Are gut dysbiosis, barrier disruption, and endotoxemia related to adipose tissue dysfunction in metabolic disorders? Overview of the mechanisms involved

Abstract

Recently, compelling evidence points to dysbiosis and disruption of the epithelial intestinal barrier as major players in the pathophysiology of metabolic disorders, such as obesity. Upon the intestinal barrier disruption, components from bacterial metabolism and bacteria itself can reach peripheral tissues through circulation. This has been associated with the low-grade inflammation that characterizes obesity and other metabolic diseases. While circulating bacterial DNA has been postulated as a common feature of obesity and even type 2 diabetes, almost no focus has been given to the existence and effects of bacteria in peripheral tissues, namely the adipose tissue. As a symbiont population, it is expected that gut microbiota modulate the immunometabolism of the host, thus influencing energy balance mechanisms and inflammation. Gut inflammatory signals cause direct deleterious inflammatory responses in adipose tissue and may also affect key gut neuroendocrine mechanisms governing nutrient sensing and energy balance, like incretins and ghrelin, which play a role in the gut-brain-adipose tissue axis. Thus, it is of major importance to disclose how gut microbiota and derived signals modulate neuroendocrine and inflammatory pathways, which contribute to the dysfunction of adipose tissue and to the metabolic sequelae of obesity and related disorders. This review summarizes the current knowledge regarding these topics and identifies new perspectives in this field of research, highlighting new pathways toward the reduction of the inflammatory burden of metabolic diseases.

Keywords: Adipose tissue microbiota; Endotoxemia; Gut dysbiosis; Intestinal permeability; Metabolic disease.

Fig. 1

The putative mechanisms linking HF diet-driven dysbiosis to impaired AT function. HFD initiates a loop of gut dysbiosis and inflammation, dampening epithelial barrier integrity, and thus increasing intestinal permeability. Because of dysbiosis, LPS levels rise while SCFAs production is impaired. 1—LPS-meditated TLR activation triggers NF-kB-dependent transcription programs for pro-inflammatory cytokines: IL-1, TNFα, and IFNy, contributing to colonic inflammation, that may spread into the circulation. 2—A reduction in the SCFAs production hinders GLP-1 secretion by L cells. Additionally, since SCFAs, mainly butyrate, directly stimulate vagal afferents in healthy conditions (left side), a decrease in the SCFAs production will likely result in decreased vagal tone, which might compromise the gut-brain axis and energy balance regulation (right side). 3—Increased intestinal permeability facilitates LPS, cytokines, and bacteria translocation and migration to distant peripheral targets, via the circulation. Colonization of AT by gut-derived bacteria and LPS-mediated TLR activation will culminate in an inflammatory response and overall impairment of AT function. Abbreviations: SCFAs short-chain fatty acids, GLP-1 glucagon-like peptide 1, GABA y-aminobutyric acid, TLR toll-like receptor, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, IL-1 interleukin 1, IFNy interferon-gamma, LPS lipopolysaccharide, TNFa Tumor necrosis factor-alpha, AT adipose tissue. Image created with Biorender.com