Do bile acids maintain gut microbial balance and suppress mucosal inflammation via FXR and TGR5 signaling?

Bile acids are essential regulators of intestinal health, functioning as hormonal signals that integrate microbial diversity with the host's immune response. The interaction between bile acids and their primary receptors, the farnesoid X receptor (FXR) and the G-protein-coupled receptor TGR5, is central to maintaining gut homeostasis.

Mechanistic signaling pathways

Bile acids act as ligands that trigger specific "enteroprotective" programs within the gut:

• FXR Activation: Located primarily in the ileum, FXR activation induces the production of antimicrobial peptides (AMPs) like Angiogenin-1 (Ang1). These peptides prevent bacterial overgrowth and maintain the integrity of the intestinal barrier by upregulating tight-junction proteins such as ZO-1 and occludin.
• TGR5 Signaling: This receptor responds to secondary bile acids (LCA and DCA), increasing intracellular cAMP. This process suppresses the pro-inflammatory NF-κB pathway in intestinal macrophages, promoting an anti-inflammatory M2-like phenotype.

Impact of impaired bile delivery

When bile delivery is compromised—due to cholestasis, malabsorption, or synthesis defects—the loss of these signaling cascades has significant clinical implications:

• Microbial Dysbiosis: The reduction in bile's natural antimicrobial pressure leads to Small Intestinal Bacterial Overgrowth (SIBO). This shift often favors Gram-negative, bile-tolerant organisms that can further exacerbate gut dysfunction.
• Immune Activation: Impaired delivery reduces FXR and TGR5 signaling, removing the "brake" on inflammatory cytokines. This leads to increased levels of TNF-α, IL-6, and IL-17.
• Barrier Failure: Reduced bile signaling increases epithelial permeability, allowing microbial products like lipopolysaccharides (LPS) to translocate. This triggers Th17 responses and NLRP3 inflammasome activation, resulting in systemic immune activation.

Bottom line

Bile acids are critical hormonal regulators; impaired delivery directly contributes to dysbiosis and mucosal inflammation by disrupting the FXR/TGR5 signaling axis and weakening the intestinal barrier.