The Gut Microbiota–NLRP3 Inflammasome Axis in Chronic Heart Failure: Mechanisms Across Heart Failure Phenotypes and Therapeutic Perspectives

Figures

• 

  Figure 1. Schematic diagram of the structure, assembly and effector functions of the NLRP3 inflammasome. (A) Domain architecture of the NLRP3 monomer, consisting of PYD, NACHT (with ATPase activity) and LRR domains. (B) Core component interactions: NLRP3 recruits ASC via PYD–PYD, ASC recruits pro-caspase-1 via CARD–CARD, and NEK7 binds to LRR as a scaffold. (C) Inflammasome assembly and activation: PAMPs, DAMPs, or K+ efflux trigger NLRP3 oligomerization and ASC speck formation, leading to caspase-1 activation, which cleaves pro-IL-1β/pro-IL-18 into mature IL-1β/IL-18 and GSDMD to induce pyroptosis.

• 

  Figure 2. Schematic diagram of the two-step activation pathway of the NLRP3 inflammasome. This figure is divided into two stages: priming and activation. (A) Priming stage: TNF, LPS, and IL-1β stimulate the receptors, activate the NF-κB pathway, induce the transcription of NLRP3, pro-IL-1β, and pro-IL-18, and the Pellino2-USP22-ATG5 pathway participates in the deubiquitination regulation of NLRP3. (B) Activation stage: Various upstream stimuli induce ion flow, lysosomal damage, and mitochondrial stress, promoting the oligomerization of NLRP3; the mature NLRP3 inflammasome mediates the activation of inflammatory factors and initiates GSDMD-dependent pyroptosis of cells.

• 

  Figure 3. Schematic diagram of post-translational modifications, organelle interactions, and endogenous inhibitory regulation of the NLRP3 inflammasome. This schematic diagram consists of two functional areas: on the left (A), it shows the regulation of NLRP3 translocation, stability and activation by phosphorylation, ubiquitination, and palmitoylation; on the right (B), it describes the ROS signals from mitochondrial-MAM sources under inflammatory conditions, the Nrf2-NF-κB pathway, and multiple endogenous regulatory pathways that inhibit NLRP3 activation.

• 

  Figure 4. Schematic diagram of intestinal microbiota characteristics, metabolites, physiological functions, disease associations, and the gut-heart axis under heart failure conditions. This schematic diagram summarizes the composition and diversity evaluation indicators of the intestinal microbiota (Chao1, Shannon index); presents key microbiota metabolites such as SCFAs, TMAO, LPS, BAs, PAGIn; elaborates on the physiological functions participated by the intestinal microbiota, the associations with various diseases, and the bidirectional regulatory relationship of the gut-heart axis, and summarizes the changes in the intestinal microbiota of patients with heart failure.

• 

  Figure 5. The Regulation of Myocardial Homeostasis and Heart Failure by Intestinal-Derived Metabolites. This figure illustrates the effects of intestinal microbiota metabolites (short-chain fatty acids, TMAO, LPS, bile acids, PAGIn) on intestinal epithelial cells and the subsequent mediation of downstream signaling pathways. Short-chain fatty acids exert myocardial protective effects through systemic anti-inflammatory effects; TMAO and LPS induce systemic inflammation and endothelial dysfunction, activate the NLRP3 non-classical pyroptosis pathway, and accelerate the progression of heart failure; bile acids, through the FXR/TGR5 pathway, produce either myocardial toxicity or cardioprotective effects; PAGIn can enhance platelet activity and indirectly regulate the activation of the NLRP3 inflammasome.