Fat Brain – Fat Planet: How Antibiot... 
Dr.Jeff
11 y
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RRR Educational
With obesity of the planet escalating and close to 40% of the population being obese, scientists may have finally found the reason for the global obesity epidemic in the widespread use of antibiotics.
Fat Brain – Fat Planet: How Antibiotics Are Driving Global Obesity - http://candidaplan.com/blog/1320/fat-brain-fat-planet-how-antibiotics-are-dri...- Fat Brain – Fat Planet: How Antibi... Dr.Jeff
11 y
1,149
This is a reply to # 2,179,642
-- A five- to seven-day course of antibiotics can destroy the entire bacterial flora within days and cause a massive release of bacterial toxins that then induces a permanent state of chronic brain inflammation.
"An appreciable decrease in faecal organisms, especially anaerobes, was apparent after 48 h of commencing the course, and most bacteria had disappeared from the stool after five days."
ProphylacticNon-Absorbable Antibiotics in Leukaemic patients. J Hyg (Lond) 1980 August; 85(1): 141–151. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC2134008/?tool= pmcentrez In this study a polyphasic approach was used to monitor the long-term ecological effects of 7 days clindamycin administration on the human intestinal microbiota. Antibiotic treatment had a dramatic impact on the Bacteroides community resulting in large and persistent changes.One specific clone type, B. thetaiotaomicron 1tIV, became dominant for 18 months and it was the only clone type identified for the first nine months post exposure to clindamycin (Figure 2a). Long Term Ecological Impacts of antibiotics administration on the human intestinal ecosystem. The ISME Journal (2007) 1, 56–66; doi:10.1038/ismej.2007.3
There are 100 trillion bacteria present in the human body, which is the equivalent of 1 Billion Endotoxin Units (EU). As little as 5 EU/kg body weight have been shown to initiate symptoms in humans. A 200 lb male would require 5 EU/90kg or 450 EUs. (225 million cells). A 5 to 7-day course of antibiotics would create 444,444x times the amount necessary to create symptoms.
One EU is approximately equivalent to 100 pg of E. Coli lipopolysaccharide—the amount present in around 105 bacteria. Humans can develop symptoms when exposed to as little as 5 EU/kg body weight. [500,000 cells]
From the beginning of the antibiotic era, it has been suggested that in some circumstances shock might be precipitated by bacterial cell lysis and the sudden release of endotoxin from gram-negative bacteria exposed to antibiotics {2-6}. The possible danger of too rapid destruction of gram-negative organisms by antibiotics was first noted by James Reilly and coworkers [5].
Effects of Antibiotics On Endotoxin Release. Yearbook of Intensive Care and Emergency Medicine, Vol. 1995, 1995, pp. 465-472.
We injected biotinylated LPS at 100 μg/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to transduce systemic inflammatory signals into the brain or to exacerbate existing pathology.
http://www.jneuroinflammation.
com/content/8/1/50/abstract
LPS is now well established as an effective initiator of dopaminergic (DA) neuron neurodegeneration. LPS-mediated dopaminergic neuronal loss induced by LPS may also have functional significance as demonstrated by behavioral tests. Thirty days following supranigral LPS injection, rats show unilateral behavioral deficits. Priming of the SN by LPS influences the impact of later neurotoxin exposure, and this process was called as neuroimmune sensitization of neurodegeneration [97].
The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease. Parkinson's Disease, Volume 2011 (2011), Article ID 487450, 25 pages. http://www.hindawi.com/
journals/pd/2011/487450/ Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are “primed” to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1β (IL-1β) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1β. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death.
Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death. The Journal of Neuroscience, 5 October 2005, 25(40): 9275-9284.
Repeated systemic LPS challenges resulted in increased brain IL-1beta, TNF-alpha and IL-12 levels, despite attenuated systemic cytokine production.
These studies reveal that the innate immune cells in the brain do not become tolerant to systemic infection, but are primed instead. This may lead to prolonged and damaging cytokine production that may have a profound effect on the onset and/or progression of pre-existing neurodegenerative disease.
http://www.jneuroinflammation.com/content/9/1/146/abstract Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor.
Metabolic Endotoxemia Initiates Obesity and Insulin Resitance. Diabetes. Vol. 56, July 2007. http://diabetes.
diabetesjournals.org/content/ 56/7/1761.full.pdf+html Endotoxic lipopolysaccharide (LPS) is a major constituent of the outer membrane of the Gram-negative microbe. Following its release from the bacterium, LPS serves as a potent proinflammatory stimulus by interacting with humoral and cellular mediator systems to stimulate production of an array of inflammatory molecules.Cell-wall active antibiotics are known to promote endotoxin release.
Bucklin S E, Morrison D C. Differences in therapeutic efficacy among cell wall-active antibiotics in a mouse model of gram-negative sepsis. J Infect Dis. 1995;172:1519–1527.
The mechanism is complex. In humans, LPS binds to a lipid binding protein (LBP) in the serum which transfers it to CD14 on the cell membrane, which in turn transfers it to another non-anchored protein, MD2, which associates withToll-like receptor-4 (TLR4). This triggers the signaling cascade for macrophage/endothelial cells to secrete pro-inflammatory cytokines and nitric oxide that lead to characteristic "endotoxic shock". CD14 and TLR4 are present on several cells of the immunological system cells, including macrophages and dendritic cells.
