GPBAR1 and cholestasis: Highest affinity for secondary, hydrophobic BA (LCA ≈ DCA >> CDCA/CA); thus microbial 7α-dehydroxylation that expands DCA/LCA pool biases signaling toward TGR5. Conjugation reduces membrane permeability but TGR5 is located basolaterally, so conjugated bile acids can still activate it after absorption. Changes in bile acid pool hydrophobicity (diet, microbiota, cholestasis, bariatric surgery) therefore strongly influence TGR5-dependent GLP-1 release, thermogenesis and anti-inflammatory effects [113,116,120].