The gut–liver axis in progressive steatotic liver disease: A focus on bile acid dysregulation

Abstract

Bile acids; Gut microbiome; Gut-liver axis

Àcids biliars; Microbioma intestinal; Eix intestí-fetge

Ácidos biliares; Microbioma intestinal; Eje intestino-hígado

Introduction The gut–liver axis regulates metabolic homeostasis, with bile acids (BAs) serving as key signalling molecules. BA dysregulation is implicated in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction- and alcohol-associated liver disease (MetALD), yet consistent identification of BA markers and their mechanistic roles across different stages of these diseases remain elusive. Methods We integrated three complementary studies to examine BA dysregulation: a population-based cohort (1522 females from TwinsUK with serum BA and liver biomarker data), a clinical cohort (30 patients with steatotic liver disease, fibrosis stages F0-F4, and 4 controls), and rodent models (20 rats with MASLD/MetALD vs. 9 controls). BA profiles were quantified via LC–MS. Results The primary bile acid taurocholate was consistently correlated with liver pathology: in TwinsUK, it associated with ALT (β [95%CI] 1.81 [1.27, 2.36], FDR < 0.05) both overall and when stratifying for age (<65 years, n = 923; ≥65 years, n = 599); in the clinical cohort, it was associated with F3 fibrosis (OR [95%CI] 8.56 × 10−10 [3.80 × 10−13, 1.93 × 10−6], FDR < 0.05); and in rodents, it was associated with MASLD/MetALD (OR [95%CI] 2.86 [1.17, 9.51], FDR < 0.05). The secondary bile acid taurochenodeoxycholate was associated with both early (F0, OR [95%CI] 13.63 [1.04, 179.17], p < 0.05) and advanced stages of disease (rodents, OR [95%CI] 15.41 [2.94, 311.82], FDR < 0.05). Conclusion Taurocholate and taurochenodeoxycholate emerge as consistent BA markers across liver disease stages, suggesting BA metabolism as potential therapeutic targets. This multi-model study bridges knowledge gaps in BA-driven mechanisms, informing personalised strategies for SLD management.

This research was funded in whole, or in part, by the Wellcome Trust (WT212904/Z/18/Z). This work was also supported by UKRI grants (MR/Y010175/1, MR/T004142/1) to AMV and CM. For the purpose of open access, the authors have applied a CC BY public copyright to any Author Accepted Manuscript version arising from this submission. TwinsUK receives support from the Wellcome Trust (212904/Z/18/Z), the Wellcome Leap Dynamic Resilience program (co-funded by Temasek Trust), the MRC/BHF (MR/M016560/1), European Union, CDRF, Zoe Global, the NIHR. Additional support comes from the National Institute for Health and Care Research Nottingham Biomedical Research Centre (AMV), the Italian Ministry of Education and Research, Dipartimenti di Eccellenza Program 2023 to 2027 and by the Italian Ministry of Health – Bando Ricerca Corrente (CM)). The study is also supported by European Commission projects (IMI-2, H2020, Horizon Europe), MICIU/AEI (FJC) and co-financed with FEDER funds. BA analysis was supported by the Edinburgh Clinical Research Facility and NHS Research Scotland. We thank Scott Denham for his mass spectrometry expertise.