At
Eternity's Gate" May 1890, oil on canvas in the Kröller-Müller
Museum. Courtesy of wikimedia commons.
Abdominal Symptoms Evaluated with Enterolabs Panel
The
patient also complains of abdominal gas and bloating, especially after
meals. Laboratory studies showed a low testosterone level of 267 (Total
Testosterone). His
Enterolabs stool antigliadin IgA antibody
was markedly elevated (90 with normal less than 10). His Enterolabs
panel also showed multiple food sensitivities. This was strongly
suggestive of "Leaky Gut " originating from wheat gluten sensitivity,
along with other food intolerances. He was immediately started on
Testosterone supplementation and a Gluten free diet, and noted
improvement in symptoms. The patient was able to taper off one of the
antidepressant meds (the Lithium) and reduced the SSRI drug dosage. A
calcium score test was done showing a high calcium score of 490 (95th
percentile) indicating high risk for underlying coronary artery disease,
and the patient's cardiologist started him on a statin anti-cholesterol
drug (Crestor).
Leaky Gut Causes Inflammation in the Brain and Heart
My
previous article
discussed how Gluten Sensitivity causes opening of the Tight Junctions
in the GI mucosa, leading to leaky gut, and through "molecular mimicry"
various autoimmune diseases. This same "Leaky Gut" mechanism may cause
MDD (Major Depressive Disorder). This has been elucidated by Michael
Maes MD PhD in many studies published over the last decade, showing that
inflammation is the real etiology of depression. (1-6)(9-16)
The
leaky gut, according to Dr Michael Maes causes inflammation in the brain
causing depression, and may also cause inflammation in other organ
systems such as the coronary arteries leading to elevated calcium score
from underlying coronary artery disease.
- SSRI Pills Don't Help Leaky Gut
Leaky Gut, LPS and Immune Activation Cause Depression and Chronic Fatigue
The
"leakage" of LPS (Lipo Poly Saccharide bacterial antigens) into the
blood stream evokes activation of the innate immune system, and
inflammation in the body and the brain and has been directly implicated
as a cause of MDD (major depressive disorder). Dr Maes reports in an
elegant study
elevated IgM and IgG antibodies to LPS in both Depression and Chronic
Fatigue. As patients are treated and the Leaky Gut Heals, symptoms
improve over time, and the antibody titers decline(link to
article).(1-6)(9-16)
Upper left image: SSRI antidepressant pills don't help with "Leaky Gut Syndrome".
Courtesy of wikimedia commons.
ALCAT testing
to reduce activation of the innate immune system
A useful medical tool for chronic fatigue and chronic depression is the
ALCAT test
which measures white blood cell activation by food or environmental
chemicals. Leaky gut allows not only bacterial LPS to leak, it also
allows food particles to leak into the blood stream which may then
activate the immune system. The ALCAT test is an elegant method to
identify which foods or chemicals are causing the problem. Once this
information is known, and the diet modified to eliminate the offending
foods, immune acitivation and inflammatory response in the body is
reduced to low levels with resolution of the fatigue and depression.
Healing the Leaky Gut
Since
the depression and chronic fatigue is directly caused by the "Leaky
Gut". healing the leaky gut is the most direct way to make the patient
better. There are a number of protocols for healing the leaky gut.
Removing wheat gluten from the diet is the first step.
Secondly, identifying foods and environmental chemicals that are activating the white blood cells (the innate imune system, the
ALCAT test) is extremely beneficial.
Thirdly, supplements to heal the gut such as
Glutamine,
GI Fortify and
GI Integrity are very useful.
Fourthly, a program from BioBotanical Reseach using anti-microbial botanicals called
Biocidin and
Olivirex,
Proflora (probiotic) are very useful.
Why Antidepressants Don't Work
Drugs
handed out by the mainstream medical system are unhelpful when the
underlying etiology is a "Leaky Gut". Taking an SSRI antidepressant
drug does nothing to ameliorate the Leaky Gut, immune activation, and
inflammation in the patient with Major Depressive Disorder or Chronic
Fatigue. Same can be said for other psychoactive drugs such as
benzodiazepines, sleeping pills, amphetamines and narcotics which are
handed out rather freely to many of these patients, causing more harm
than good.
