It’s about five years since I started actively reading health literature. During these years, I’ve read dozens of health books, thousands of scientific articles and I’ve followed more than 200 different health blogs to gather as many good ideas as possible.
There have been many interesting approaches to optimal health, but it has always been difficult to understand which opinion is the “right” one. Some of the common questions include:
- Should we avoid saturated fats, or polyunsaturated fats, or omega-6, or omega-3 fats? (William Lands vs. Chris Masterjohn vs. Ray Peat vs. Brian Peskin vs. Dariush Mozaffarian vs. Caldwell Esselstyn)
- Is sugar healthy or bad? Can starch be healthy? (Ray Peat vs. low carb community vs. Paul Jaminet)
- Is animal protein a good or bad thing (T. Colin Campbell & Vegan community vs. Denise Minger & Loren Cordain & Paleo community)
At first it felt like it was very difficult to trust anybody’s point of view on these issues, because there always seemed to be some contradictory evidence or “paradoxes.”
However, at some point, I started focusing mostly on the possible mechanisms of chronic disease in general and finally found some powerful ideas that seemed to explain some of these important questions, and the paradoxes as well.
2. Metabolic Rate, Health and Red Light
One of my first important findings was the Broda Barnes’ idea that insufficient thyroid function is a very important cause of many kinds of ailments such as heart disease, depression, fibromyalgia, migraine, menstrual problems, and skin diseases. Many 180DegreeHealth ideas have been heavily influenced by Barnes’ work.
In 1976, Barnes wrote that 40% of the U.S. population suffered from low metabolic rate, but he didn’t really speculate about the possible mechanisms causing this problem. However, I noticed that biologist Ray Peat had been thinking of these issues for decades.
In some of his articles, Peat pointed out that red light has important metabolic effects, and when I started investigating the issue, I found out that red light and near-infrared light have been beneficially used for almost all kinds of diseases – and they have very important pro-metabolic effects. In some cases, it seems that near-infrared light in the form of a “low level laser therapy” could even cure chronic diseases such as clinical hypothyroidism.
The biological effects of red light seemed to explain at least a part of the “low metabolism” epidemic, but there were also alternative explanations I wanted to investigate.
3. Diet, Endotoxin and Inflammation
Many studies showed that “endotoxin” and inflammation could cause disturbations of thyroid hormone metabolism. When I looked more closely at the research, many of the dietary “paradoxes” finally started to make a lot of sense.
When you eat an unbalanced diet high in fat/sugar/alcohol, you get bacterial stuff called “endotoxin” into your bloodstream.
Endotoxin is not very harmful in itself, but it can activate your immune system via a toll-like receptor 4 (TLR4) which is a very important factor behind metabolic syndrome and other chronic diseases.
Many animal studies have shown that inappropriate amounts of junk food increase endotoxin and lead to abdominal obesity and other problems such as high blood pressure and impaired thyroid hormone metabolism. Studies have also shown that you get the same health problems from a sole endotoxin injection, without the junk food.
It seems that the fat/sugar/alcohol we are eating is actually not so harmful. The harm doesn’t come from these macronutrients. It comes from the diet-induced increase in the blood levels of endotoxin and the subsequent immune reaction. There are actually many studies showing that if you reduce endotoxin levels or reduce inflammation, you make rats very resistant to diet-induced obesity and other problems.[2-15]
More on this subject has been written on-site HERE by Andrew Kim.
4. Glycine: The “Miracle Nutrient”
At some point, I found some interesting research articles about glycine which is a “non-essential” amino acid.
There were papers showing that dietary glycine gives a strong protection from endotoxin, and also protects the liver from many kinds of poisons.
But when I looked further, I also found more than two hundred glycine articles showing that this nutrient also protected animals from diabetes, cancer, methionine, ischemia, hemorrhagic shock, hypercholesterolemia, lead and cadmium toxicity, dental caries, gastric ulcers, birth defects, and several other harmful things. In one study, it also significantly increased the lifespan of rats.
But those effects weren’t even the most interesting ones. I got very excited when I saw the astonishing findings of one Mexican research group.
This research group did something quite nasty to their rats. They added 30% sucrose to their water for 20 weeks. Consequently, the rats got a huge amount of calories from their drinking water and thus their food intake decreased by more than fifty percent. That equals a huge decrease in protein, mineral, and vitamin intake as well.
The rats developed full-blown metabolic syndrome in 20 weeks. But then after 20 weeks the researchers also added 1% glycine to the drinking water. In 4 weeks, the sugar-fed rats became almost as healthy as the control group. With glycine, the rats’ blood pressure, fat cells, blood markers and many other things quickly became normalized despite the continued sugar feeding and low nutrient intake.
This result wouldn’t sound even believable to me, if there weren’t a couple of other reports showing similar effects. For example, one study showed that a high-glycine protein source (scallop) prevented the harmful effects of a high-fat, high-sugar diet while other protein sources led to a very significant weight gain:
“In conclusion, intake of scallop muscle as the sole dietary protein source completely prevented high-fat, high-sucrose-induced body mass gain and fat accretion without affecting lean body mass. Furthermore, scallop feeding improved plasma lipid profile in C57BL/6J mice compared to mice fed diets with protein from chicken, cod, or crab. Correlation analyses revealed strong, highly significant inverse correlations between intake of taurine and glycine and body fat mass, as well as strong, highly significant correlations between glycine and especially taurine intake and improved plasma lipid profiles.”[17-20]
These protective effects of glycine seem to be related to the fact that glycine decreases inflammation by hyperpolarizing immune cells via “glycine-gated chloride channels,” preventing an exaggerated, harmful immune response to endotoxin and other stimuli. I have written about this in my own blog.
5. An anti-inflammatory diet
I mostly agree with Matt’s ideas about a healthy diet (outlined in his books such as Diet Recovery 2 or Eat for Heat), but I would personally emphasize the importance of nutrients that protect us from endotoxin and the subsequent immune reaction.
