Age-Related Ileal ASBT Decline Driven by Taurine Deficiency and Disrupted FXR Signaling

Hypothesis

We propose that aging reduces ileal apical sodium‑dependent bile acid transporter (ASBT) expression and function primarily through a taurine‑dependent mechanism: declining circulating taurine limits taurine‑conjugated bile acid formation, lowering FXR activation in enterocytes, which in turn diminishes ASBT transcription and impairs bile acid reabsorption independent of hepatic changes.

Mechanistic Basis

• Circulating taurine falls with age across species, reducing the pool of taurine‑conjugated bile acids that are high‑affinity substrates for ASBT (4).
• Taurine‑conjugated bile acids are potent agonists of intestinal FXR; reduced FXR signaling decreases fibroblast growth factor 19 (FGF19) secretion and weakens the FXR‑dependent positive feedback on ASBT gene expression (6).
• Aging‑associated shifts toward muricholic acids and away from deoxycholic acid (DCA)/chenodeoxycholic acid (CDCA) further lower FXR activation, mirroring the opposite pattern seen under calorie restriction that boosts ASBT‑friendly bile acids (5).
• Microbiota‑mediated deconjugation of bile acids may amplify taurine scarcity, creating a vicious loop where reduced reabsorption raises fecal bile acid loss, driving hepatic synthesis of less‑taurinated species.

Testable Predictions

1. Cross‑sectional human data: Older adults (>65 yr) will show lower ileal ASBT mRNA and protein (via biopsy) and reduced SeHCAT retention compared with younger adults (<35 yr), even after adjusting for liver volume and fibrosis scores (1, 3).
2. Mediation analysis: Serum taurine levels will mediate the relationship between age and ileal ASBT expression, accounting for >30 % of the variance.
3. Bile acid profiling: The ratio of taurine‑ to glycine‑conjugated bile acids in portal plasma will decline with age and correlate positively with ASBT activity measured ex vivo.
4. Intervention: Twelve‑week oral taurine supplementation (3 g/day) in older adults will increase ileal ASBT expression (biopsy) and SeHCAT retention by ≥15 % without altering liver stiffness or hepatic bile acid synthesis enzymes.
5. Microbiota modulation: Antibiotics that suppress bile‑acid‑deconjugating microbes will potentiate the effect of taurine on ASBT expression, indicating a microbiota‑dependent component.

Potential Interventions

• Taurine supplementation: Directly replenishes the taurine pool for bile acid conjugation.
• FXR agonists: Enteric‑selective FXR activators could bypass taurine limitation and stimulate ASBT transcription.
• Microbiota‑targeted therapies: Prebiotics or narrow‑spectrum antibiotics to reduce deconjugating taxa, preserving taurine‑conjugated species.

Implications

Confirming this hypothesis would shift focus from liver‑centric models of metabolic aging to the ileum as a key regulator of enterohepatic circulation decline. It would also provide a nutritionally actionable target—taurine—to mitigate age‑related metabolic dysfunction, potentially delaying onset of MASLD, insulin resistance, and neuro‑degenerative processes linked to altered bile acid signaling.