Also see:
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Exercise and Endotoxemia
Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart
Ray Peat, PhD on the Benefits of the Raw Carrot
Protection from Endotoxin
Endotoxin-lipoprotein Hypothesis
Protective Bamboo Shoots
The effect of raw carrot on serum lipids and colon function
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Bowel Toxins Accelerate Aging
Benefits of Aspirin
The Truth about Low Cholesterol
Microbial Influence
Are Happy Gut Bacteria Key to Weight Loss?
Imbalance Of Gut Bacteria Linked To Elevated Risk For Diabetes

Quotes by Ray Peat, PhD:
“Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes maladaptive inflammation.”

“Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a minimally “Warburgian” approach–i.e,, a merely reasonable approach–would involve minimizing the absorption of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine’s energy production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring constructive hormonal functions.”

“Bacterial endotoxin causes some of the same effects as adrenalin. When stress reduces circulation to the bowel, causing injury to the barrier fun ction of the intestinal cells, endotoxin can enter the blood, contributing to a shock state, with further impairment of circulation.”

“One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin, bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999).”

“Oatmeal and potatoes do provide fiber, but they are good food for bacteria, and bacterial endotoxin is usually the basic problem causing hormone imbalance, by being a chronic burden for the liver, keeping it from storing enough sugar to process thyroid and the other hormones effectively.”

Anaesth Intensive Care. 1989 Feb;17(1):49-55.
Endotoxins and anti-endotoxins (their relevance to the anaesthetist and the intensive care specialist).
Brock-Utne JG, Gaffin SL.
Endotoxins (lipopolysaccharides, LPS) are potent bacterial poisons always present within the intestines in considerable amounts. Several pathophysiological conditions such as hypovolaemia, hypoxia, intestinal ischaemia, burns and radiation lead to a breakdown in the barrier and depending upon the extent of the injury, endotoxins enter the systemic circulation in increasing amounts. Antibiotics do not inactivate the endotoxins which continue to exert their toxic effects leading to nausea, vomiting, diarrhoea, fever, disseminated intravascular coagulation, vascular collapse and organ failure. When nonabsorbable antibiotics are given prior to the insult, systemic endotoxaemia is prevented. Immunotherapy, using anti-lipopolysaccharide IgG, inactivates plasma endotoxins, destroys gram-negative bacteria and opsonises them and may become a major form of therapy. An outline of endotoxin and anti-lipopolysaccharide and its importance to the anaesthetist and intensive care specialist is presented.

Journal of Neurochemistry Volume 72, Issue 2, pages 652–660, February 1999
The Bacterial Endotoxin Lipopolysaccharide Causes Rapid Inappropriate Excitation in Rat Cortex
Yushan S. Wang, Thomas D. White
Abstract : There is mounting evidence that inflammation and associated excitotoxicity may play important roles in various neurodegenerative disorders, such as bacterial infections, Alzheimer’s disease, AIDS dementia, and multiple sclerosis. The immunogen E. coli lipopolysaccharide (LPS, endotoxin) has been widely used to stimulate immune/inflammatory responses both systemically and in the CNS. Here, we show that exposure of parietal cortical slices from adult rats to LPS triggered very rapid (<2.5 min) and sustained releases of the neurotransmitters glutamate and noradrenaline, and of the neuromodulator adenosine. The responses to LPS declined rapidly following removal of the LPS and exhibited no tachyphylaxis to repeated exposures to LPS. The detoxified form of LPS had no effect. LPS-evoked release of [3H]noradrenaline, but not of glutamate or adenosine, appears to be partly due to the released glutamate acting at ionotropic receptors on the noradrenergic axons present in the cortical slices. LPS appears to release glutamate, which then acts at non-NMDA receptors to remove the voltage-sensitive Mg2+ block of NMDA receptors, thus permitting NMDA receptors to be activated and noradrenaline release to proceed. It seems possible that rapid, inappropriate excitation may occur in the immediate vicinity of gram-negative bacterial infections in the brain. If similar inappropriate excitations are also triggered by those immunogens specifically associated with Alzheimer’s disease (β-amyloid), AIDS dementia (gp 120 and gp41), or multiple sclerosis (myelin basic protein), they might explain some of the acute, transient neurological and psychiatric symptoms associated with these disorders.

