Hypothesis

Age‑related decline in circulating taurine creates a substrate shortage for bile acid conjugation, prompting the ileum to upregulate ASBT (SLC10A2) to reclaim taurine‑conjugated bile acids. This compensatory increase exacerbates systemic accumulation of unconjugated primary bile acids and ammonia, fueling neuroinflammation and cognitive loss. Restoring taurine levels should normalize ileal ASBT expression, rebalance the bile acid pool, and ameliorate gut‑brain axis dysfunction.

Mechanistic Rationale

Taurine is a obligatory amide for the synthesis of taurocholic acid, the dominant conjugated bile acid in mice. When hepatic taurine falls with age Taurine depletion link, hepatocytes produce fewer tauro‑conjugates, shifting the bile acid pool toward glycine‑conjugated and unconjugated species. Unconjugated bile acids are poorer substrates for ASBT, reducing reabsorption efficiency and lowering the luminal bile acid signal that normally suppresses ASBT via FXR‑FGF19 signaling. The intestine senses diminished FXR activation and responds by increasing ASBT transcription to scavenge any remaining taurine‑conjugated molecules, a maladaptive loop that elevates circulating unconjugated bile acids and ammonia. Sex differences arise because estrogen enhances FXR activity; its decline in females further weakens FXR signaling, amplifying ASBT upregulation in older women.

Predictions & Experimental Design

1. Taurine supplementation lowers ileal ASBT – Aged female mice receiving 1% taurine in drinking water for 8 weeks will show reduced Slc10a2 mRNA and protein in ileal epithelium compared with untreated controls.
2. Serum and brain bile‑acid/ammonia normalize – Taurine‑treated animals will exhibit decreased circulating unconjugated primary bile acids and ammonia, accompanied by lowered hippocampal TNF‑α and IL‑1β levels.
3. Cognitive rescue correlates with ASBT suppression – Improvements in novel‑object recognition and maze performance will correlate inversely with ileal ASBT expression across individuals.
4. FXR dependence – Co‑administration of the FXR antagonist glyphosate will abolish taurine‑induced ASBT down‑regulation and cognitive benefits, confirming FXR as the mediator.

Experimental groups (n = 10 per group, aged 20‑month female C57BL/6J):

• Vehicle control
• Taurine (1 % w/v)
• Taurine + FXR antagonist
• Young (3‑month) baseline

Outcomes measured: ileal Slc10a2 qPCR/Western blot, serum unconjugated CA/DCA, plasma ammonia, hippocampal cytokine ELISA, and behavioral testing.

Potential Outcomes & Implications

If taurine restores FXR signaling and curtails ileal ASBT, the data would support a substrate‑repletion strategy that targets the intestine rather than the liver. This approach could bypass hepatic CYP7A1 feedback, avoiding rebound bile‑acid overproduction. Positive results would justify clinical trials of taurine in older adults, especially women, to mitigate bile‑acid‑driven neuroinflammation and delay onset of metabolic‑neurodegenerative disorders. Conversely, failure to reduce ASBT or improve cognition would refute the substrate‑deficiency model and redirect focus toward alternative regulators of intestinal bile‑acid transport.