Gut microbe-derived extracellular vesicles induce insulin resistance, thereby impairing glucose metabolism in skeletal muscle

Abstract

Gut microbes might influence host metabolic homeostasis and contribute to the pathogenesis of type 2 diabetes (T2D), which is characterized by insulin resistance. Bacteria-derived extracellular vesicles (EVs) have been suggested to be important in the pathogenesis of diseases once believed to be non-infectious. Here, we hypothesize that gut microbe-derived EVs are important in the pathogenesis of T2D. In vivo administration of stool EVs from high fat diet (HFD)-fed mice induced insulin resistance and glucose intolerance compared to regular diet (RD)-fed mice. Metagenomic profiling of stool EVs by 16S ribosomal DNA sequencing revealed an increased amount of EVs derived from Pseudomonas panacis (phylum Proteobacteria) in HFD mice compared to RD mice. Interestingly, P. panacis EVs blocked the insulin signaling pathway in both skeletal muscle and adipose tissue. Moreover, isolated P. panacis EVs induced typical diabetic phenotypes, such as glucose intolerance after glucose administration or systemic insulin injection. Thus, gut microbe-derived EVs might be key players in the development of insulin resistance and impairment of glucose metabolism promoted by HFD.

Gut Microbiota Contribute to Age-Related Changes in Skeletal Muscle Size, Composition, and Function: Biological Basis for a Gut-Muscle Axis

“…Endotoxin-mediated reductions in glucose tolerance have been similarly shown in humans inoculated with LPS, as evidenced by significant increases in skeletal muscle NF-κβ binding activity and JNK phosphorylation, which synergistically inhibit insulin signaling [36]. These studies and others [30, 37], show that circulating LPS, a prominent component of gut microbiota, induces skeletal muscle inflammation and insulin resistance thereby contributing to the development of metabolic syndrome. While these findings implicate LPS and inflammation as causative agents in the process, inflammation-independent alterations in skeletal muscle metabolism have also been observed.…”

“…Meanwhile, excess nutrient uptake and storage (i.e., obesity) is associated with low microbial diversity and changes in the relative abundance of the major bacterial phyla (Bacteroidetes and Firmicutes) [27–29]. While these findings provide support for microbial regulation of local metabolic function, evidence also suggests that gut microbiota may impact distal metabolic activity in skeletal muscle tissues [23, 30]. …”

“…For example, in response to the gut microbiota-specific metabolite indoxyl sulfate [38], C2C12 myoblasts exhibit an up-regulation of glycolysis and an increase in the activity of the pentose phosphate pathway [39]. Similarly, exposure of myotubes to gut microbial-derived extracellular vesicles induces insulin resistance [30], highlighting the multitude of ways in which gut microbiota may influence the metabolic function of skeletal muscle.…”

The PPAR–microbiota–metabolic organ trilogy to fine‐tune physiology

“…In addition, the skeletal muscle is a major organ in glucose homeostasis, taking up and storing up to 80% of postprandial glucose via insulin-mediated processes. Gut dysbiosis disrupts the physical and metabolic function in muscles through microbial products such as LPS (29) and gut microbe-derived extracellular vesicles that impair glucose metabolism in skeletal muscle (234). These microbial products leak into the systemic circulation, prompting a proinflammatory response via the release of inflammatory cytokines such as TNF-a and IL-6, culminating in smaller, fat-infiltrated muscles with disrupted insulin signaling pathways and eventually leading to the pathogenesis of metabolic syndrome and sarcopenia (235)(236)(237)(238)(239)(240)(241).…”

Vésicules extracellulaires, biomarqueurs et bioeffecteurs du syndrome métabolique

“…Fas/ Fas ligand [48]. Les VE apparaissent donc comme un nouvel acteur dans la communication complexe reliant l'hôte et son microbiote.…”