Scand J Gastroenterol. 1999 Mar;34(3):291-6.
Lipopolysaccharide- and proinflammatory cytokine-induced energy production in intestinal and colonic epithelial cell lines.
Fukushima K, Sasaki I, Takahashi K, Naito H, Matsuno S.
BACKGROUND:
Although epithelial cells in ulcerative colitis may be metabolically deficient, it remains unknown whether epithelial cells modulate energy metabolism in inflamed mucosa. The purpose of the present study is to investigate whether inflammatory mediators such as lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) alter energy metabolism in epithelial cells.
METHODS:
Adenosine 5′-triphosphate (ATP) levels in HT29 cells cultured with LPS, IL-1beta, IL-6, or TNF-alpha were measured with high-performance liquid chromatography, using a reversed-phase chromatography column. Cellular and mitochondrial (antimycin A-sensitive) respiration rates were determined polarographically, using a Clark-type oxygen electrode.
RESULTS:
When the cells were cultured with LPS, IL-6, and TNF-alpha but not IL-1beta, ATP levels increased significantly at 6 h, followed by a decrease at 24 h. Enhancement of oxygen consumption, which was completely blocked by antimycin A, was also shown at 3 h by the exposure to these substrates.
CONCLUSION:
LPS and proinflammatory cytokines induced cellular ATP generated by mitochondrial phosphorylation. An active energy production in epithelial cells on the exposure to inflammatory mediators may be critical for escape from chronic mucosal inflammation.

Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E909-16.
Endotoxemia reduces skeletal muscle protein synthesis in neonates.
Orellana RA, O’Connor PM, Nguyen HV, Bush JA, Suryawan A, Thivierge MC, Fiorotto ML, Davis TA.
Protein synthesis in skeletal muscle is reduced by as much as 50% as early as 4 h after a septic challenge in adults. However, the effect of sepsis on muscle protein synthesis has not been determined in neonates, a highly anabolic population whose muscle protein synthesis rates are elevated and uniquely sensitive to insulin and amino acid stimulation. Neonatal piglets (n = 10/group) were infused for 8 h with endotoxin [lipopolysaccharide (LPS), 0 and 10 microg. kg(-1). h(-1)]. Plasma amino acid and glucose concentrations were kept at the fed level by infusion of dextrose and a balanced amino acid mixture. Fractional protein synthesis rates were determined by use of a flooding dose of [(3)H]phenylalanine. LPS infusion produced a septic-like state, as indicated by an early and sustained elevation in body temperature, heart rate, and plasma tumor necrosis factor-alpha, interleukin-1, cortisol, and lactate concentrations. Plasma levels of insulin increased, whereas glucose and amino acids decreased, suggesting the absence of insulin resistance. LPS significantly reduced protein synthesis in longissimus dorsi muscle by only 11% and in gastrocnemius by only 15%, but it had no significant effect in masseter and cardiac muscles. LPS increased protein synthesis in the liver (22%), spleen (28%), kidney (53%), jejunum (19%), diaphragm (21%), lung (50%), and skin (13%), but not in the stomach, pancreas, or brain. These findings suggest that, when substrate supply is maintained, skeletal muscle protein synthesis in neonates compared with adults is relatively resistant to the catabolic effects of sepsis.

Hepatology. 2010 Oct;52(4):1322-33.
Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents.
Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, Tang L, Lin Y, He YQ, Zou SS, Wang C, Zhang HL, Cao GW, Wu MC, Wang HY.
Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation. CONCLUSION: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC.

Metabolism. 2011 Sep 22. [Epub ahead of print]
Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid-deficient diet alters the response to endotoxin in rats.
Ling PR, Malkan A, Le HD, Puder M, Bistrian BR.
This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid-deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase-1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Biochem Pharmacol. 1995 Jan 6;49(1):65-8.
Endotoxin inhibits glucuronidation in the liver. An effect mediated by intercellular communication.
Bánhegyi G, Mucha I, Garzó T, Antoni F, Mandl J.
Endotoxin [lipopolysaccharide (LPS) 50 micrograms/mL] added to the perfusion medium increased glucose production and inhibited the glucuronidation of p-nitrophenol in perfused mouse liver both in recirculating and non-recirculating systems, while sulfation of p-nitrophenol was unchanged. The effects of endotoxin could be prevented by the addition of cyclooxygenase inhibitors, while PGD2 and PGE2 also caused a decrease in p-nitrophenol glucuronidation in perfused liver. In isolated hepatocytes endotoxin failed to affect p-nitrophenol conjugation, while PGD2 and PGE2 decreased the rate of it. Our results suggest that endotoxin inhibits glucuronidation through an intercellular communication presumably mediated by eicosanoids.

