A Gly-β-muricholic acid and FGF15 combination therapy synergistically reduces “humanized” bile acid pool toxicity in cholestasis mice

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Hydrophobic bile acid-mediated hepatobiliary injury is a major driver of cholestasis progression. Most anticholestasis treatments being tested clinically are based on a single agent, which does not always sufficiently alleviate bile acid toxicity to slow disease progression. This study investigates a therapeutic strategy of combining glycine-conjugated β-muricholic acid (Gly-βMCA) and fibroblast growth factor-15 (FGF15) to alleviate bile acid hepatobiliary toxicity in Cyp2c70 KO mice that lack endogenous muricholic acid (MCA) synthesis and have a "humanized" hydrophobic bile acid pool composition. The effects of the single and combination treatments on bile acid metabolism, liver injury, and gut microbiome were investigated in female Cyp2c70 KO mice with progressive cholangiopathy and portal fibrosis. While all three treatments significantly reduced biochemical and histologic features of liver injury, the Gly-βMCA and FGF15 combination achieved a remarkably higher reduction in both bile acid pool size and hydrophobicity than either single treatment. Mechanistically, this resulted from synergistically increased biliary hydrophilic MCA species derived from Gly-βMCA, inhibited intestine endogenous bile acid absorption by Gly-βMCA, and repressed cholesterol 7α-hydroxylase (CYP7A1) by FGF15, which counteracted the undesirable farnesoid X receptor antagonism activity of Gly-βMCA. Furthermore, a hydrophobic bile acid pool in Cyp2c70 KO mice was associated with markedly reduced beneficial Lactobacillaceae family bacteria abundance, which was enriched by Gly-βMCA and the combination treatments. In conclusion, the Gly-βMCA and FGF15 combination shows enhanced efficacy in decreasing humanized bile acid pool size and hydrophobicity and holds potential as a therapeutic strategy to decrease bile acid burden in cholestasis.