If Major Depressive Disorder is caused by inflammation
related to "Leaky Gut Syndrome", as proposed by Dr Michael Maes and
others, then SSRI drugs and other Psycho-Active drugs should not be
expected to resolve the issue, and probably cause more harm than good.
Articles with Related Interest:
http://jeffreydach.com/2012/11/30/leaky-gut-autoimmune-gluten-wheat.aspx
Wheat Gluten, Leaky Gut, and Autoimmune Disease by Jeffrey Dach MD
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, FL 33314
954-792-4663
Links and References
2007 Chronic Fatigue Syndrome
1)
www.ncbi.nlm.nih.gov/pubmed/17007934 http://www.cfids-cab.org/rc/Maes.pdf J Affect Disord. 2007 Apr;99(1-3):237-40. Epub 2006 Sep 27.
Increased serum IgA and IgM against LPS of enterobacteria in chronic
fatigue syndrome (CFS): indication for the involvement of gram-negative
enterobacteria in the etiology of CFS and for the presence of an
increased gut-intestinal permeability.
Maes M, Mihaylova I, Leunis JC. Source MCare4U Outpatient Clinics, Antwerp, Belgium.
Abstract
There is now evidence that chronic fatigue syndrome (CFS) is
accompanied by immune disorders and by increased oxidative stress. The
present study has been designed in order to examine the serum
concentrations of IgA and IgM to LPS of gram-negative enterobacteria,
i.e. Hafnia alvei; Pseudomonas aeruginosa, Morganella morganii, Proteus
mirabilis, Pseudomonas putida, Citrobacter koseri, and Klebsiella
pneumoniae in CFS patients, patients with partial CFS and normal
controls. We found that the prevalences and median values for serum IgA
against the LPS of enterobacteria are significantly greater in patients
with CFS than in normal volunteers and patients with partial CFS. Serum
IgA levels were significantly correlated to the severity of illness, as
measured by the FibroFatigue scale and to symptoms, such as irritable
bowel, muscular tension, fatigue, concentration difficulties, and
failing memory. The results show that enterobacteria are involved in the
etiology of CFS and that an increased gut-intestinal permeability has
caused an immune response to the LPS of gram-negative enterobacteria. It
is suggested that all patients with CFS should be checked by means of
the IgA panel used in the present study and accordingly should be
treated for increased gut permeability.
full pdf 2008
2)
intestinalbarriertest.com/pdf/MaesGutBrainDepression.pdf 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.
The
findings of the present study show that MDD is accompanied 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 feeling of infection.
3)
integrativehealthconnection.com/wp-content/uploads/2011/11/Leaky-gut-in-CFS-treatment-of-leaky-gut.pdf 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
----------------
2008
4)
www.ncbi.nlm.nih.gov/pubmed/18283240 Neuro Endocrinol Lett. 2008 Feb;29(1):117-24.
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.
Maes M, Kubera M, Leunis JC. Source M-Care4U Outpatient Clinics, Antwerp, Belgium.
Abstract
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.
2012 chronic depression
5)
www.ncbi.nlm.nih.gov/pubmed/22410503 J Affect Disord. 2012 Dec 1;141(1):55-62.
Increased IgA and IgM responses against gut commensals in chronic
depression: further evidence for increased bacterial translocation or
leaky gut.
Maes M, Kubera M, Leunis JC, Berk M. Source Maes Clinics @ Tria, Bangkok, Thailand.
Recently,
we discovered that depression is accompanied by increased IgM and IgA
responses directed against gram negative gut commensals. The aim of this
study was to replicate these findings in a larger study group of
depressed patients and to examine the associations between the IgA and
IgM responses to gut commensals and staging of depression as well as the
fatigue and somatic (F&S) symptoms of depression.
METHODS: We
measured serum concentrations of IgM and IgA against the LPS of
gram-negative enterobacteria, i.e. Hafnia alvei, Pseudomonas aeruginosa,
Morganella morganii, Pseudomonas putida, Citrobacter koseri, and
Klebsiella pneumoniae in 112 depressed patients and 28 normal controls.
The severity of F&S symptoms was measured using the Fibromyalgia and
Chronic Fatigue Syndrome Rating Scale.
RESULTS: The prevalences
and median values of serum IgM and IgA against LPS of these commensals
were significantly higher in depressed patients than in controls. The
IgM levels directed against the LPS of these commensal bacteria were
significantly higher in patients with chronic depression than in those
without. The immune responses directed against LPS were not associated
with melancholia or recurrent depression. There was a significant
correlation between the IgA response directed against LPS and
gastro-intestinal symptoms.