J Biol Chem. 1988 May 25;263(15):6953-5.
Endotoxin stimulates glycogenolysis in the liver by means of intercellular communication.
Casteleijn E, Kuiper J, Van Rooij HC, Kamps JA, Koster JF, Van Berkel TJ.
Escherichia coli endotoxin (lipopolysaccharide) was shown to increase glycogenolysis in the perfused liver 2-3-fold. In isolated parenchymal liver cells, however, endotoxin did not influence glycogenolysis, whereas stimulation by endotoxin of glycogenolysis in the perfused liver could be blocked by aspirin. This suggests that the effect of endotoxin on liver glycogenolysis is mediated by eicosanoids. The amount of prostaglandin D2 (which is the major prostanoid formed by Kupffer cells) in the liver perfusates was increased 5-fold upon endotoxin addition, with a time course which preceded the increase in glucose output. It is concluded that endotoxin stimulates glycogenolysis in the liver by stimulating prostaglandin D2 release from Kupffer cells, with a subsequent activation of glycogenolysis in parenchymal liver cells. This mechanism of intercellular communication may be designed to provide the carbohydrate source of energy necessary for the effective destruction of invaded microorganisms, by phagocytic cells, including the Kupffer cells.

Yale J Biol Med. 1979 Jan-Feb; 52(1): 127–133.
PMCID: PMC2595710
The Contribution of Gut-Derived Endotoxins to Liver Injury
James P. Nolan
The liver serves as the key organ for the removal and detoxification of bacterial endotoxins that are continously absorbed in small amounts from the gastrointestinal tract. This paper postulates that liver injury impairs this detoxification process leading to further liver damage and systemic effects as well. Evidence is reviewed to support the contention that endotoxin may be a major common pathway for liver injury by a variety of agents, and methods of reducing endotoxicity of gut origin are proposed. Finally, a new solid phase radioimmunometric assay for E. coli 026 is described and its usefulness as a gut marker suggested.

January 2009 The Journal of Lipid Research, 50, 1-2.
Endotoxin in the gut and chylomicrons: translocation or transportation?
Carl Grunfeld 2 and Kenneth R. Feingold, Associate Editor
The intestine contains trillions of microorganisms and massive amounts of endotoxin, which if absorbed from the intestinal lumen into the body would result in overwhelming septic shock and death. Recently there has been an increasing appreciation of the role of gut microorganisms and their translocation into the systemic circulation in promoting metabolic disorders including obesity and insulin resistance, as well as in the pathogenesis of very different disorders, such as inflammatory bowel disease, HIV infection, ethanol-induced liver disease, and hemorrhagic shock.

Diabetes Care February 2011 vol. 34 no. 2 392-397
Endotoxemia Is Associated With an Increased Risk of Incident Diabetes
Pirkko J. Pussinen, PHD1, Aki S. Havulinna, MSC2, Markku Lehto, PHD3,4, Jouko Sundvall, MSC2 and Veikko Salomaa, MD2
OBJECTIVE Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria.
RESEARCH DESIGN AND METHODS We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25–74 years and followed up for 10 years.
RESULTS Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001–1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome.
CONCLUSIONS Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

Diabetes Care. 2011 Feb;34(2):392-7.
Endotoxemia is associated with an increased risk of incident diabetes.
Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

Endocr Rev. 2010 Dec;31(6):817-44. Epub 2010 Jun 30.
Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk.
Manco M, Putignani L, Bottazzo GF.
Compelling evidence supports the concepts that gut microbiota actively promotes weight gain and fat accumulation and sustains, indirectly, a condition of low-grade inflammation, thus enhancing the cardiovascular risk. Fewer Bacteroidetes and more Firmicutes seem to characterize the gut microbiota of obese people as compared with that of lean individuals. This difference translates into an increased efficiency of microbiota of obese individuals in harvesting energy from otherwise indigestible carbohydrates. Furthermore, the microbiota also seems able to favor fat accumulation. Indeed, studies performed in germ-free animals have demonstrated that conventionalization of sterile intestine with gut microbiota is associated with an enhanced expression of various lipogenic genes in different tissues, i.e., hepatic, adipose, and muscle tissues. Finally, the microbiota favors systemic exposure to the lipopolysaccharides (LPSs), large glycolipids derived from the outer membrane of Gram-negative bacteria. LPSs can cause a condition of “metabolic endotoxemia” characterized by low-grade inflammation, insulin resistance, and augmented cardiovascular risk. LPSs are a powerful trigger for the innate immune system response. Upon binding to the Toll-like receptor 4 and its coreceptors, LPSs trigger a cascade of responses ultimately resulting in the release of proinflammatory molecules that interfere with modulation of glucose and insulin metabolism, promote development and rupture of the atherosclerotic plaque, and favor progression of fatty liver disease to steatohepatitis. This review gives a comprehensive breakdown of the interaction among gut microbiota, LPSs, and the innate immune system in the development of obesity and promotion of an individual’s cardiovascular risk.

