Gut Microbiota, Lipopolysaccharides, and Innate Immunity in the Pathogenesis of Obesity and Cardiovascular Risk

Abstract

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.

The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study

“…25 In animal models lowgrade 'metabolic' endotoxemia has been described as a key factor in weight gain, insulin resistance and low-grade inflammation. 26 However, in our study we could not detect endotoxin in peripheral blood of any of the patients with MetS although we used an optimized endotoxin test. 27 The reason why we could not detect endotoxin in the serum of our subjects could be that the metabolic and inflammatory processes of MetS were not advanced enough in our patient cohort to cause detectable endotoxin levels in the circulation.…”

Lipopolysaccharide binding protein, obesity status and incidence of metabolic syndrome: a prospective study among middle-aged and older Chinese

“…Likewise, a recent cross-sectional study in 420 Spanish individuals also indicated that higher LBP was associated with MetS and its components, including central obesity and low HDL-cholesterol [12]. However, the cross-sectional nature of previous studies could lead to reverse causation, since common symptoms of MetS may also alter gastrointestinal conditions and promote occurrence of subclinical endotoxaemia [10,11]. With a prospective design, our current analyses provided stronger evidence to support the putative contributions of endotoxaemia to the development of metabolic abnormalities.…”

“…On the other hand, the components of MetS, such as hypertriacylglycerolaemia, hyperglycaemia and hyperinsulinaemia, have been hypothesised to contribute to endotoxaemia through altering jejunal motility and gastrointestinal transit time, conditions that may favour bacterial overgrowth and leak endotoxins into the intestinal mucosa [10,11]. Whether endotoxaemia predisposes to the onset of metabolic deterioration in free-living populations remains to be elucidated.…”

The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood

“…This phenomenon, which extends to perinatal and postnatal age, is known as disease programming during the development phase (46). Indeed, it is known that the gut microbiota has an effect on the individual risk to develop diseases in adulthood, especially in case of cardiovascular diseases, as a result of weight gain, fat accumulation, and maintenance of a basic mild inflammation condition (47). In addition, epidemiological studies on human populations have shown some associations between neurological development Figure 2.…”