DISCUSSION: The results indicate that
increased bacterial translocation with immune responses to the LPS of
commensal bacteria may play a role in the pathophysiology of depression,
particularly chronic depression.
Bacterial translocation may a)
occur secondary to systemic inflammation in depression and intensify and
perpetuate the primary inflammatory response once the commensals are
translocated; or b) be a primary trigger factor associated with the
onset of depression in some vulnerable individuals. The findings suggest
that "translocated" gut commensal bacteria activate immune cells to
elicit IgA and IgM responses and that this phenomenon may play a role in
the pathophysiology of (chronic) depression by causing progressive
amplifications of immune pathways.
2012 Chronic Fatigue Syndrome
6)
www.ncbi.nlm.nih.gov/pubmed/21967891 J Affect Disord. 2012 Feb;136(3):909-17. Epub 2011 Oct 2.
Increased IgA responses to the LPS of commensal bacteria is associated
with inflammation and activation of cell-mediated immunity in chronic
fatigue syndrome.
Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M. Source Maes Clinics @ TRIA, Bangkok, Thailand.
Abstract
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
is accompanied by a) systemic IgA/IgM responses against the
lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g.
increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)a; and
c) activation of cell-mediated immunity (CMI), as demonstrated by
increased neopterin.
METHODS: To study the relationships between
the IgA/IgM responses to the LPS of microbiota, inflammation, CMI and
the symptoms of ME/CFS we measured the IgA/IgM responses to the LPS of 6
different enterobacteria, serum IL-1, TNFa, neopterin, and elastase in
128 patients with ME/CFS and chronic fatigue (CF). Severity of symptoms
was assessed by the Fibromyalgia and Chronic Fatigue Syndrome (FF)
Rating Scale.
RESULTS: Serum IL-1, TNFa, neopterin and elastase
are significantly higher in patients with ME/CFS than in CF patients.
There are significant and positive associations between the IgA
responses to LPS and serum IL-1, TNFa, neopterin and elastase. Patients
with an abnormally high IgA response show increased serum IL-1, TNFa and
neopterin levels, and higher ratings on irritable bowel syndrome (IBS)
than subjects with a normal IgA response. Serum IL-1, TNFa and neopterin
are significantly related to fatigue, a flu-like malaise, autonomic
symptoms, neurocognitive disorders, sadness and irritability.
CONCLUSIONS: The findings show that increased IgA responses to commensal
bacteria in ME/CFS are associated with inflammation and CMI activation,
which are associated with symptom severity. It is concluded that
increased translocation of commensal bacteria may be responsible for the
disease activity in some ME/CFS patients.
2012 Emory Atlanta Dr Haroon
inflammation and depression
7)
www.ncbi.nlm.nih.gov/pubmed/21918508 www.jain-resources.info/uploads/3/3/5/8/3358541/haroon_-_deplin_ds.pdf Neuropsychopharmacology. 2012 Jan;37(1):137-62.
Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.
Haroon E, Raison CL, Miller AH. Source Department of Psychiatry and
Behavioral Sciences, Emory University School of Medicine, Atlanta, GA
30322, USA.
Abstract The potential contribution of chronic
inflammation to the development of neuropsychiatric disorders such as
major depression has received increasing attention. Elevated biomarkers
of inflammation, including inflammatory cytokines and acute-phase
proteins, have been found in depressed patients, and administration of
inflammatory stimuli has been associated with the development of
depressive symptoms. Data also have demonstrated that inflammatory
cytokines can interact with multiple pathways known to be involved in
the development of depression, including monoamine metabolism,
neuroendocrine function, synaptic plasticity, and neurocircuits relevant
to mood regulation. Further understanding of mechanisms by which
cytokines alter behavior have revealed a host of pharmacologic targets
that may be unique to the impact of inflammation on behavior and may be
especially relevant to the treatment and prevention of depression in
patients with evidence of increased inflammation. Such targets include
the inflammatory signaling pathways cyclooxygenase, p38
mitogen-activated protein kinase, and nuclear factor-κB, as well as the
metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down
tryptophan into kynurenine. Other targets include the cytokines
themselves in addition to chemokines, which attract inflammatory cells
from the periphery to the brain. Psychosocial stress, diet, obesity, a
leaky gut, and an imbalance between regulatory and pro-inflammatory T
cells also contribute to inflammation and may serve as a focus for
preventative strategies relevant to both the development of depression
and its recurrence. Taken together, identification of mechanisms by
which cytokines influence behavior may reveal a panoply of personalized
treatment options that target the unique contributions of the immune
system to depression.