Diabetes Care. 2009 Sep;32(9):1689-93. Epub 2009 Jun 5.
Serum lipopolysaccharide activity is associated with the progression of kidney disease in finnish patients with type 1 diabetes.
Nymark M, Pussinen PJ, Tuomainen AM, Forsblom C, Groop PH, Lehto M; FinnDiane Study Group.
High serum LPS activity is associated with the development of diabetic nephropathy in Finnish patients with type 1 diabetes.

Circ Res. 2010 Jul 9;107(1):56-65. Epub 2010 May 20.
Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia.
Wiesner P, Choi SH, Almazan F, Benner C, Huang W, Diehl CJ, Gonen A, Butler S, Witztum JL, Glass CK, Miller YI.
The cooperative engagement of AP-1 and nuclear factor (NF)-kappaB by mmLDL and LPS may constitute a mechanism of increased transcription of inflammatory cytokines within atherosclerotic lesions.

Diabetes. 2007;56(7):1161-1772.
Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Patrice D. Cani; Jacques Amar; Miguel Angel Iglesias; Marjorie Poggi; Claude Knauf; Delphine Bastelica; Audrey M. Neyrinck; Francesca Fava; Kieran M. Tuohy; Chantal Chabo; Aurélie Waget; Evelyne Delmée; Béatrice Cousin; Thierry Sulpice; Bernard Chamontin; Jean Ferrières; Jean-François Tanti; Glenn R. Gibson; Louis Casteilla; Nathalie M. Delzenne; Marie Christine Alessi; Rémy Burcelin
Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

Diabetes June 2008 vol. 57 no. 6 1470-1481
Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice
Patrice D. Cani, Rodrigo Bibiloni, Claude Knauf, Aurélie Waget, Audrey M. Neyrinck, Nathalie M. Delzenne, and Rémy Burcelin
OBJECTIVE—Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases.
RESEARCH DESIGN AND METHODS—We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect.
RESULTS—We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat–fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14−/− mutant mice mimicked the metabolic and inflammatory effects of antibiotics.
CONCLUSIONS—This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders.

J Lipid Res. 1998 Jun;39(6):1220-30.
Regulation of microsomal triglyceride transfer protein mRNA expression by endotoxin and cytokines.
Navasa M, Gordon DA, Hariharan N, Jamil H, Shigenaga JK, Moser A, Fiers W, Pollock A, Grunfeld C, Feingold KR.
We studied the effect of endotoxin (LPS), and cytokines (TNF, IL-1, and IL-6) on hepatic microsomal triglyceride transfer protein (MTP) mRNA levels in vivo in Syrian hamsters and in vitro in HepG2 cells. LPS, interleukin-1 (IL-1), and to a lesser extent tumor necrosis factor (TNF) significantly decreased MTP mRNA levels in hamster liver. These effects required several hours. Furthermore, IL-1 and IL-6 significantly decreased MTP mRNA levels in HepG2 cells. This decrease appeared soon after IL-1 administration (8 h) and at very low doses (0.1 ng/ml). MTP activity and protein levels of the large subunit of MTP also decreased modestly in HepG2 cells with prolonged cytokine treatment. IL-1 reduced the expression of an MTP promoter luciferase construct to a similar degree as seen with MTP mRNA, indicating that transcriptional regulation plays a major role in the decrease of MTP gene expression. Deletional analysis of the MTP promoter identified the region -121 to -88 bp upstream to the coding sequence as the site of the negative regulation by IL-1. This region contains an insulin response element (IRE), activating protein 1 (AP-1), hepatic nuclear factor 1 (HNF-1) and hepatic nuclear factor 4 (HNF-4) consensus sequences; mutations of the IRE and HNF-4 sites did not affect the response to IL-1. In contrast, mutating AP-1 or HNF-1 sites led to a marked decrease in basal expression and the loss of the IL-1 effect, suggesting that an intact AP-1 and/or HNF-1 regulatory element are crucial for the IL-1 regulation of MTP gene expression. However, prolonged incubation with IL-1 did not alter HepG2 apolipoprotein B secretion suggesting that MTP mRNA down-regulation does not contribute significantly to the cytokine-induced effects on lipid metabolism.