While glycine seems to be the most promising anti-inflammatory nutrient, other nutrients such as antioxidants, fiber, probiotics, carnosine, short-chain fatty acids, zinc and vitamin K1/K2 have been shown to have some similar protective effects. Histidine seems to be an especially healthy nutrient according to a recent double-blind supplementation trial with very impressive results.[21-47]
I suspect that saturated fat is the healthiest type of fat, but I also think that it’s healthy only in the context of an anti-inflammatory diet that includes antioxidants, fiber, or glycine. Without the antioxidants, fiber, or glycine, saturated fat might increase endotoxin and inflammation, and cause health problems.[23,48]
And similarly, the effects of sugar also appear to be very context-dependent. The research I’ve seen suggests that sugar is safe when the diet is high in antioxidants or glycine. Honey is healthier than the sugars it contains.
When we are thinking about the health effects of a single nutrient, I think the context matters a lot.
And this logic applies not only to fat and sugar, but also to protein. Denise Minger has explained that animal protein or methionine can be harmful but mostly on a glycine-deficient diet.
As Ray Peat said, “Context is everything.”
In this article, I’m mostly just scratching the surface of the topic of chronic diseases and metabolic syndrome.
What I’m trying to say, is that most health problems seem to be largely associated with inflammation and low thyroid function. These are the health markers that we should possibly prioritize over others.
When we try to prevent heart disease, we most often focus on only cholesterol levels, ignoring that thyroid function might be much more important. Same with fibromyalgia, in which the focus should probably be on energy metabolism.
When we try to prevent diabetes, obesity or liver cirrhosis, we most often focus on blood sugar regulation or sugar/fat intake, ignoring the role of endotoxin and inflammatory processes, which are the main factors behind those diseases.
Some food for thought.
For the interested ones, here are the slides of my glycine presentation:
Vladimir Heiskanen of Finland has been researching and writing about health for several years. Currently a chemistry student at the University of Helsinki and a blogger since 2010, he has a keen interest in human biology, and has studied scores of books, reports and cutting-edge health websites, especially the work of Chris Masterjohn, Paul Jaminet, and Matt Stone. You can read all of his fascinating articles published at 180D HERE, and his own blog HERE.
Valtsu’s – Fibromyalgia (a draft)
 This has been investigated by a researcher Danilo B. Höfling, in a few studies.
 J Mol Endocrinol. 2013 Sep 11;51(2):R51-64. Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. Neves AL, Coelho J, Couto L, Leite-Moreira A, Roncon-Albuquerque R Jr.
 Diabetes. 2010 Jan;59(1):172-81. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, Tabita-Martinez J, Sellers KF, Rickels MR, Reilly MP.
 J Transl Med. 2012 Jun 18;10:124. A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial. Mehta NN, Heffron SP, Patel PN, Ferguson J, Shah RD, Hinkle CC, Krishnamoorthy P, Shah R, Tabita-Martinez J, Terembula K, Master SR, Rickels MR, Reilly MP.
 Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E740-7. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Creely SJ, McTernan PG, Kusminski CM, Fisher fM, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S.
 Diabetes. 2007 Jul;56(7):1761-72. Metabolic endotoxemia initiates obesity and insulin resistance. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R.
Am J Clin Nutr. 2013 Aug;98(2):349-57. doi: 10.3945/ajcn.112.057331. Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Kavanagh K, Wylie AT, Tucker KL, Hamp TJ, Gharaibeh RZ, Fodor AA, Cullen JM.
 J Nutr. 2008 Aug;138(8):1452-5. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Königsrainer A, Maier KP, Bischoff SC, Bergheim I.
 Diabetes. 2010 Feb;59(2):347-57. doi: 10.2337/db09-0016. Epub 2009 Nov 23. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O’Doherty RM.
 Methods Mol Biol. 2008;447:199-212. doi: 10.1007/978-1-59745-242-7_15. Isolation of Kupffer cells from rats fed chronic ethanol. McMullen MR, Pritchard MT, Nagy LE.
 Diabetes. 2007 Aug;56(8):1986-98. Epub 2007 May 22. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araújo EP, Vassallo J, Curi R, Velloso LA, Saad MJ.
 Hepatology. 1994 Aug;20(2):453-60. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG.
 J Hepatol. 2008 Jun;48(6):983-92. doi: 10.1016/j.jhep.2008.01.035. Epub 2008 Mar 14. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. Bergheim I, Weber S, Vos M, Krämer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC. “Total caloric intake and weight gain were highest in mice exposed to glucose.”
 Gastroenterology. 1995 Jan;108(1):218-24. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Adachi Y1, Moore LE, Bradford BU, Gao W, Thurman RG.
 Diabetes. 2008 Jun;57(6):1470-81. doi: 10.2337/db07-1403. Epub 2008 Feb 27. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R.
 Am J Physiol Regul Integr Comp Physiol. 2004 Dec;287(6):R1387-93. Epub 2004 Aug 26. Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats. El Hafidi M, Pérez I, Zamora J, Soto V, Carvajal-Sandoval G, Baños G.
 Clin Sci (Lond). 2014 Jan 1;126(1):19-29. doi: 10.1042/CS20130164. Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. Ruiz-Ramírez A, Ortiz-Balderas E, Cardozo-Saldaña G, Diaz-Diaz E, El-Hafidi M.
 Amino Acids. 2014 Mar 23. [Epub ahead of print] Scallop protein with endogenous high taurine and glycine content prevents high-fat, high-sucrose-induced obesity and improves plasma lipid profile in male C57BL/6J mice. Tastesen HS, Keenan AH, Madsen L, Kristiansen K, Liaset B.
 Can J Physiol Pharmacol. 2011 Dec;89(12):899-910. doi: 10.1139/y11-086. Epub 2011 Nov 24. Effect of glycine on the cyclooxygenase pathway of the kidney arachidonic acid metabolism in a rat model of metabolic syndrome. Pérez-Torres I1, Ibarra B, Soria-Castro E, Torrico-Lavayen R, Pavón N, Diaz-Diaz E, Flores PL, Infante O, Baños G.
