Abstract
An intact intestinal barrier, representing the interface between inner and outer environments, is an integral regulator of health. Among several factors, bacteria and their products have been evidenced to contribute to gut barrier impairment and its increased permeability. Alterations of tight junction integrity - caused by both external factors and host metabolic state - are important for gut barrier, since they can lead to increased influx of bacteria or bacterial components (endotoxin, bacterial DNA, metabolites) into the host circulation. Increased systemic levels of bacterial endotoxins and DNA have been associated with an impaired metabolic host status, manifested in obesity, insulin resistance, and associated cardiovascular complications. Bacterial components and cells are distributed to peripheral tissues via the blood stream, possibly contributing to metabolic diseases by increasing chronic pro-inflammatory signals at both tissue and systemic levels. This response is, along with other yet unknown mechanisms, mediated by toll like receptor (TLR) transduction and increased expression of pro-inflammatory cytokines, which in turn can further increase intestinal permeability leading to a detrimental positive feedback loop. The modulation of gut barrier function through nutritional and other interventions, including manipulation of gut microbiota, may represent a potential prevention and treatment target for metabolic diseases.
Highlights
While the obesity and type 2 diabetes (T2D) pandemics are increasing at a fast pace [1], new factors relevant to the lack of adaptation toward the increasingly rapid changes in our environment have been proposed as possible perpetrators
A more recent study by Cox et al used LPS, LPS-binding protein (LBP) as well as intestinal fatty acid binding protein to calculate a permeability risk score, which was increased in individuals with type 2 diabetes [123]
Using gnobiotic mice treated with C. innocuum, the bacterium most frequently isolated in Crohns disease (CD), Ha et al evidenced translocation of these bacteria into adipose tissue. This was accompanied by increases in adiponectin and Peroxisome proliferator-activated receptor Gamma (PPARG) expression and adipose tissue expansion. These results suggest that, at least in the case of CD, specific bacteria including C. innocuum can restructure mesenteric adipose tissue leading to the expansion and fibrosis of creeping fat
Summary
While the obesity and type 2 diabetes (T2D) pandemics are increasing at a fast pace [1], new factors relevant to the lack of adaptation toward the increasingly rapid changes in our environment have been proposed as possible perpetrators. One poorly understood feature of metabolic disease is the alteration and dysfunction of the intestinal barrier, accompanied with an increase in intestinal permeability. While the influx of microbial products has been suggested to underlie chronic inflammation observed in metabolic disease and T2D [9], clinical features of metabolic diseases such as hyperglycemia in T2D have been associated with increased influx of microbial products in humans reflective of glucotoxicity [10]. Possible associations between intestinal permeability and characteristics of a metabolic disease like obesity or T2D have emerged as plausible and attractive targets in the field of obesity research. We aim to highlight underlying mechanisms of an impaired intestinal barrier and its possible impact on metabolic health. We discuss recent findings on how endotoxemia and translocation of bacteria, bacterial genetic material and products may cause tissue and organ dysfunction subsequently contributing to metabolic diseases
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