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.
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 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.
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.
The ISME Journal advance online publication 13 December 2012
An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice
Na Fei and Liping Zhao
Lipopolysaccharide endotoxin is the only known bacterial product which, when subcutaneously infused into mice in its purified form, can induce obesity and insulin resistance via an inflammation-mediated pathway. Here we show that one endotoxin-producing bacterium isolated from a morbidly obese human’s gut induced obesity and insulin resistance in germfree mice. The endotoxin-producing Enterobacter decreased in relative abundance from 35% of the volunteer’s gut bacteria to non-detectable, during which time the volunteer lost 51.4 kg of 174.8 kg initial weight and recovered from hyperglycemia and hypertension after 23 weeks on a diet of whole grains, traditional Chinese medicinal foods and prebiotics. A decreased abundance of endotoxin biosynthetic genes in the gut of the volunteer was correlated with a decreased circulating endotoxin load and alleviated inflammation. Mono-association of germfree C57BL/6J mice with strain Enterobacter cloacae B29 isolated from the volunteer’s gut induced fully developed obesity and insulin resistance on a high-fat diet but not on normal chow diet, whereas the germfree control mice on a high-fat diet did not exhibit the same disease phenotypes. The Enterobacter-induced obese mice showed increased serum endotoxin load and aggravated inflammatory conditions. The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.