 Cell Biochem Funct. 2004 Mar-Apr;22(2):123-8. Protective effect of glycine supplementation on the levels of lipid peroxidation and antioxidant enzymes in the erythrocyte of rats with alcohol-induced liver injury. Senthilkumar R, Sengottuvelan M, Nalini N
 Am J Clin Nutr. 2010 Apr;91(4):940-9. Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P.
 J Clin Endocrinol Metab. 2011 May;96(5):1409-14. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, Chaudhuri A, Dandona P.
 Endocrine Abstracts (2012) The intake of fiber suppresses the high fat high carbohydrate meal induced endotoxemia, oxidative stress and inflammation H. Ghanim, M. Batra, S. Dhindsa, K. Green, S. Abuaysheh, A. Chaudhuri & P. Dandona
 Br J Nutr. 2009 Apr;101(7):961-6. Probiotic yogurt in the elderly with intestinal bacterial overgrowth: endotoxaemia and innate immune functions. Schiffrin EJ1, Parlesak A, Bode C, Bode JC, van’t Hof MA, Grathwohl D, Guigoz Y.
 Nutrition. 2012 May;28(5):539-43. Probiotic yogurt improves antioxidant status in type 2 diabetic patients. Ejtahed HS1, Mohtadi-Nia J, Homayouni-Rad A, Niafar M, Asghari-Jafarabadi M, Mofid V. “Probiotic yogurt significantly decreased fasting blood glucose (P < 0.01) and hemoglobin A1c (P < 0.05) and increased erythrocyte superoxide dismutase and glutathione peroxidase activities and total antioxidant status (P < 0.05) compared with the control group [conventional yogurt].”
 Ann Nutr Metab. 2013;63(1-2):1-9. Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Asemi Z1, Zare Z, Shakeri H, Sabihi SS, Esmaillzadeh A. “prevented a rise in FPG and resulted in a decrease in serum hs-CRP and an increase in plasma total GSH”
 Iran J Pharm Res. 2013 Fall;12(4):929-36. Probiotic yogurt Affects Pro- and Anti-inflammatory Factors in Patients with Inflammatory Bowel Disease. Shadnoush M, Shaker Hosseini R, Mehrabi Y, Delpisheh A, Alipoor E, Faghfoori Z, Mohammadpour N, Zaringhalam Moghadam J.
 Biochem Biophys Res Commun. 2013 Feb 8;431(2):258-63. Lactobacillus rhamnosus GG improves insulin sensitivity and reduces adiposity in high-fat diet-fed mice through enhancement of adiponectin production. Kim SW, Park KY, Kim B, Kim E, Hyun CK.
 PLoS One. 2014 Jan 27;9(1):e80169. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. Ritze Y1, Bárdos G1, Claus A1, Ehrmann V1, Bergheim I2, Schwiertz A3, Bischoff SC1.
 Am J Pathol. 2011 Dec;179(6):2866-75. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Wang Y1, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ, Feng W.
 J Nutr Biochem. 2013 Sep;24(9):1609-15. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury. Wang Y1, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, Suttles J, McClain C, Feng W.
 World J Gastroenterol. 2013 Jan 14;19(2):274-83. Dual probiotic strains suppress high fructose-induced metabolic syndrome. Park DY, Ahn YT, Huh CS, McGregor RA, Choi MS.
 Diabetologia. 2013 May;56(5):985-94. Histidine supplementation improves insulin resistance through suppressed inflammation in obese women with the metabolic syndrome: a randomised controlled trial. Feng RN, Niu YC, Sun XW, Li Q, Zhao C, Wang C, Guo FC, Sun CH, Li Y.
 Eur J Pharmacol. 2011 Feb 25;653(1-3):82-8. Histidine and carnosine alleviated hepatic steatosis in mice consumed high saturated fat diet. Mong MC1, Chao CY, Yin MC.
 Eur J Pharmacol. 2005 Apr 18;513(1-2):145-50. Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Lee YT, Hsu CC, Lin MH, Liu KS, Yin MC. “1 g/l histidine and carnosine treatments significantly reduced cholesterol level in heart and liver (P < 0.05). The administration of histidine or carnosine significantly enhanced catalase activity and decreased lipid oxidation levels in kidney and liver (P < 0.05); however, only 1 g/l histidine and carnosine treatments significantly increased glutathione peroxidase activity (P < 0.05). The increased interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in diabetic mice were significantly suppressed by the intake of histidine or carnosine (P < 0.05).”
 Food Chem Toxicol. 2008 May;46(5):1503-9. Beneficial effects of histidine and carnosine on ethanol-induced chronic liver injury. Liu WH, Liu TC, Yin MC.
 J Food Sci. 2009 Oct;74(8):H259-65. Protective effects from carnosine and histidine on acetaminophen-induced liver injury. Yan SL, Wu ST, Yin MC, Chen HT, Chen HC.
 Tohoku J Exp Med. 2000 Jun;191(2):85-99. Effect of carnosine on rats under experimental brain ischemia. Gallant S, Kukley M, Stvolinsky S, Bulygina E, Boldyrev A.
 Nutr Res Pract. 2011 Oct;5(5):421-8. Effects of α-lipoic acid and L-carnosine supplementation on antioxidant activities and lipid profiles in rats. Kim MY1, Kim EJ, Kim YN, Choi C, Lee BH.
 PLoS One. 2011 Mar 15;6(3):e17971. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, Canzoniero LM, Ciavardelli D, Rizzarelli E, Sensi SL.
 J Physiol Biochem. 2014 Jun;70(2):385-95. Effect of carnosine alone or combined with α-tocopherol on hepatic steatosis and oxidative stress in fructose-induced insulin-resistant rats. Giriş M, Doğru-Abbasoğlu S, Kumral A, Olgaç V, Koçak-Toker N, Uysal M.
 Diabetes. 2009 Jul;58(7):1509-17. doi: 10.2337/db08-1637. Epub 2009 Apr 14. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. “On the high-fat diet, supplementation of butyrate prevented development of insulin resistance and obesity in C57BL/6 mice.”
