For cholestatic liver diseases, bile acid–related treatments aim at (a) reducing hepatic bile acid accumulation, (b) reducing bile acid toxicity, (c) promoting bile flow, and (d) reducing inflammation. As for (a) reducing hepatic bile acid accumulation, an approach is to reduce the bile acid pool size by interrupting the bile acid enterohepatic circulation (Fig.
1). This can be achieved by bile acid–binding resins (e.g., cholestyramine, which is used for cholestatic pruritus and hypercholesterolemia) or by inhibition of intestinal ASBT, as these treatments increase the fecal loss of bile acids. This treatment strategy is similar to partial external biliary diversion performed in children with PFIC and Alagille disease [
193]. ASBT inhibitors improved cholestatic injury in mice [
194,
195] and cholestatic pruritus in PBC patients [
196]. The ASBT inhibitor maralixibat was recently approved for the treatment of cholestatic pruritus in patients with Alagille syndrome [
197], whereas trials for other cholestatic disorders are ongoing [
198,
199]. The most common side effects were diarrhea and abdominal pain. The deficiency of fat-soluble vitamins, which require bile acids for intestinal absorption, was also reported [
196,
197]. Besides bile acid–binding resins and ASBT inhibition, inhibition of hepatic NTCP may reduce bile acid uptake by hepatocytes. Because hepatocyte NTCP is the entry receptor for hepatitis D virus (HDV), the NTCP inhibitor bulevirtide was recently approved in Europe for the treatment of chronic HDV infection in HDV RNA positive patients with compensated liver disease. In mouse models of cholestatic liver damage, bulevirtide attenuated liver injury by reducing biliary bile acid output and increasing biliary lipid output [
200,
201]. Reduction of hepatic synthesis of bile acids can be achieved by agonists of FXR and PXR and recombinant FGF19, as discussed in the previous sections (Fig.
1). The FXR agonist OCA is approved for PBC patients, as discussed above. As for (b) reducing bile acid toxicity and (c) promoting bile flow, biliary bile acid composition can be modulated by UDCA, TUDCA, and norUDCA, which render bile less hydrophobic and thus less cytotoxic, and by NTCP inhibition, which increases the phospholipids/bile acid ratio [
200,
201] (Fig.
1). (T)UDCA and norUDCA further promote bicarbonate-rich bile flow [
202]. In particular, norUDCA escapes hepatic conjugation and can be thereby reabsorbed passively by the biliary epithelium, to be returned to hepatocytes for re-secretion (cholehepatic shunting). Both re-secretion by hepatocytes and bicarbonate secretion into bile upon norUDCA reabsorption can contribute to increased bile flow [
203]. UDCA is approved for PBC, cholestasis of pregnancy, and cholesterol gallstone dissolution. UDCA is also used for PFIC3, cystic fibrosis–related liver disease (CFLD), and PSC, although long-term efficacy is uncertain due to the lack of large clinical trials [
204]. norUDCA as a treatment for PSC is being evaluated in a phase 3 study (NCT03872921) after promising results in a phase 2 study [
205]. As for (d) reducing inflammation, besides anti-inflammatory and immune-modulatory agents [
206], bile acid–related targets include hepatic FXR, PXR, and TGR5 agonists, as discussed in the previous sections. Interestingly, immunomodulatory effects of norUDCA were recently demonstrated in
Mdr2−/− mice and mice infected with non-cytolytic lymphocytic choriomeningitis virus (LCMV), a model of non-cholestatic liver injury. By modulating mTORC1 activity in CD8
+ cells, norUDCA impaired the activation-induced metabolic reprogramming of CD8
+ cells and significantly alleviated hepatic inflammation [
207]. UDCA also has anti-inflammatory actions, reviewed elsewhere [
204]. In addition to cholestatic diseases, targeting FXR, FGF19, and TGR5 signaling have also shown important therapeutic benefits for the treatment of NASH [
208].
Bile acids shape the gut microbiome by providing feeding substrate and by exerting antimicrobial activities. In turn, the gut microbiome shapes the bile acid pool composition by carrying out enzymatic activities (e.g., deconjugation and dehydroxylation) that modify primary bile acids, resulting in bile acids that have different affinities to bile acid receptors and can thus influence bile acid receptors signaling [
209]. The gut-liver axis has been implicated in the pathophysiology of several liver diseases and the gut microbiota is altered in several liver diseases. Therefore, modulation of the gut microbiota is a potential therapeutic approach and can be achieved by dietary changes, prebiotics, probiotics, antibiotics, as well as by fecal microbiota transplantation and bacteriophages [
210]. The relevance of the gut microbiota in liver diseases has been recently reviewed [
211].