Impaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases

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.

Keywords: adipose tissue microbiota; endotoxemia; intestinal permeability; metabolic disease; microbiome; obesity; type 2 diabetes; zonulin.

Figure 1

Causes and consequences of increased intestinal permeability; (A) An interplay between environmental factors, nutrients, drugs and the microbiome defines our intestinal lumen and can directly or indirectly alter permeability of the epithelial cell layer; (B) Increased cell shedding under pathophysiological conditions or the reversible interaction with and opening of tight junctions under allow an influx of pathogens including bacteria or their nucleic acids, metabolites, and lipopolysaccharides as well as further substances and toxins; (C) Paracellular transport via tight junctions is regulated by various kinases and inflammatory cytokines, nutrients and bacteria can interfere with claudin and occludin expression; (D) First entry points of invading substances are capillaries and lymph vessels of the villi and tissues in close proximity such as mesenteric adipose tissue; (E) Endotoxin is rapidly and constantly cleared in the liver; (F) Next to the gut lumen, pathogens could also invade through the oral cavity, the skin and the lung; (G) Under constant interactions and clearance with the immune system the LPS and bacteria are transported in the circulation, thereby LPS can be bound to various proteins and cells including erythrocytes and lipoproteins; (H) Effected distant organs include adipose tissue, pancreas tissue and possibly muscle tissue; (I) Pathogens interact with many receptors, i.e., LPS is recruited to TLR-4 leading to increased expression and secretion of inflammatory cytokines.