8)
www.ncbi.nlm.nih.gov/pmc/articles/PMC3038963/ www.biomedcentral.com/content/pdf/1757-4749-3-1.pdf Gut Pathog. 2011; 3: 1.
Acne vulgaris, probiotics and the gut-brain-skin axis - back to the future?
Whitney P Bowe Alan C Logan
Department of Dermatology, State University of New York Downstate
Medical Center, Brooklyn, New York, 11203, USA 2Integrative Care Centre
of Toronto, 3600 Ellesmere Road, Unit 4, Toronto, ON M1C 4Y8, Canada
1999 Michael Maes
9)
link.springer.com/chapter/10.1007%2F978-0-585-37970-8_2?LI=true Cytokines, Stress, and Depression Advances in Experimental Medicine and Biology Volume 461, 1999, pp 25-46
Major
Depression and Activation of The Inflammatory Response System Michael
Maes M.D., Ph.D. Contemporary models of major depression emphasize the
role of hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity and of
dysfunctions in the turnover of serotonin (5-HT) or catecholamines in
the etiopathogenesis of major depression. Contemporary models of major
depression do not incorporate the effects of the inflammatory response
system (IRS), even though the IRS powerfully influences HPA-axis
activity, 5-HT and catecholaminergic turnover and even though activation
of the IRS may induce depression-like behavior in animals and humans.
There is now evidence that major depression is accompanied by a moderate
activation of the IRS (reviews: Maes, 1993; 1995; 1997; Maes, Smith,
& Scharpe, 1995c; Holden, Pakula, & Mooney, 1997; Maes &
Smith, 1997; Connor & Leonard, 1998; Maier & Watkins, 1998). In
this paper we propose a concise IRS model of major depression.
---------------------------
10)
pluto.huji.ac.il/~msrazy/PDF/MaesMetabBrainDis09.pdf
Metab Brain Dis. 2009 Mar;24(1):27-53. doi: 10.1007/s11011-008-9118-1.
Epub 2008 Dec 16. The inflammatory & neurodegenerative (I&ND)
hypothesis of depression: leads for future research and new drug
developments in depression.
Maes M, Yirmyia R, Noraberg J, Brene
S, Hibbeln J, Perini G, Kubera M, Bob P, Lerer B, Maj M. Source Clinical
Research Center for Mental Health, Olmenlaan 9, Antwerp Wilrijk 2610,
Belgium. neutrim@telenet.be
Abstract Despite extensive research,
the current theories on serotonergic dysfunctions and cortisol
hypersecretion do not provide sufficient explanations for the nature of
depression. Rational treatments aimed at causal factors of depression
are not available yet.
2011
11)
www.ncbi.nlm.nih.gov/pubmed/20599581 Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):664-75. doi: 10.1016/j.pnpbp.2010.06.014. Epub 2010 Jun 20.
Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Maes M.
The
first findings that depression is characterized by cell-mediated immune
activation and inflammation were published between 1990-1993 (Maes et
al.). Recently, it was reported that--based on meta-analysis
results--depression is an inflammatory disorder because the plasma
levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor
necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2
and interferon-(IFN)γ levels are not altered in depression, suggesting
that there is no T cell activation in that illness. The present paper
reviews the body of evidence that depression is accompanied by
cell-mediated immune activation. The findings include: increased serum
levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule;
increased numbers and percentages of T cells bearing T cell activation
markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated
production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels;
induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of
plasma tryptophan and increased levels of tryptophan catabolites along
the IDO pathway (TRYCATs); and glucocorticoid resistance in immune
cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and
IFNα-induced activation of T cells, IDO activity and TRYCAT formation
are related to the development of IFNα-induced depressive symptoms.
Animal models of depression show that a cell-mediated immune response is
related to the development of depression-like behavior. Antidepressants
and mood stabilizers suppress different aspects of cell-mediated
immunity and rather specifically target IFNγ production. This review
shows that inflammation and cell-mediated immune activation are key
factors in depression.