 Am J Pathol. 2004 May;164(5):1547-56. Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. Zhou Z, Wang L, Song Z, Saari JT, McClain CJ, Kang YJ.
 J Pharmacol Exp Ther. 2003 Jun;305(3):880-6. Epub 2003 Mar 6. Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice. Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ.
 Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):7003-8. Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Kaliannan K, Hamarneh SR, Economopoulos KP, Nasrin Alam S, Moaven O, Patel P, Malo NS, Ray M, Abtahi SM, Muhammad N, Raychowdhury A, Teshager A, Mohamed MM, Moss AK, Ahmed R, Hakimian S, Narisawa S, Millán JL, Hohmann E, Warren HS, Bhan AK, Malo MS, Hodin RA.
 J Nutr Sci Vitaminol (Tokyo). 2007 Jun;53(3):219-24. Enhancement effects of vitamin K1 (phylloquinone) or vitamin K2 (menaquinone-4) on intestinal alkaline phosphatase activity in rats. Sogabe N1, Maruyama R, Hosori T, Goseki-Sone M.
 Bone. 2011 May 1;48(5):1036-42. Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats. Sogabe N1, Maruyama R, Baba O, Hosoi T, Goseki-Sone M.
 Int J Environ Res Public Health. 2009 Oct;6(10):2626-38. Food choices and coronary heart disease: a population based cohort study of rural Swedish men with 12 years of follow-up. Holmberg S, Thelin A, Stiernström EL.
 J Nutr. 2002 Nov;132(11):3379-82. Substituting honey for refined carbohydrates protects rats from hypertriglyceridemic and prooxidative effects of fructose. Busserolles J, Gueux E, Rock E, Mazur A, Rayssiguier Y.
Extra references (lots of very useful literature)
[extra] Bol Med Hosp Infant Mex Vol. 67, March-April 2010 Obesity as an inflammatory process. Blancas-Flores G, Almanza-Pérez JC, López-Roa RI, Alarcón-Aguilar FJ, García-Macedo R, Cruz M.
[extra] Diabetes Care. 2011 Aug;34(8):1809-15. doi: 10.2337/dc10-2197. Epub 2011 Jun 2. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Lassenius MI, Pietiläinen KH, Kaartinen K, Pussinen PJ, Syrjänen J, Forsblom C, Pörsti I, Rissanen A, Kaprio J, Mustonen J, Groop PH, Lehto M; FinnDiane Study Group.
[extra] Dig Dis Sci. 2012 Jul;57(7):1932-41. doi: 10.1007/s10620-012-2112-9. Epub 2012 Mar 17. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Volynets V, Küper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, Königsrainer A, Bischoff SC, Bergheim I. “Despite no differences in the prevalence of bacterial overgrowth and in the orocecal transit time, intestinal permeability, alcohol, and endotoxin levels in plasma were significantly higher in patients with NAFLD than in controls.”
[extra] Surgery. 2012 Apr;151(4):587-93. doi: 10.1016/j.surg.2011.09.038. Epub 2011 Nov 16. Reduction in endotoxemia, oxidative and inflammatory stress, and insulin resistance after Roux-en-Y gastric bypass surgery in patients with morbid obesity and type 2 diabetes mellitus. Monte SV, Caruana JA, Ghanim H, Sia CL, Korzeniewski K, Schentag JJ, Dandona P. “LPS, NF-κB DNA binding, TLR-4, TLR-2, and CD14 expression, CRP, MMP-9, and MCP-1 decreased significantly after RYGB. The mechanism underlying resolution of insulin resistance and T2DM after RYGB may be attributable, at least in part, to the reduction of endotoxemia and associated proinflammatory mediators.”
[extra] 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. “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.”
[extra] Diabetes Care. 2009 Dec;32(12):2281-7. doi: 10.2337/dc09-0979. Epub 2009 Sep 15. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Ghanim H1, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, Dandona P. “HFHC meal intake induced an increase in plasma LPS concentration and the expression of SOCS-3, TLR2, and TLR4 protein, reactive oxygen species generation, and nuclear factor-kappaB binding activity (P < 0.05 for all). These increases were totally absent after the AHA meal rich in fiber and fruit.”
[extra] Am J Clin Nutr. 2007 Nov;86(5):1286-92. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Erridge C, Attina T, Spickett CM, Webb DJ. “Baseline endotoxin concentrations were 8.2 pg/mL (interquartile range: 3.4-13.5 pg/mL) but increased significantly (P < 0.05) by approximately 50% after a high-fat meal or after a high-fat meal with cigarettes but not after no meal or cigarettes alone. These results were validated by the observations that a high-fat meal with or without cigarettes, but not no meal or smoking, also significantly (P < 0.05) reduced plasma endotoxin neutralization capacity, which is an indirect measure of endotoxin exposure”
[extra] Diabetes Care. 2010 May;33(5):991-7. doi: 10.2337/dc09-1630. Epub 2010 Jan 12. Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan P, Chaudhuri A, Dandona P. “Although both glucose and cream induce NF-kappaB binding and an increase in the expression of SOCS3, TNF-alpha, and IL-1beta in MNCs, only cream caused an increase in LPS concentration and TLR-4 expression. Equicaloric amounts of orange juice or water did not induce a change in any of these indexes. These changes are relevant to the pathogenesis of atherosclerosis and insulin resistance.”
[extra] Diabetes. 2012 Jun;61(6):1455-62. doi: 10.2337/db11-0390. Epub 2012 Apr 20. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB, Caricilli AM, Torsoni MA, Prada PO, Saad MJ, Velloso LA. “Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR)4 or tumor necrosis factor (TNF)α, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNFα reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production”
[extra] PLoS One. 2014 May 14;9(5):e96864. doi: 10.1371/journal.pone.0096864. eCollection 2014. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. Bala S, Marcos M, Gattu A, Catalano D, Szabo G.
[extra] Am J Gastroenterol. 2002 Sep;97(9):2364-70. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Bauer TM, Schwacha H, Steinbrückner B, Brinkmann FE, Ditzen AK, Aponte JJ, Pelz K, Berger D, Kist M, Blum HE.
