Taurine‑FXR Axis Controls Age‑Dependent Ileal ASBT Decline and Drives Metabolic Aging

Hypothesis

Age‑dependent loss of apical sodium‑dependent bile acid transporter (ASBT) in the ileum is a primary driver of metabolic aging, not a passive consequence. Reduced circulating taurine with age diminishes FXR activation in enterocytes, lowering ASBT transcription and impairing bile acid reabsorption. The resulting increase in fecal bile acid loss shifts the bile acid pool toward unconjugated, microbial‑deconjugated species, which further suppresses FXR signaling and exacerbates intestinal stem cell dysfunction, creating a feed‑forward loop that accelerates systemic metabolic decline.

Testable predictions

1. Expression: ASBT mRNA and protein levels in the ileum will be significantly lower in 24‑month‑old mice compared with 3‑month‑old controls (2).
2. Taurine link: Serum taurine concentrations will correlate positively with ileal ASBT levels across the lifespan (3).
3. FXR mediation: Pharmacological activation of FXR (e.g., with GW4064) in aged mice will restore ASBT expression and improve bile acid reabsorption, whereas intestinal‑specific FXR knockout will mimic the age‑related ASBT decline even in young animals.
4. Microbiome feedback: Aged mice with low ASBT will show increased fecal unconjugated bile acids and heightened abundance of bile‑acid‑deconjugating bacterial taxa (e.g., Clostridium spp.), which can be reversed by taurine supplementation or FXR agonism.
5. Functional outcome: Radiolabeled taurocholate kinetic studies will reveal decreased ileal uptake rate and increased fecal loss in old mice; rescuing ASBT via taurine or FXR will normalize enterohepatic circulation and improve metabolic readouts (glucose tolerance, lipid profile).

Experimental approach

• Use cohorts of male and female C57BL/6 mice at 3, 12, and 24 months.
• Quantify ileal ASBT by qPCR and immunoblotting; measure serum and hepatic taurine by LC‑MS.
• Treat subsets with taurine (1% w/v in drinking water) or FXR agonist for 4 weeks.
• Perform bile acid pool profiling (conjugated vs unconjugated) and 16S rRNA sequencing to assess deconjugator abundance.
• Conduct enterohepatic circulation assays with [^3H]‑taurocholate to calculate reabsorption efficiency and cycling frequency.
• Assess intestinal stem cell markers (Lgr5, Ki67) and barrier function (FITC‑dextran permeability).

If ASBT decline is causally linked to taurine‑FXR signaling, restoring either should prevent the age‑related shift in bile acid metabolism and ameliorate intestinal and systemic phenotypes. Conversely, if ASBT remains unchanged despite taurine/FXR manipulation, the hypothesis would be falsified, prompting a re‑evaluation of intestinal versus hepatic drivers of metabolic aging.