12)
www.ncbi.nlm.nih.gov/pubmed/21930301 J Affect Disord. 2011 Dec;135(1-3):414-8.
IgM-mediated autoimmune responses directed against multiple neoepitopes
in depression: new pathways that underpin the inflammatory and
neuroprogressive pathophysiology. Maes M, Mihaylova I, Kubera M, Leunis
JC, Geffard M. Source Maes Clinics @ TRIA, Bangkok, Thailand.
dr.michaelmaes@hotmail.com
Abstract BACKGROUND: There is evidence
that depression is accompanied by oxidative and nitrosative stress
(O&NS), as indicated by increased free radical levels, lipid
peroxidation, and lowered antioxidant levels. The aims of the present
study are to examine whether depression is accompanied by autoimmune
responses directed against a) neoepitopes that are formed following
O&NS damage; and b) the major anchorage molecules, i.e. palmitic and
myristic acids and S- farnesyl-L-cysteine.
METHODS: We examined
serum IgM antibodies to the conjugated fatty acids, palmitic and
myristic acids; acetylcholine; S-farnesyl-L-cysteine; and NO-modified
adducts in 26 depressed patients and 17 normal controls. Severity of
depression was measured with the Hamilton Depression Rating Scale and
severity of fatigue and somatic (F&S) symptoms with the Fibromyalgia
and Chronic Fatigue Syndrome (FF) Rating Scale.
RESULTS: The
prevalences and mean values for the serum IgM levels directed against
conjugated palmitic and myristic acids, acetylcholine,
S-farnesyl-L-cysteine; and the conjugated NO adducts, NO-tyrosine,
NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were
significantly higher in depressed patients than in normal controls. The
autoimmune responses were significantly related to FF symptoms, such as
fatigue and a flu-like malaise, whereas the indicants of nitrosative
stress were related to gastro-intestinal and autonomic symptoms.
DISCUSSION: Depression is characterized by IgM-related autoimmune
responses directed against a) neoepitopes that are normally not detected
by the immune system but that due to damage by O&NS have become
immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic
acids, and S-farnesyl-L-cysteine. These autoimmune responses play a role
in the inflammatory and O&NS pathophysiology of depression and may
mediate the cellular dysfunctions that contribute to neuroprogression,
e.g. aberrations in signal transduction, cellular differentiation and
apoptosis.
13)
www.ncbi.nlm.nih.gov/pubmed/21945535 Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 10;36(1):169-75. doi: 10.1016/j.pnpbp.2011.09.006. Epub 2011 Sep 16.
Activation
of cell-mediated immunity in depression: association with inflammation,
melancholia, clinical staging and the fatigue and somatic symptom
cluster of depression. Maes M, Mihaylova I, Kubera M, Ringel K. Source
Maes Clinics @ TRIA, Bangkok, Thailand. dr.michaelmaes@hotmail.com
Abstract
BACKGROUND: Depression is characterized by activation of cell-mediated
immunity (CMI), including increased neopterin levels, and increased
pro-inflammatory cytokines (PICs), such as interleukin-1 (IL-1) and
tumor necrosis factor-α (TNFα). These PICs may induce depressive,
melancholic and chronic fatigue (CF) symptoms.
METHODS: We
examined serum neopterin and plasma PIC levels in depressive subgroups
in relation to the depressive subtypes and the melancholic and CF
symptoms of depression. Participants were 85 patients with depression
and in 26 normal controls. Severity of depression was assessed with the
Hamilton Depression Rating Scale (HDRS) and severity of CF with the
Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.
RESULTS:
Serum neopterin was significantly higher in depressed patients and in
particular in those with melancholia. There were positive correlations
between serum neopterin, the plasma PICs and the number of previous
depressive episodes. Neopterin and TNFα were associated with
melancholia, while both PICs were associated with CF. Melancholia-group
membership was predicted by the HDRS and neopterin, and CF group
membership by age, the FF score and serum TNFα.
DISCUSSION:
Depression and melancholia are accompanied by CMI activation, suggesting
that neopterin plays a role in their pathophysiology, e.g. through
activation of oxidative and nitrosative stress and apoptosis pathways.
The intertwined CMI and inflammatory responses are potentially
associated with the onset of depression and with the melancholic and CF
symptoms of depression. Exposure to previous depressive episodes may
magnify the size of CMI and PIC responses, possibly increasing the
likelihood of new depressive episodes. CMI activation and inflammation
may contribute to the staging or recurrence of depression.
