Metabolic Endotoxemia The Link Between Obesity And Metabolic Disease?

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Wei Perng, PhD

In parallel with the childhood obesity epidemic, chronic metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are on the rise among youth worldwide, with a staggering 18.5% prevalence of one of these conditions among adolescents and young adults in the U.S. While the behavioral and biological causes are complex and multifaceted, a “Western diet” high in refined carbohydrates and unhealthy fats is recognized as a key behavioral risk factor. One biological mechanism linking a Western diet to obesity and obesity-related conditions is metabolic endotoxemia, or the translocation of the gut-derived endotoxin bacterium lipopolysaccharide (LPS) and its binding protein, LPS binding protein (LBP), in blood. In short, this happens when bacteria (or parts of bacteria) move from the inside of the intestine into the bloodstream where they do not belong. The presence of the endotoxin bacterium in the bloodstream is concerning because it results in insulin resistance, causes inflammation, and can alter how the body handles fat or lipids.

​What we know. In adults, research links long-term endotoxin exposure to development of T2D, cardiovascular disease, and NAFLD. A few studies have examined these associations during childhood or adolescence, two important life stages for development of cardiovascular and metabolic diseases. Current understanding of endotoxin and cardiometabolic risk in youth comes from small studies (n<100) and focus on LPS in relation to NAFLD and/or obesity. For example, in a study of 51 Chinese adolescents, Yuan et al. 2014 reported higher serum LPS among youth with non-alcoholic steatohepatitis (NASH, an advanced form of NAFLD increases inflammation and is likely to cause liver scarring) or obesity as compared to youth with normal weight. Studies in German (n=49) and Italian (n=49) children found higher serum LPS in participants with NAFLD as compared to their healthy counterparts. Similarly, studies in Hispanic adolescents with obesity observed higher LPS among participants with vs. without NAFLD, and noted positive correlations among serum LPS, body mass index (BMI), triglycerides, and waist circumference. While these findings suggest that endotoxin exposure is related to the development of obesity and related conditions, most studies took place at a single point in time, leaving it uncertain as to whether elevated endotoxin is a cause or consequence of these health problems. Moreover, it’s hard to measure LPS and LBP; most measures that we have likely measure only short- rather than long-term exposure, meaning that we might be overinterpreting these measures in the above studies.
What we need to find out. First, we need to learn more about whether endotoxin exposure comes before the development of weight gain, obesity and cardiometabolic risk in youth. Additionally, chronic metabolic diseases like T2D and NAFLD progress silently and are notoriously difficult to reverse once established. Therefore, prevention of these conditions is of monumental importance. Some particularly promising targets for prevention include treatment and reversal of maternal overweight/obesity, gestational weight gain and gestational diabetes; these are established risk factors of metabolic risk in children and may also contribute to metabolic endotoxemia in offspring. Addressing these issues are likely to have the great effect on children’s health. However, there may be opportunities to address high endotoxin levels, such as changing the gut microbiome, if these prove to be a causal factor in metabolic disease. Hopefully there will be more to come on this soon!