Bile acids, bioactive signalling molecules in interoceptive gut-to-brain communication

Aside from facilitating solubilisation and absorption of dietary lipids and lipid-soluble vitamins, amphipathic bile acids (BAs) also act as bioactive signalling molecules. A plethora of conjugated or unconjugated primary and bacterially modified secondary BA moieties have been identified, with significant divergence between species. These molecules are excreted into the external environment of the intestinal lumen, yet nuclear and membrane receptors that are sensitive to BAs are expressed internally in the liver, intestinal and neural tissues, amongst others. The diversity of BAs and receptors underpins the multitude of distinct bioactive functions attributed to BAs, but also hampers elucidation of the physiological mechanisms underpinning these actions. In this Topical Review, we have considered the potential of BAs as cross-barrier signalling molecules that contribute to interoceptive pathways informing the central nervous system of environmental changes in the gut lumen. Activation of BAs on FGF₁₉ -secreting enterocytes, enteroendocrine cells coupled to sensory nerves or intestinal immune cells would facilitate indirect signalling, whereas direct activation of BA receptors in the brain is likely to occur primarily under pathophysiological conditions when concentrations of BAs are elevated.