The role of bile salts in itch receptor activation

Cholestasis-associated pruritus is a distressing symptom. Bile salts and bilirubin are often implicated in the etiology of pruritus. We evaluated whether these compounds activate known itch receptors.

Activation of the established pruriceptors TRPA1, TRPV1, TRPV3, TRPV4, MRGPRX4 in cells overexpressing these receptors, by monitoring cytosolic free Ca²⁺. TGR5 activation was assayed by means of cAMP ELISA in TGR5 overexpressing cells. Serum from 43 cholestatic patients and 15 controls was analyzed for receptor activation; plasma bile salt concentrations were quantified by HPLC-MS.

Plasma levels of conjugated bile salts and their sulphated and glucuronidated derivatives correlated with pruritus intensity; most unconjugated bile salts did not. TRPA1 and MRGPRX4 were activated by bile salts only at high concentrations. Bilirubin only weakly activated MRGPRX4. However, physiological levels of albumin completely abrogated these activations. Incubation of receptor-expressing cells with patient serum (containing albumin) did not activate any of the itch receptors. In contrast, physiological concentrations of albumin reduced but did not completely abrogate bile salt-induced TGR5 activation, and the extent of this activation correlated with pruritus intensity. However, TGR5 activation was also induced by plasma from NTCP-deficient individuals.

While TGR5 activation correlates with pruritus, this receptor was also activated by plasma of NTCP deficient patients who do not suffer from pruritus, indicating that activation of TGR5 is not a dominant factor. The absence of receptor activation in the presence of physiological concentrations of albumin indicates that bile salts and bilirubin do not play a direct role in activation of these receptors.