14)
www.ncbi.nlm.nih.gov/pubmed/20471444 Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):676-92. doi: 10.1016/j.pnpbp.2010.05.004. Epub 2010 May 12.
A review on the oxidative and nitrosative stress (O&NS) pathways in
major depression and their possible contribution to the
(neuro)degenerative processes in that illness.
Maes M, Galecki P, Chang YS, Berk M. Source Maes@TRIA Clinics, Bangkok, Thailand. dr.michaelmaes@hotmail.com
Abstract
This paper reviews the body of evidence that major depression is
accompanied by a decreased antioxidant status and by induction of
oxidative and nitrosative (IO&NS) pathways. Major depression is
characterized by significantly lower plasma concentrations of a number
of key antioxidants, such as vitamin E, zinc and coenzyme Q10, and a
lowered total antioxidant status. Lowered antioxidant enzyme activity,
e.g. glutathione peroxidase (GPX), is another hallmark of depression.
The abovementioned lowered antioxidant capacity may impair protection
against reactive oxygen species (ROS), causing damage to fatty acids,
proteins and DNA by oxidative and nitrosative stress (O&NS).
Increased ROS in depression is demonstrated by increased levels of
plasma peroxides and xanthine oxidase. Damage caused by O&NS is
shown by increased levels of malondialdehyde (MDA), a by-product of
polyunsaturated fatty acid peroxidation and arachidonic acid; and
increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage.
There is also evidence in major depression, that O&NS may have
changed inactive autoepitopes to neoantigens, which have acquired
immunogenicity and serve as triggers to bypass immunological tolerance,
causing (auto) immune responses. Thus, depression is accompanied by
increased levels of plasma IgG antibodies against oxidized LDL; and
increased IgM-mediated immune responses against membrane fatty acids,
like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and
NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and
NO-arginine; and NO-albumin. There is a significant association between
depression and polymorphisms in O&NS genes, like manganese
superoxide dismutase, catalase, and myeloperoxidase. Animal models of
depression very consistently show lowered antioxidant defences and
activated O&NS pathways in the peripheral blood and the brain. In
animal models of depression, antidepressants consistently increase
lowered antioxidant levels and normalize the damage caused by O&NS
processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic
GPX activity, and zinc exhibit antidepressive effects. This paper
reviews the pathways by which lowered antioxidants and O&NS may
contribute to depression, and the (neuro)degenerative processes that
accompany that illness. It is concluded that aberrations in O&NS
pathways are--together with the inflammatory processes--key components
of depression. All in all, the results suggest that depression belongs
to the spectrum of (neuro)degenerative disorders.
15)
www.ncbi.nlm.nih.gov/pubmed/20035260 Neuro Endocrinol Lett. 2009;30(6):715-22.
Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to
DNA, in major depression and myalgic encephalomyelitis / chronic fatigue
syndrome.
Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N,
Bosmans E. Source Maes Clinics, Wilrijk - Antwerp, Belgium.
crc.mh@telenet.be
Abstract BACKGROUND: There is now evidence that
major depression and myalgic encephalomyelitis / chronic fatigue
syndrome (ME/CFS) are accompanied by partially overlapping
pathophysiological mechanisms, i.e. activation of various inflammatory
and oxidative & nitrosative (IO&NS) pathways. OBJECTIVE: The aim
of the present study was to examine the urinary excretion of
8-hydroxy-deoxyguanosine (
hdG),
a marker of oxidative damage to DNA, in depression; ME/CFS; and
depression and ME/CFS. METHODS: Toward this end, morning urine was
sampled for the assays of
HdG
and creatinine, in 44 patients with ME/CFS; 25 with major depression;
23 with depression and ME/CFS; and 17 normal controls. Severity of
fatigue and somatic symptoms was measured by means of the Fibromyalgia
and CFS Rating (FF) scale. RESULTS: We found that 49.0% of the variance
in the urinary excretion of
HdG was predicted by the regression on creatinine. Consequently, the urinary
HdG excretion should be expressed as the residualized
HdG values after partialling out the effects of creatinine and not by computing the
HdG / creatinine ratio. We found that the residualized urinary excretion of
HdG
(adjusted for creatinine) was significantly higher in patients with
depression and ME/CFS than in normal controls and all other patients. In
the patient group, there were significant correlations between the
urinary
HdG
and the total score on the FF scale and sadness and flu-like malaise.