[extra] Diabetes Care. 2011 Feb;34(2):392-7. doi: 10.2337/dc10-1676. Endotoxemia is associated with an increased risk of incident diabetes. Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V.
[extra] Nutr Metab (Lond). 2013 Jan 10;10(1):6. Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Mani V, Hollis JH, Gabler NK.
[extra] Exp Physiol. 2014 Jun 27. [Epub ahead of print] Fructose supplementation worsens the deleterious effects of short term high fat feeding on hepatic steatosis and lipid metabolism in adult rats. Crescenzo R, Bianco F, Coppola P, Mazzoli A, Tussellino M, Carotenuto R, Liverini G, Iossa S.
[extra] Alcohol Clin Exp Res. 2012 May;36(5):835-46. doi: 10.1111/j.1530-0277.2011.01673.x. Epub 2011 Dec 7. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Kirpich IA, Feng W, Wang Y, Liu Y, Barker DF, Barve SS, McClain CJ. “Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group.”
[extra] J Neurochem. 2007 May;101(3):729-36. Epub 2007 Jan 24. Neuroprotective actions of a histidine analogue in models of ischemic stroke. Tang SC, Arumugam TV, Cutler RG, Jo DG, Magnus T, Chan SL, Mughal MR, Telljohann RS, Nassar M, Ouyang X, Calderan A, Ruzza P, Guiotto A, Mattson MP. “We recently synthesized and characterized histidine analogues related to the natural dipeptide carnosine, which selectively scavenge the toxic lipid peroxidation product 4-hydroxynonenal (HNE)[...]”
[extra] Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1162-70. doi: 10.1161/ATVBAHA.112.300572. Epub 2013 Apr 4. Dietary carnosine prevents early atherosclerotic lesion formation in apolipoprotein E-null mice. Barski OA, Xie Z, Baba SP, Sithu SD, Agarwal A, Cai J, Bhatnagar A, Srivastava S.
[extra] Br J Pharmacol. 2012 Jun;166(4):1344-56. doi: 10.1111/j.1476-5381.2012.01834.x. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Menini S, Iacobini C, Ricci C, Scipioni A, Blasetti Fantauzzi C, Giaccari A, Salomone E, Canevotti R, Lapolla A, Orioli M, Aldini G, Pugliese G.
[extra] Gastroenterology. 2009 Feb;136(2):564-74.e2. doi: 10.1053/j.gastro.2008.09.062. Epub 2008 Oct 7. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T.
[extra] Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1095-104. Epub 2007 Jan 12. Protective effect of orally administered carnosine on bleomycin-induced lung injury. Cuzzocrea S, Genovese T, Failla M, Vecchio G, Fruciano M, Mazzon E, Di Paola R, Muià C, La Rosa C, Crimi N, Rizzarelli E, Vancheri C.
[extra] Diabetes. 2013 Jul;62(7):2266-77. doi: 10.2337/db12-1701. Epub 2013 Mar 8. Histidine augments the suppression of hepatic glucose production by central insulin action. Kimura K1, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara S, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H.
[extra] Hum Exp Toxicol. 2010 Aug;29(8):659-65. The effect of carnosine pretreatment on oxidative stress and hepatotoxicity in binge ethanol administered rats. Artun BC, Küskü-Kiraz Z, Güllüoğlu M, Cevikbaş U, Koçak-Toker N, Uysal M. “In conclusion, carnosine prevented the increases in serum transaminase activities and lipid peroxides in liver of ethanol-treated rats, without any change on steatosis in liver.”
[extra] Neurosci Lett. 2012 Feb 21;510(1):1-5. Effects of L-carnosine on splenic sympathetic nerve activity and tumor proliferation. Horii Y, Shen J, Fujisaki Y, Yoshida K, Nagai K. “The tumor volumes of the control mice given water gradually and markedly increased and reached a value of 869.8 ± 132.9 mm3 on day 22 after implantation (Fig. 3b). The tumor volumes of the l-carnosine group also increased; however, the increase was less than that of the control group, reaching a value of 407.8 ± 121.7 mm3 (46.9% of the tumor volume of the control group) on day 22.”
[extra] Nutr Clin Pract. 2013 Oct;28(5):609-16. doi: 10.1177/0884533613493333. Epub 2013 Jul 8. Effects of L-carnosine and its zinc complex (Polaprezinc) on pressure ulcer healing. Sakae K, Agata T, Kamide R, Yanagisawa H. “After 4 weeks, the rate of pressure ulcer healing, assessed by the mean weekly improvement in PUSH score, was significantly greater in the CAR (1.6 ± 0.2, P = .02) and PLZ groups (1.8 ± 0.2, P = .009) than in the control group (0.8 ± 0.2).”
[extra] Intern Med. 2011;50(15):1569-74. Inflammatory cytokines, adiponectin, insulin resistance and metabolic control after periodontal intervention in patients with type 2 diabetes and chronic periodontitis. Sun WL, Chen LL, Zhang SZ, Wu YM, Ren YZ, Qin GM.
[extra] J Clin Periodontol. 2010 Jan;37(1):53-8. Effect of periodontal treatment on metabolic control, systemic inflammation and cytokines in patients with type 2 diabetes. Correa FO1, Gonçalves D, Figueredo CM, Bastos AS, Gustafsson A, Orrico SR.