Textbook of Bacteriology. http://
textbookofbacteriology.net/ endotoxin.html Results of in vitro, animal, and clinical studies support the hypothesis that endotoxin is released during antibiotic treatment of infections caused by gram negative organisms. Clinical Relevance of Antibiotic-Induced Endotoxin. Antimicrobial Agents and Chemotherapy, June1994,p.1211-1218. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC188188/pdf/ aac00020-0019.pdf
”To investigate whether these fundamentally different systemic inflammatory stimuli drive different systemic inflammatory responses, we investigated the plasma levels of 11 key cytokines 3 h after LPS or anaphylaxis (at the time MCAo is performed). LPS induced profound (10-1000 fold) increases in G-CSF, IL-6, KC, MCP-1, TNFα, and RANTES and a 4-fold, but significant increase in IL-1β, without significantly affecting IFNγ, IL-17A, IL-1α and IL-10 levels. Anaphylaxis increased G-CSF, IL-6, KC, MCP-1, TNFα, and RANTES levels 4-30 fold (not significant), and significantly elevated IL-10 levels (80 fold) while no IL-1β or IL-1α was detected.”Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood-brain barrier damage and brain edema independently of infarct size.-- With that chronic state of inflammation, a patient can experience headaches, depression, anxiety, and nervousness.
-- If left untreated long enough, it could eventually play a role in creating Alzheimer's, Parkinson's, Chronic Fatigue Syndrome, seizures, and even obesity.
Peripheral inflammation sparks off exacerbation in the central brain’s ongoing damage in several neurodegenerative diseases, such as Alzheimer’s disease (AD), multiple sclerosis, Parkinson’s disease, prion disease, stroke, and Wallerian degeneration [8, 9, 22–26].
LPS causes a systemic inflammatory reaction known as sickness behaviour characterized by fever, anorexia, weight loss, and reduction of activity [97].
Parkinson's Disease and Systemic Inflammation. Parkinson's Disease, Volume 2011 (2011), Article ID 436813, 9 pages, http://www.hindawi.com/
journals/pd/2011/436813/ We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss.
Activation of microglia, bone marrow-derived macrophage-like cells that function as the resident immune defense system of the brain (1), is a characteristic feature of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, AIDS dementia complex, and amyotrophic lateral sclerosis as well as ischemia and posttraumatic brain injury (2–4).
Activation of innate immunity in the CNS triggers neurodegenration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. Jul 8, 2003; 100(14): 8514–8519. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC166260/ Lipopolysaccharide (LPS) induced release of NO by pericytes in a dose-dependent manner that was mediated through MAPK pathways. Nitrative stress resulted in S-nitrosylation of cellular proteins. Eighteen of twenty-three cytokines measured were released constitutively by pericytes or with stimulation by LPS, including interleukin (IL)-12, IL-13, IL-9, IL-10, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, eotaxin, chemokine (C-C motif) ligand (CCL)-3, and CCL-4. Pericyte expressions of both subunits of LRP-1 were upregulated by LPS. Our results show that cultured mouse brain microvascular pericytes secrete cytokines, chemokines, and nitric oxide and respond to the innate immune system stimulator LPS. These immune properties of pericytes are likely important in their communication within the neurovascular unit and provide a mechanism by which they participate in neuroinflammatory processes in brain infections and neurodegenerative diseases.
Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide. Journal of Neuroinflammation 2011, 8:139 . http://www.jneuroinflammation.
com/content/8/1/139/abstract
Further, our recent data suggest that neuroinflammation is present in the brain well prior to cognitive decline.
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. Journal of Neuroinflammation 2012, 9:179 . http://www.jneuroinflammation.
com/content/9/1/179 We found that leptin receptors were expressed in hypothalamic astrocytes and that their conditional deletion led to altered glial morphology and synaptic inputs onto hypothalamic neurons involved in feeding control. Leptin-regulated feeding was diminished, whereas feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data reveal an active role of glial cells in hypothalamic synaptic remodeling and control of feeding by leptin.
Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nature Neuroscience 17, 908–910 (2014). http://www.nature.com/neuro/
journal/v17/n7/full/nn.3725. html. Leptin is an adipocyte hormone that functions as an afferent signal in a negative feedback loop that regulates energy balance (1–3). Mice with mutations in leptin (ob/ob) or its receptor (db/db) are hyperphagic and severely obese (4–6). These mutant mice also manifest a large number of metabolic and endocrine abnormalities including diabetes, hypercortisolemia, infertility, and cold intolerance (7, 8).
Selective depletion of leptin receptor in neurons leads to obesity. J Clin Invest. Oct 15, 2001; 108(8): 1113–1121. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC209535/ The increased serum IgM and IgA levels against LPS in Major Depressive Disorder, MDD, indicate that MDD is accompanied by an in- creased gut permeability and that there is an immune response directed against LPS of enterobacteria. 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. 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. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT: Systemic LPS causes chronic neuroinflammation and pro- gressive neurodegeneration. Glia 2007; 55(5): 453–462. http://www.
integratedhealth.com.au/wp- content/uploads/2014/04/ MaesGutBrainDepression2-Copy1. pdf 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 lipopolysaccharides (LPS) may induce depressive symptoms.
http://www.integratedhealth.com.au/wp-content/uploads/ 2014/04/ MaesGutBrainDepression2-Copy1. pdf
- Fat Brain – Fat Planet: How Antibi... Dr.Jeff
11 y
1,149
