Hypothesis

Aging‑associated shifts in sex‑specific gut microbiota bile salt hydrolase (BSH) activity alter the pool of inhibitory versus stimulatory bile acids that regulate ileal ASBT (SLC10A2) expression through the FXR‑FGF19 axis, producing opposite trajectories of ASBT in females and males.

Mechanistic Model

In aged females, estrogen decline favors expansion of Clostridia strains with low BSH activity, preserving conjugated primary bile acids (CPBAs) that act as weak FXR agonists. Reduced FXR activation diminishes FGF19 secretion, relieving its repression of ASBT transcription via the ERK1/2‑SGK1 pathway previously linked to glucocorticoid signaling【4】. Consequently, ASBT rises, increasing CPBA reabsorption and systemic delivery to the brain【1】.

In aged males, androgen‑dependent microbiota retain high BSH activity, generating elevated levels of deconjugated bile acids (e.g., cholic acid, deoxycholic acid) that are potent FXR antagonists. Strong FXR antagonism reduces FGF19 output, but paradoxically, the accumulated deconjugated acids activate TGR5‑cAMP signaling that suppresses ASBT via PKA‑mediated phosphorylation of the transporter, consistent with the observed ~50% drop in ileal taurocholate uptake【3】.

This model integrates the intestinal transport‑longevity link from Drosophila studies where loss of nutrient transporters extends lifespan【5】, suggesting that modulating BSH‑FXR‑FGF19 signaling could similarly affect mammalian aging.

Predictions & Experimental Design

1. BSH activity profiling – Quantify fecal BSH activity in young vs. aged male and female mice and humans; predict low BSH in aged females, high BSH in aged males.
2. Microbiota transfer – Colonize germ‑female aged mice with male‑derived microbiota (and vice versa) and measure ileal ASBT expression, serum CPBA, and cognitive performance. Expect ASBT levels to follow donor microbiota sex phenotype.
3. FXR/FGF19 interrogation – Treat aged mice with an FXR agonist (e.g., GW4064) or FGF19 analog; predict that FXR activation will normalize ASBT in females (decrease) and rescue ASBT suppression in males (increase).
4. Isotope‑labeled bile acid kinetics – Feed ^13C‑taurocholate and track recycling frequency via serial blood sampling; anticipate higher recycling index in aged females, lower in males, correlating with ASBT and BSH metrics.
5. Longevity readout – Chronic BSH inhibition (using nicotinic acid) or ASBT modulation in aged mice; assess lifespan extension alongside cognitive outcomes.

Potential Implications

If validated, targeting sex‑specific microbial BSH activity could serve as a precision‑medicine strategy to rebalance enterohepatic cycling, mitigate age‑related cognitive decline, and potentially extend healthspan. It also explains why ASBT inhibitors improve cognition in females but may have limited effect in males, guiding sex‑stratified clinical trials.

Falsifiability

Demonstrating that BSH activity does not diverge by sex with age, or that FXR/FGF19 manipulation fails to reverse ASBT expression patterns, would refute the hypothesis.