[extra] FEBS Letters Volume 581, Issue 3, 6 February 2007, Pages 349–354: Augmentation of 11β-hydroxysteroid dehydrogenase type 1 in LPS-activated J774.1 macrophages – Role of 11β-HSD1 in pro-inflammatory properties in macrophages Takako Ishii, Hiroaki Masuzaki, Tomohiro Tanaka, Naoki Arai, Shintaro Yasue, Nozomi Kobayashi, Tsutomu Tomita, Michio Noguchi, Junji Fujikura, Ken Ebihara, Kiminori Hosoda, Kazuwa Nakao
[extra] J Neurochem. 2012 Mar;120(6):1060-71. doi: 10.1111/j.1471-4159.2012.07660.x. Epub 2012 Feb 6. Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. Gupta S, Knight AG, Gupta S, Keller JN, Bruce-Keller AJ. “Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFα and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. [...] Finally, data show that the essential ω-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro.“
[extra] J Neurosci. 2009 Jan 14;29(2):359-70. doi: 10.1523/JNEUROSCI.2760-08.2009. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R, Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA. “According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity”
[extra] Endocrinology. 2011 Apr;152(4):1314-26. doi: 10.1210/en.2010-0659. Epub 2011 Jan 25. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho DP, Carvalheira JB, Velloso LA. “In Wistar rats, hypothalamic TNFα blunts the anorexigenic effect of leptin, which is accompanied by reduced leptin signaling and increased expression of suppressor of cytokine signaling 3. In addition, hypothalamic TNFα reduces O(2) consumption and the expression of thermogenic proteins in brown adipose tissue and skeletal muscle. Furthermore, hypothalamic inflammation increases base-line plasma insulin and insulin secretion by isolated pancreatic islets, which is accompanied by an impaired insulin signal transduction in liver and skeletal muscle. Hypothalamic inflammation induced by stearic acid also reduces O(2) consumption and blunts peripheral insulin signal transduction. The use of intracerebroventricular infliximab restores O(2) consumption in obese rats, whereas TNF receptor 1-knockout mice are protected from diet-induced reduced thermogenesis and defective insulin signal transduction. Thus, low-grade inflammation of the hypothalamus is sufficient to induce changes in a number of parameters commonly impaired in obesity and DM2, and TNFα is an important mediator of this process.”
[extra] J Biol Chem. 2009 Dec 25;284(52):36213-22. doi: 10.1074/jbc.M109.030874. Epub 2009 Oct 26. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. Romanatto T1, Roman EA, Arruda AP, Denis RG, Solon C, Milanski M, Moraes JC, Bonfleur ML, Degasperi GR, Picardi PK, Hirabara S, Boschero AC, Curi R, Velloso LA.
[extra] Br J Nutr. 2012 Jan;107(2):229-41. doi: 10.1017/S0007114511002868. Epub 2011 Jun 29. Saturated fatty acids activate microglia via Toll-like receptor 4/NF-κB signalling. Wang Z, Liu D, Wang F, Liu S, Zhao S, Ling EA, Hao A.
[extra] J Biol Chem. 2001 May 18;276(20):16683-9. Epub 2001 Mar 2. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. Lee JY, Sohn KH, Rhee SH, Hwang D.
[extra] vDiabetologia. 2007 Jun;50(6):1267-76. Epub 2007 Apr 11. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC.
[extra] Obesity (Silver Spring). 2008 Jun;16(6):1248-55. doi: 10.1038/oby.2008.210. Epub 2008 Apr 10. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Davis JE1, Gabler NK, Walker-Daniels J, Spurlock ME.
[extra] J Nutr Biochem. 2011 Feb;22(2):136-41. doi: 10.1016/j.jnutbio.2009.12.008. Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. Davis JE, Braucher DR, Walker-Daniels J, Spurlock ME.
[extra] Cell Metab. 2009 Oct;10(4):249-59. doi: 10.1016/j.cmet.2009.08.013. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Brüning JC.
[extra] Circ Res. 2007 Jun 8;100(11):1589-96. Epub 2007 May 3. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Kim F1, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW.
[extra] FASEB J. 2012 Aug;26(8):3493-502. doi: 10.1096/fj.12-208868. Epub 2012 May 16. Timed high-fat diet resets circadian metabolism and prevents obesity. Sherman H, Genzer Y, Cohen R, Chapnik N, Madar Z, Froy O. “Although timed HF-diet-fed mice consumed the same amount of calories as ad libitum low-fat diet-fed mice, they showed 12% reduced body weight, 21% reduced cholesterol levels, and 1.4-fold increased insulin sensitivity. Compared with the HF diet ad libitum, the timed HF diet led to 18% lower body weight, 30% decreased cholesterol levels, 10% reduced TNF-α levels, and 3.7-fold improved insulin sensitivity. Timed HF-diet-fed mice exhibited a better satiated and less stressed phenotype of 25% lower ghrelin and 53% lower corticosterone levels compared with mice fed the timed low-fat diet.”
[extra] FASEB J. 2010 Dec;24(12):4948-59. doi: 10.1096/fj.10-164921. Epub 2010 Aug 19. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. Rabot S, Membrez M, Bruneau A, Gérard P, Harach T, Moser M, Raymond F, Mansourian R, Chou CJ.
[extra] PLoS One. 2010 Aug 16;5(8):e12191. doi: 10.1371/journal.pone.0012191. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. Ding S, Chi MM, Scull BP, Rigby R, Schwerbrock NM, Magness S, Jobin C, Lund PK. “Bacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.”
[extra] Atherosclerosis. 2011 May;216(1):1-6. doi: 10.1016/j.atherosclerosis.2011.02.043. Epub 2011 Feb 26. Diet, commensals and the intestine as sources of pathogen-associated molecular patterns in atherosclerosis, type 2 diabetes and non-alcoholic fatty liver disease. Erridge C. “This review summarises the evidence supporting the proposal that ‘pathogen-associated molecular patterns’ (PAMPs) derived from dietary and commensal sources may contribute to the chronic inflammatory processes that underpin the development of these diseases via stimulation of TLR2 and TLR4.”
[extra] Metabolism. 2006 Sep;55(9):1177-85. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Aljada A, Friedman J, Ghanim H, Mohanty P, Hofmeyer D, Chaudhuri A, Dandona P.
[extra] Diabetologia. 2007 Feb;50(2):278-85. Epub 2006 Dec 16. Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects. Ghanim H, Aljada A, Daoud N, Deopurkar R, Chaudhuri A, Dandona P. “We conclude that in obesity the MNC is characterised by reduced p-INSR-beta and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-beta and might mediate the inhibition of p-INSR-beta.”