CONCLUSIONS: The findings show increased oxidatively generated DNA
damage in patients with major depression and ME/CFS and, therefore,
further extent the role played by IO&NS pathways in the
pathophysiology of both disorders. Since oxidatively damage to DNA is a
risk factor for atherosclerosis and neurodegeneration, our results also
explain previous findings on increased cardiovascular morbidity in
depression and ME/CFS, and neurodegenerative processes in depression.
----------------------
16)
www.triaintegrativewellness.com/leaky-gut-a-potentially-dangerous-but-treatable-condition/
article
by Michael Maes, M.D., Ph.D. Leaky gut: a potentially dangerous but
treatable condition When you suffer from an impaired transit, diarrhea
or constipation, bloating, and intestinal cramps, it may be that you
suffer from leaky gut.
---------
17)
dralexrinehart.com/nutrition-benefits/does-leaky-gut-exist/
Does Leaky Gut Exist? Written on April 4, 2012 by Dr. Alexander
Rinehart, MS, DC, CCN in Nutrition Benefits When a gastroenterologist or
other health professional claims that “leaky gut does not exist”, I
cringe. I believe that they are really stating that, in their opinion,
leaky gut has no scientific basis. I personally feel that such bold
claims are a discriminatory technique used against alternative providers
such as Naturopathic doctors, Chiropractors and Nutritionists who are
increasingly seeing clients for problems once restricted to medical
care.
18)
syontix.com/why-do-i-feel-so-blue-the-role-of-endotoxemia-and-leaky-gut-in-the-cause-of-major-depression/
Why Do I Feel So Blue? The Role of Endotoxemia and Leaky Gut in the
Cause of Major Depression Published October 14, 2012 | By Ray Medina
19)
leakygutsyndrometreatment.net/healing-leaky-gut-syndrome/ Healing Leaky Gut Syndrome
Multiple SClerosis and Leaky Gut
20)
www.msrc.co.uk/index.cfm/fuseaction/show/pageid/737 Leaky Gut and MS Leaky Gut
There are many parties that are convinced that increased intestinal
permeability or a leaky gut may be connected to a good many people with
Multiple Sclerosis. The MS Diet Research Group connected to the Best Bet
Diet Group are making progress getting academics and doctors interested
in researching this field as to date only very limited research has
been carried out. Having said that the results of this research have
indicated a plausible connection. If is also people with MS themselves
who are proving that measures taken to heal the gut can often result in
improvement in their MS symptoms.
21)
sanjosefuncmed.com/intestinal-permeability-leaky-gut/
What is Intestinal Permeability or “Leaky Gut”? What is intestinal
permeability or “leaky gut”? Why haven’t I heard of this? Intestinal
permeability causes systemic inflammation. Intestinal permeability as a
precondition for the development of autoimmune disease.
22)
www.ncbi.nlm.nih.gov/pubmed/21278760 www.iem.cas.cz/miranda2/export/sitesavcr/data.avcr.cz/lifesci/uem/research/publications/pharmacology/files/tlaskalova-hogenova-2011.pdf Cell Mol Immunol. 2011 Mar;8(2):110-20. doi: 10.1038/cmi.2010.67. Epub 2011 Jan 31.
The
role of gut microbiota (commensal bacteria) and the mucosal barrier in
the pathogenesis of inflammatory and autoimmune diseases and cancer:
contribution of germ-free and gnotobiotic animal models of human
diseases.
Tlaskalová-Hogenová H, Stěpánková R, Kozáková H,
Hudcovic T, Vannucci L, Tučková L, Rossmann P, Hrnčíř T, Kverka M,
Zákostelská Z, Klimešová K, Přibylová J, Bártová J, Sanchez D, Fundová
P, Borovská D, Srůtková D, Zídek Z, Schwarzer M, Drastich P, Funda DP.