Nature Reviews Gastroenterology and Hepatology 7, 691-701 (December 2010)
The role of the gut microbiota in nonalcoholic fatty liver disease
Ahmed Abu-Shanab & Eamonn M. M. Quigley
Important metabolic functions have been identified for the gut microbiota in health and disease. Several lines of evidence suggest a role for the gut microbiota in both the etiology of nonalcoholic fatty liver disease (NAFLD) and progression to its more advanced state, nonalcoholic steatohepatitis (NASH). Both NAFLD and NASH are strongly linked to obesity, type 2 diabetes mellitus and the metabolic syndrome and, accordingly, have become common worldwide problems. Small intestinal bacterial overgrowth of Gram-negative organisms could promote insulin resistance, increase endogenous ethanol production and induce choline deficiency, all factors implicated in NAFLD. Among the potential mediators of this association, lipopolysaccharide (a component of Gram-negative bacterial cell walls) exerts relevant metabolic and proinflammatory effects. Although the best evidence to support a role for the gut microbiota in NAFLD and NASH comes largely from animal models, data from studies in humans (albeit at times contradictory) is accumulating and could lead to new therapeutic avenues for these highly prevalent conditions.

Eur J Gastroenterol Hepatol. 1999 Apr;11(4):409-12.
Intestinal permeability in liver cirrhosis.
Ersöz G, Aydin A, Erdem S, Yüksel D, Akarca U, Kumanlioglu K.
This study shows that intestinal permeability increased in cirrhotic patients regardless of the grade and aetiology of disease.

Korean J Gastroenterol. 2004 Feb;43(2):104-11.
[Intestinal permeability in patients with viral and alcoholic liver disease].
[Article in Korean]
Kim JW, Jeon WK, Yun JW, Park DI, Cho YK, Sung IK, Park CY, Sohn CI, Kim BI, Kim EJ, Shin MS.
Increased intestinal permeability has been possible contributing factors to the pathogenesis of alcoholic liver disease. Moreover, it can contribute to the development of bacterial infection and intestinal endotoxemia in patients with liver cirrhosis. This study aimed to examine the difference of intestinal barrier dysfunction between alcoholic and viral liver disease patients through the comparison of the intestinal permeabilities of patients with clinical characteristics…
Although the main mechanism involved in the decrease in MAN% is likely a reduction in area of the intestinal absorptive surface, these results argue in favour of an increased intestinal permeability in liver cirrhosis, especially in patients with severe infectious complications. The impairment of intestinal function barrier may contribute to severe septic complications in these patients.

Korean J Obes. 2010 Sep;19(3):78-84. Korean.
The Association between Visceral Fat and Endotoxin.
Chung JH, Kang MK, Rho JS, Yum KS.
Department of Family Medicine, Jeju National Hospital, Korea.
BACKGROUND: Visceral fat accumulation has been known to be an independent risk factor of cardiovascular disease with increased risk of diabetes. It is also associated with inflammation factor, such as adiponectin, leptin, IL-6 and IL-10. Endotoxin is also related with many inflammation factors and atherosclerosis. There are only few studies regarding the correlation between endotoxin concentration and visceral fat in adults. Thus, the purpose of this study was to investigate the relationship between visceral fat and serum endotoxin concentration in adults. METHODS: A total of 40 of subjects (26 men and 14 women) were enrolled for this study. The subjects were selected among Korean adults who visited the Department of Family Medicine from January 2009 to August 2009. Abdominal fat area was calculated from CT scan taken at the umbilical level. Serum endotoxin concentration was measured by Endo-Chek TM (Diatech Korea Co..Ltd., Seoul, Korea). RESULTS: Serum endotoxin concentration was positively correlated with visceral fat in adults (P < 0.05). CONCLUSION: Based on the results of this study, serum endotoxin concentration was positively correlated with visceral fat in adults. Further appropriate studies are required to better elucidate the relationship between visceral fat and serum endotoxin concentration among Korean adult population.