[extra] Gut. 2012 Dec;61(12):1701-7. doi: 10.1136/gutjnl-2011-301689. Epub 2012 Apr 25. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Caesar R1, Reigstad CS, Bäckhed HK, Reinhardt C, Ketonen M, Lundén GÖ, Cani PD, Bäckhed F.
[extra] FASEB J. 2008 Jul;22(7):2416-26. doi: 10.1096/fj.07-102723. Epub 2008 Mar 7. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, Corthesy I, Macé K, Chou CJ.
[extra] PLoS One. 2012;7(3):e32967. doi: 10.1371/journal.pone.0032967. Epub 2012 Mar 7. Leptin resistance in vagal afferent neurons inhibits cholecystokinin signaling and satiation in diet induced obese rats. de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE.
[extra] MBio. 2014 Jun 10;5(3). pii: e01011-14. doi: 10.1128/mBio.01011-14. Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice. Everard A, Matamoros S, Geurts L, Delzenne NM, Cani PD.
[extra] Diabetes Metab Syndr Obes. 2012;5:175-89. doi: 10.2147/DMSO.S33473. Epub 2012 Jul 6. Comparison with ancestral diets suggests dense acellular carbohydrates promote an inflammatory microbiota, and may be the primary dietary cause of leptin resistance and obesity. Spreadbury I.
[extra] Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):84-91. Epub 2006 Nov 2. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. “These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappaB activation.”
[extra] Cell. 2011 Nov 11;147(4):868-80. doi: 10.1016/j.cell.2011.09.051. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC. “These data establish that upon microbial detection, an upstream PRR (CD14) controls the trafficking and signaling functions of a downstream PRR (TLR4).”
[extra] Ann Surg. 2003 Feb;237(2):246-55. Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. Kono H, Fujii H, Asakawa M, Yamamoto M, Matsuda M, Maki A, Matsumoto Y. “All rats given corn oil died after LPS administration; however, this mortality was prevented by MCT in a dose-dependent manner. Rats given corn oil showed liver injury after LPS administration. In contrast, MCT prevented this pathologic change nearly completely. MCT blunted CD14 expression on the Kupffer cells and TNF-alpha production by isolated Kupffer cells; however, there were no differences in phagocytic index between the two groups. The length of the intestinal epithelium was increased in the MCT group compared to the corn oil group. Further, after LPS administration, increases in gut permeability and injury were prevented by MCT. Importantly, MCT also prevented hepatic energy charge and gut injuries in this condition.”
[extra] Am J Physiol Gastrointest Liver Physiol. 2013 Dec;305(12):G919-32. doi: 10.1152/ajpgi.00226.2013. Epub 2013 Oct 10. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Zhong W, Li Q, Xie G, Sun X, Tan X, Sun X, Jia W, Zhou Z.
[extra] J Gastroenterol. 2013 Aug 17. Toll-like receptor 4 activation in Barrett’s esophagus results in a strong increase in COX-2 expression. Verbeek RE, Siersema PD, Ten Kate FJ, Fluiter K, Souza RF, Vleggaar FP, Bus P, van Baal JW.
[extra] Gastroenterology. 2006 Sep;131(3):862-77. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Fukata M, Chen A, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, Xu R, Inoue H, Arditi M, Dannenberg AJ, Abreu MT.
[extra] J Leukoc Biol. 2009 Oct;86(4):971-80. doi: 10.1189/jlb.0708396. Epub 2009 Jun 29. TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage. Moses T, Wagner L, Fleming SD.
[extra] BMC Gastroenterol. 2010 Jul 16;10:82. doi: 10.1186/1471-230X-10-82. The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia. Hernandez Y, Sotolongo J, Breglio K, Conduah D, Chen A, Xu R, Hsu D, Ungaro R, Hayes LA, Pastorini C, Abreu MT, Fukata M.
[extra] Inflamm Bowel Dis. 2011 Jul;17(7):1464-73. Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Fukata M1, Shang L, Santaolalla R, Sotolongo J, Pastorini C, España C, Ungaro R, Harpaz N, Cooper HS, Elson G, Kosco-Vilbois M, Zaias J, Perez MT, Mayer L, Vamadevan AS, Lira SA, Abreu MT.
[extra] J Immunol. 2009 Feb 15;182(4):2476-84. doi: 10.4049/jimmunol.0802059. Lactate boosts TLR4 signaling and NF-kappaB pathway-mediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. Samuvel DJ1, Sundararaj KP, Nareika A, Lopes-Virella MF, Huang Y.
[extra] J Neurosci. 2010 Jun 16;30(24):8285-95. doi: 10.1523/JNEUROSCI.0976-10.2010. Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage. Alfonso-Loeches S, Pascual-Lucas M, Blanco AM, Sanchez-Vera I, Guerri C.
[extra] Front Cell Neurosci. 2014 May 27;8:146. doi: 10.3389/fncel.2014.00146. eCollection 2014. TLR4-mediated brain inflammation halts neurogenesis: impact of hormonal replacement therapy. Mouihate A. “These data strongly suggest that combined 17β-estradiol and progesterone, and not 17β-estradiol alone, rescues neurogenesis from the deleterious effect of brain inflammation likely via the inhibition of the signaling pathways leading to the activation of proinflammatory genes.”
[extra] Wiad Lek. 2013;66(1):3-9. [The role of TLR4 receptor in development of inflammation and carcinogenesis in ulcerative colitis and pharmacotherapy of this disorder]. [Article in Polish] Szumilas D1, Krysiak R, Okopień B. “The increased expression of TLR4 and the development of the uncontrolled inflammatory response in UC (increased production of COX-2, PGE2, TNFalpha and CCL2) impairs regeneration of the mucosa, resulting in its damage, and may later lead to the development of colon cancer.”
[extra] AAPS J. 2014 Mar;16(2):246-57. doi: 10.1208/s12248-013-9558-3. Epub 2014 Jan 15. Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-κB signaling by 6-shogaol. Zhou L, Qi L, Jiang L, Zhou P, Ma J, Xu X, Li P. “Overall, our results suggest that 6-shogaol can inhibit the growth of human pancreatic tumors and sensitize them to gemcitabine by suppressing of TLR4/NF-κB-mediated inflammatory pathways linked to tumorigenesis.”
