Figure 4: Multi-faceted regulation of cardiac fibrosis and inflammation.

The stress response interconnects inflammation, and fibrosis, which can be further influenced by the gut microbiome though derived metabolites. Fibrosis is heavily influenced by inflammation, and cardiac fibroblasts and immune cells are plastic and have effects on each other’s actions. Stress induces fibroblast responses to damage-associated molecular patterns (DAMPs) and advanced glycation end products (AGEs), and activates TGFβ signaling pathways, αSMA expression, and fibrosis. Additionally, stress induces pro-inflammatory mediators that invoke innate and adaptive immune cell activity and result in inflammation. The gut microbiome, known to modulate immunity locally, also regulates immunity in distal sites possibly through derived metabolites with actions in immune cells, and potentially on cardiac cells, something that remains largely unexplored. At the interface of fibrosis and inflammation, modulation of the microbiome or derived metabolites may be considered for therapeutic purposes to treat cardiac inflammation and fibrosis in heart failure.