Eur J Gastroenterol Hepatol. 1999 Jul;11(7):755-9.
Intestinal permeability in liver cirrhosis: relationship with severe septic complications.
Campillo B, Pernet P, Bories PN, Richardet JP, Devanlay M, Aussel C.
these results argue in favour of an increased intestinal permeability in liver cirrhosis, especially in patients with severe infectious complications. The impairment of intestinal function barrier may contribute to severe septic complications in these patients.

Ann Surg. 1995 April; 221(4): 398–405.
Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effects of recombinant bactericidal/permeability-increasing protein.
Y M Yao, S Bahrami, G Leichtfried, H Redl, and G Schlag
CONCLUSIONS: These data suggest that hemorrhagic shock may lead to bacterial/endotoxin translocation with concomitant TNF formation, endogenous endotoxemia may play an important role in the pathogenesis of multiple-organ failure after shock and trauma, TNF formation at an early stage might be related mainly to mechanisms other than Kupffer’s cells activation via lipopolysaccharide, and rBPl21 might be a useful therapeutic agent against endogenous bacteria/endotoxin related disorders in severe hemorrhagic shock.

Infect Immun. 1996 Mar;64(3):769-74.
Lipopolysaccharide-induced lethality and cytokine production in aged mice.
Tateda K, Matsumoto T, Miyazaki S, Yamaguchi K.
This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS-induced cytokine production, in spite of full down-regulating responses by corticosterone and IL- 10, may explain at least in part LPS sensitivity in aged mice.

J Lipid Res. 1992 Dec;33(12):1765-76.
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
Feingold KR, Staprans I, Memon RA, Moser AH, Shigenaga JK, Doerrler W, Dinarello
Hyperlipidemia frequently accompanies infectious diseases and may be due to increases in lipoprotein production or decreases in lipoprotein clearance. The administration of endotoxin (LPS) has been used to mimic infection and prior studies demonstrate that LPS produces hypertriglyceridemia. In the present study in rodents, the dose of LPS necessary to induce hyperlipidemia was orders of magnitude less than that necessary to induce shock and death. As little as 10 ng/100 g body weight induced hypertriglyceridemia and this increase in serum triglyceride levels occurred rapidly (78% increase at 2 h). At high doses of LPS (50 micrograms/100 g body weight), the clearance of triglyceride-rich lipoproteins was decreased. At low doses of LPS (100 ng/100 g body weight), triglyceride clearance was not altered but the hepatic secretion of triglyceride was increased. Low dose LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided a source of fatty acids for the increase in hepatic triglyceride production. High dose LPS did not increase hepatic fatty acid synthesis or peripheral lipolysis, and hepatic triglyceride secretion was not stimulated. Thus, low dose LPS produces hypertriglyceridemia by increasing hepatic lipoprotein production, while high dose LPS produces hypertriglyceridemia by decreasing lipoprotein catabolism. Administration of anti-tumor necrosis factor (TNF) antibodies or interleukin 1 (IL-1) receptor antagonist did not prevent the increase in serum triglyceride levels induced by LPS. However, anti-TNF antibodies and interleukin 1 receptor antagonist (IL-1ra) blocked the increase in serum triglycerides induced by TNF or IL-1, respectively. These data suggest that neither of these cytokines is absolutely required for the increase in serum triglycerides induced by LPS, raising the possibility that other cytokines, small molecular mediators, or LPS itself may play a crucial role.

J Lipid Res. 1992 Dec;33(12):1765-76.
Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance.
Feingold KR, Staprans I, Memon RA, Moser AH, Shigenaga JK, Doerrler W, Dinarello CA, Grunfeld C.
Hyperlipidemia frequently accompanies infectious diseases and may be due to increases in lipoprotein production or decreases in lipoprotein clearance. The administration of endotoxin (LPS) has been used to mimic infection and prior studies demonstrate that LPS produces hypertriglyceridemia. In the present study in rodents, the dose of LPS necessary to induce hyperlipidemia was orders of magnitude less than that necessary to induce shock and death. As little as 10 ng/100 g body weight induced hypertriglyceridemia and this increase in serum triglyceride levels occurred rapidly (78% increase at 2 h). At high doses of LPS (50 micrograms/100 g body weight), the clearance of triglyceride-rich lipoproteins was decreased. At low doses of LPS (100 ng/100 g body weight), triglyceride clearance was not altered but the hepatic secretion of triglyceride was increased. Low dose LPS stimulated hepatic de novo fatty acid synthesis and lipolysis, both of which provided a source of fatty acids for the increase in hepatic triglyceride production. High dose LPS did not increase hepatic fatty acid synthesis or peripheral lipolysis, and hepatic triglyceride secretion was not stimulated. Thus, low dose LPS produces hypertriglyceridemia by increasing hepatic lipoprotein production, while high dose LPS produces hypertriglyceridemia by decreasing lipoprotein catabolism. Administration of anti-tumor necrosis factor (TNF) antibodies or interleukin 1 (IL-1) receptor antagonist did not prevent the increase in serum triglyceride levels induced by LPS. However, anti-TNF antibodies and interleukin 1 receptor antagonist (IL-1ra) blocked the increase in serum triglycerides induced by TNF or IL-1, respectively. These data suggest that neither of these cytokines is absolutely required for the increase in serum triglycerides induced by LPS, raising the possibility that other cytokines, small molecular mediators, or LPS itself may play a crucial role.