[extra] Inflammation. 2014 Apr;37(2):467-77. doi: 10.1007/s10753-013-9760-6. Saturated fatty acids up-regulate COX-2 expression in prostate epithelial cells via toll-like receptor 4/NF-κB signaling. Liu J, Hu S, Cui Y, Sun MK, Xie F, Zhang Q, Jin J.
[extra] Biochem Biophys Res Commun. 2013 Aug 23;438(2):249-56. doi: 10.1016/j.bbrc.2013.07.006. Epub 2013 Jul 11. Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies. Kirkby NS, Zaiss AK, Wright WR, Jiao J, Chan MV, Warner TD, Herschman HR, Mitchell JA. “LPS induced Cox2 expression in all tissues examined. In contrast, poly(I:C) elicited a milder response, limited to a subset of tissues.”
[extra] J Dent Res. 2009 Jun;88(6):519-23. doi: 10.1177/0022034509338353. Is obesity an oral bacterial disease? Goodson JM, Groppo D, Halem S, Carpino E. “Classification tree analysis of salivary microbiological composition revealed that 98.4% of the overweight women could be identified by the presence of a single bacterial species (Selenomonas noxia) at levels greater than 1.05% of the total salivary bacteria.”
[extra] Aging Cell. 2013 Dec;12(6):1041-9. doi: 10.1111/acel.12133. Epub 2013 Aug 20. The phytochemical, EGCG, extends lifespan by reducing liver and kidney function damage and improving age-associated inflammation and oxidative stress in healthy rats. Niu Y, Na L, Feng R, Gong L, Zhao Y, Li Q, Li Y, Sun C.
[extra] Biochem Biophys Res Commun. 2012 Oct 5;426(4):480-5. doi: 10.1016/j.bbrc.2012.08.096. Epub 2012 Aug 29. Green tea polyphenol epigallocatechin-3-gallate inhibits TLR4 signaling through the 67-kDa laminin receptor on lipopolysaccharide-stimulated dendritic cells. Byun EB, Choi HG, Sung NY, Byun EH.
[extra] J Immunol. 2010 Jul 1;185(1):33-45. doi: 10.4049/jimmunol.0903742. Epub 2010 May 28. TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. Hong Byun E1, Fujimura Y, Yamada K, Tachibana H.
[extra] Mediators Inflamm. 2009;2009:704706. doi: 10.1155/2009/704706. Epub 2010 Feb 16. Oxymatrine downregulates TLR4, TLR2, MyD88, and NF-kappaB and protects rat brains against focal ischemia. Fan H, Li L, Zhang X, Liu Y, Yang C, Yang Y, Yin J. “The excessive inflammatory immune reaction often resides in region of necrosis and ischemic tissue after cerebral infarction and leads to inflammatory injury. The relationship between toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), and nonbiological inflammatory injury has been proved [1–3]. It is believed that injured tissue and necrotic cells release endogenous activators (adjuvants). These activators can combine with TLR4 in the cell membrane. [...] An excessive inflammatory reaction can also damage target cells and tissue [4, 5]. Reducing the inflammatory injury is therefore regarded to be one of major ways to treat acute cerebral infarction.”
[extra] Stroke. 2013 Jan;44(1):205-12. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A. “In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity.”
[extra] Rejuvenation Res. 2008 Feb;11(1):201-14. doi: 10.1089/rej.2007.0608. Dietary supplementation exerts neuroprotective effects in ischemic stroke model. Yasuhara T, Hara K, Maki M, Masuda T, Sanberg CD, Sanberg PR, Bickford PC, Borlongan CV.
[extra] Cardiovasc Res. 2004 Feb 15;61(3):538-47. Modulating Toll-like receptor mediated signaling by (1–>3)-beta-D-glucan rapidly induces cardioprotection. Li C, Ha T, Kelley J, Gao X, Qiu Y, Kao RL, Browder W, Williams DL. “GP treatment reduced infarct size by 47% in rat hearts subjected to reperfusion for 4 h”
[extra] J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Epub 2007 Aug 14. Association between hypothyroidism and small intestinal bacterial overgrowth. Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A.
[extra] Gut. 2007 Feb;56(2):168-75. Epub 2006 Jun 15. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Mahmood A, FitzGerald AJ, Marchbank T, Ntatsaki E, Murray D, Ghosh S, Playford RJ.
[extra] J Clin Biochem Nutr. 2010 May;46(3):234-43. doi: 10.3164/jcbn.09-125. Epub 2010 Apr 10. Polaprezinc Protects Mice against Endotoxin Shock. Ohata S, Moriyama C, Yamashita A, Nishida T, Kusumoto C, Mochida S, Minami Y, Nakada J, Shomori K, Inagaki Y, Ohta Y, Matsura T. “PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-alpha after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury.”
[extra] ISME J. 2013 Apr;7(4):880-4. doi: 10.1038/ismej.2012.153. Epub 2012 Dec 13. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. Fei N, Zhao L.
[extra] J Am Coll Cardiol. 1999 Dec;34(7):1975-81. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. Wiedermann CJ1, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J. “Median endotoxin concentration amounted to 14.3 pg/ml (range, 6.0 to 209.2 pg/ml). Subjects with levels beyond 50 pg/ml (90th percentile) faced a threefold risk of incident atherosclerosis (odds ratio [95% confidence interval] 2.9 [1.4-6.3]; p < 0.01). The risk associated with high endotoxin was most pronounced in subjects with chronic infections and in current and ex-smokers.”
[extra] Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2227-36. Epub 2004 Oct 7. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Stoll LL, Denning GM, Weintraub NL. “In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways.”
[extra] Metab Brain Dis. 2014 Mar;29(1):19-36. doi: 10.1007/s11011-013-9435-x. Epub 2013 Sep 10. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Morris G, Maes M. “Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways.”