Duodenal Nerve‑EEC Axis Determines Age‑Related GLP‑1 Decline via Microbiota‑Wnt Crosstalk

Hypothesis: Age‑associated loss of duodenal GLP‑1‑secreting L‑cells results from a combined decline in visceral sensory innervation and Wnt‑dependent stem‑cell support, whereas colonic L‑cells persist due to residual nerve‑rich crypt niches. This nerve‑EEC communication sustains L‑cell longevity through activity‑dependent induction of the transcription factor c‑Fos, which maintains an epigenetic program preventing transdifferentiation. Aging reduces enteric neuron density, lowering c‑Fos activation in duodenal L‑cells and promoting their conversion to other enteroendocrine fates. Concurrently, age‑related enrichment of Akkermansia muciniphila inhibits Wnt signaling in intestinal stem cells, shrinking the progenitor pool that replenishes L‑cells. The duodenum, lacking the dense nerve‑enriched crypts seen in the colon, suffers a disproportionate loss of L‑cells, while colonic L‑cells retain survival signals from nearby visceral fibers. Elevated GIP from hyperplasia of K‑cells further antagonizes GLP‑1 action, exacerbating metabolic dysfunction.

Testable predictions:

1. In young mice, chemogenetic activation of duodenal visceral afferents will increase c‑Fos expression in L‑cells and extend their lifespan, as measured by lineage‑tracing reporters (e.g., Glucagon‑CreERT2;Rosa26‑tdTomato) over 14 days.
2. In aged mice, the same neuronal activation will fail to prolong L‑cell survival unless Wnt signaling is pharmacologically enhanced (e.g., with a PORCN agonist), indicating dependence on both nerves and Wnt.
3. Antibiotic‑mediated reduction of Akkermansia muciniphila in aged mice will restore Wnt activity in intestinal crypts, increase L‑cell numbers, and improve glucose‑stimulated GLP‑1 secretion without altering neuronal density.
4. Optogenetic silencing of duodenal sensory nerves in young mice will recapitulate the aged phenotype: decreased c‑Fos in L‑cells, accelerated L‑cell loss, and reduced GLP‑1 response to a mixed nutrient load, even when Wnt signaling is intact.
5. Combined nerve inhibition and Akkermansia enrichment will produce additive loss of duodenal L‑cells, whereas either manipulation alone yields a partial effect.

Falsification: If activating duodenal visceral afferents in aged mice consistently increases L‑cell lifespan and GLP‑1 secretion regardless of Wnt pathway status, or if Wnt activation alone rescues L‑cell numbers without neuronal input, the hypothesis that nerve‑EEC c‑Fos signaling is essential and Wnt‑dependent would be refuted.

This framework integrates nerve‑mediated epigenetic maintenance, stem‑cell niche integrity, and microbial modulation to explain regional differences in enteroendocrine aging and offers combinatorial targets (neuronal modulators, Wnt agonists, microbiota adjustment) to preserve incretin function in older individuals.