Source Institute of Microbiology, Academy of Sciences of the Czech
Republic, v.v.i., Prague, Czech Republic. tlaskalo@biomed.cas.cz
Abstract
Metagenomic approaches are currently being used to
decipher the genome of the microbiota (microbiome), and, in parallel,
functional studies are being performed to analyze the effects of the
microbiota on the host. Gnotobiological methods are an indispensable
tool for studying the consequences of bacterial colonization. Animals
used as models of human diseases can be maintained in sterile conditions
(isolators used for germ-free rearing) and specifically colonized with
defined microbes (including non-cultivable commensal bacteria). The
effects of the germ-free state or the effects of colonization on disease
initiation and maintenance can be observed in these models. Using this
approach we demonstrated direct involvement of components of the
microbiota in chronic intestinal inflammation and development of colonic
neoplasia (i.e., using models of human inflammatory bowel disease and
colorectal carcinoma). In contrast, a protective effect of microbiota
colonization was demonstrated for the development of autoimmune diabetes
in non-obese diabetic (NOD) mice. Interestingly, the development of
atherosclerosis in germ-free apolipoprotein E (ApoE)-deficient mice fed
by a standard low-cholesterol diet is accelerated compared with
conventionally reared animals. Mucosal induction of tolerance to
allergen Bet v1 was not influenced by the presence or absence of
microbiota. Identification of components of the microbiota and
elucidation of the molecular mechanisms of their action in inducing
pathological changes or exerting beneficial, disease-protective
activities could aid in our ability to influence the composition of the
microbiota and to find bacterial strains and components (e.g.,
probiotics and prebiotics) whose administration may aid in disease
prevention and treatment.
-----------------
PArkinson's Diease and Leaky Gut
23)
www.ncbi.nlm.nih.gov/pmc/articles/PMC3228722/ www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0028032
PLoS
One. 2011; 6(12): e28032. Published online 2011 December 1. doi:
10.1371/journal.pone.0028032 PMCID: PMC3228722 Increased Intestinal
Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and
Endotoxin Exposure Markers in Early Parkinson's Disease Christopher B.
Forsyth,1,* Kathleen M. Shannon,2 Jeffrey H. Kordower,3 Robin M. Voigt,1
Maliha Shaikh,1 Jean A. Jaglin,2 Jacob D. Estes,4 Hemraj B. Dodiya,3
and Ali Keshavarzian1 1Department of Internal Medicine, Section of
Gastroenterology, Rush University Medical Center, Chicago, Illinois,
United States of America 2Department of Neurological Sciences, Rush
University Medical Center, Chicago, Illinois, United States of America
3Center for Brain Repair, Rush Medical College, Chicago, Illinois,
United States of America 4AIDS and Cancer Virus Program, SAIC-Frederick,
Inc., National Cancer Institute-Frederick, Frederick, Maryland, United
States of America University Hospital La Paz, Spain
Parkinson's
disease (PD) is the second most common neurodegenerative disorder of
aging. The pathological hallmark of PD is neuronal inclusions termed
Lewy bodies whose main component is alpha-synuclein protein. The finding
of these Lewy bodies in the intestinal enteric nerves led to the
hypothesis that the intestine might be an early site of PD disease in
response to an environmental toxin or pathogen. One potential mechanism
for environmental toxin(s) and proinflammatory luminal products to gain
access to mucosal neuronal tissue and promote oxidative stress is
compromised intestinal barrier integrity. However, the role of
intestinal permeability in PD has never been tested. We hypothesized
that PD subjects might exhibit increased intestinal permeability to
proinflammatory bacterial products in the intestine. To test our
hypothesis we evaluated intestinal permeability in subjects newly
diagnosed with PD and compared their values to healthy subjects. In
addition, we obtained intestinal biopsies from both groups and used
immunohistochemistry to assess bacterial translocation, nitrotyrosine
(oxidative stress), and alpha-synuclein. We also evaluated serum markers
of endotoxin exposure including LPS binding protein (LBP). Our data
show that our PD subjects exhibit significantly greater intestinal
permeability (gut leakiness) than controls.
In addition, this
intestinal hyperpermeability significantly correlated with increased
intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and
alpha-synuclein as well as serum LBP levels in PD subjects.
These
data represent not only the first demonstration of abnormal intestinal
permeability in PD subjects but also the first correlation of increased
intestinal permeability in PD with intestinal alpha–synuclein (the
hallmark of PD), as well as staining for gram negative bacteria and
tissue oxidative stress. Our study may thus shed new light on PD
pathogenesis as well as provide a new method for earlier diagnosis of PD
and suggests potential therapeutic targets in PD subjects.
----------------------
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