J Biol Chem. 2009 Feb 27;284(9):5915-26. Epub 2009 Jan 3.
Bacterial endotoxin stimulates adipose lipolysis via toll-like receptor 4 and extracellular signal-regulated kinase pathway.
Zu L, He J, Jiang H, Xu C, Pu S, Xu G.
Bacterial endotoxin/lipopolysaccharide elicits inflammatory responses and also elevates circulating levels of free fatty acids (FFAs) and impairs insulin sensitivity. Serum FFA elevation in acute endotoxemia has long been thought to be due to endotoxin dysregulating lipid disposal and counterregulatory hormones and cytokines. Here, we investigated the direct lipolysis effect of endotoxin in rodents and in isolated primary adipocytes. Endotoxin increases lipolysis in vivo in adipose tissues, elevates circulating FFA level, induces insulin resistance in rats, and directly stimulates chronic lipolysis in vitro in adipocytes. The lipolytic action of endotoxin is mediated via its lipid A moiety and is blocked by anti-endotoxin peptides. Neither adipocytokine secretion nor nuclear factor-kappaB activation is involved in endotoxin-induced lipolysis. Different from catecholamine, endotoxin stimulates lipolysis without elevating cAMP production and activating protein kinase A and protein kinase C. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2. Upon inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis ceases. Endotoxin causes perilipin down-regulation and phosphorylation and increases the activity and protein levels of hormone-sensitive lipase and adipose triglyceride lipase but does not induce hormone-sensitive lipase translocation to intracellular lipid droplets. In TLR4 (Toll-like receptor 4)-deficient mice and adipocytes, endotoxin fails to increase in vivo and in vitro lipolysis. These findings suggest that endotoxin stimulates lipolysis via TLR4 and ERK1/2 signaling in adipocytes. The lipolytic action of endotoxin liberates FFA efflux from adipocytes to the bloodstream, which is a possible basis for systemic FFA elevation and insulin resistance in endotoxemia or Gram-negative bacterial infection.

Gastroenterology. 2012 May;142(5):1100-1101.e2. doi: 10.1053/j.gastro.2012.01.034. Epub 2012 Feb 8.
A high-fat diet is associated with endotoxemia that originates from the gut.
Pendyala S1, Walker JM, Holt PR.
Endotoxemia, characterized by an excess of circulating bacterial wall lipopolysaccharide, is associated with systemic inflammation and the metabolic syndrome. Placing 8 healthy subjects on a Western-style diet for 1 month induced a 71% increase in plasma levels of endotoxin activity (endotoxemia), whereas a prudent-style diet reduced levels by 31%. The Western-style diet might, therefore, contribute to endotoxemia by causing changes in gastrointestinal barrier function or the composition of the microbiota. Endotoxemia might also develop in individuals with gastrointestinal barrier impairment. Therapeutic reagents that reduce endotoxemia might reduce systemic inflammation in patients with gastrointestinal diseases or metabolic syndrome.

Alcohol. 2008 Aug;42(5):349-61. doi: 10.1016/j.alcohol.2008.03.131. Epub 2008 May 27.
Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium.
Purohit V, Bode JC, Bode C, Brenner DA, Choudhry MA, Hamilton F, Kang YJ, Keshavarzian A, Rao R, Sartor RB, Swanson C, Turner JR.
This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram-negative bacteria in the intestine, which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram-negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan, which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram-negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, l-glutamine, oats supplementation, or zinc, thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram-negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries.