Endotoxemia and Platelets

Figures

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  Figure 1. Gut Dysfunction and Endotoxemia in NAFLD (A) In nonalcoholic fatty liver disease (NAFLD), small intestine bacterial overgrowth increases gut permeability down-regulating adhesion proteins. An impaired gut barrier allows lipopolysaccharide (LPS) translocation into the portal circulation and eventually causes liver damage interacting with its receptor toll-like receptor 4 (TLR4) on hepatocytes. (B) The mechanisms that contribute to detoxify the human body from LPS include: 1) remotion, by the enzyme intestinal alkaline phosphatase (IAP) of 1 of the 2 phosphate groups of lipid A moiety resulting in LPS degradation to monophosphoryl-LPS; and 2) expression of the cholesterol transporter ABCA1 on intestinal epithelial cells, thus generating high-density lipoprotein 3 (HDL3), which is able to bind lipopolysaccharide-binding protein (LBP), thus failing LPS recognition by TLR4 at the level of hepatocytes and intestinal epithelial cells. SIBO = small intestine bacterial overgrowth.

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  Figure 2. LPS-Mediated Prothrombotic Effects in NAFLD LPS and platelet TLR4 play a role as trigger of platelet activation. LPS interaction with TLR4 with ensuing recruitment of the adaptor proteins TIRAP and MyD88 promotes activation of downstream signaling, resulting in stimulation of platelet granule secretion leading to potentiation and amplification of platelet activation and aggregation to the common agonists by overproduction of eicosanoids, such as thromboxane A2 and F2-isoprostanes, and oxidant species produced by Nox2. In addition, LPS may also act indirectly eliciting a proaggregating effect via reducing ADAMTS13 activity. Finally, after stimulation of LPS, platelets are able to interact with neutrophils resulting in neutrophil extracellular traps (NETs); tissue factor (TF) by NETs results in activation of coagulation cascade. ADP = adenosine diphosphate; TxB2 = thromboxane B2; vWF = Von Willebrand factor; other abbreviations as in Figure 2.

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  Figure 3. Detoxification of LPS: Therapeutic Strategies Reduction of levels lipopolysaccharide (LPS) or counteraction of LPS toxicity could occur by: 1) rifaximin, a nonabsorbable antibiotic; 2) short-chain fatty acids (SCFAs) such as propionate, butyrate, and acetate; 3) probiotics (live bacteria or microbial metabolites including Lactobacillus plantarum or Akkermansia muciniphila), microbial metabolites such as urolithin A, or oxyberberine or lactose-fermenting Lactobacilli and Bifidobacteria; 4) prebiotics (fermentable fiver [oligofructose]); 5) fish oils and glucagon-like peptides; and 6) statins. FXR = farnesoid X receptor; ZO-1 = zonula occludens-1.

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  Central Illustration. Gut-Derived Low-Grade Endotoxaemia and Platelet Activation in NAFLD Schematic representation of the impact of gut barrier dysfunction and endotoxemia in NAFLD process; the relationship between endotoxemia platelet activation and micro-thrombosis in NAFLD; the potential therapeutic approach to modulate endotoxemia and eventually platelet activation. LPS = lipopolysaccharide; NAFLD = nonalcoholic fatty liver disease.