Immune IL-1α signaling stabilizes HIF-1α in colonocytes, repressing butyrate‑producing bacteria and tightening the inflammaging loop

Hypothesis

Aged immune cells secrete excess IL-1α, which acts on colonic epithelial HIF-1α to suppress the transcription of mucin-2 and tight-junction genes while simultaneously up-regulating glycolytic enzymes that shift the luminal environment away from butyrate-oxidizing conditions. This epithelial reprogramming disfavors obligate anaerobes such as Faecalibacterium prausnitzii and Roseburia spp., lowering luminal butyrate, weakening the barrier, and feeding back to increase immune IL-1α production.

Mechanistic rationale

1. IL-1α signaling activates the PI3K-AKT-mTOR axis, inhibiting prolyl hydroxylases and stabilizing HIF-1α even under normoxia [1].
2. HIF-1α directly binds the promoter of MUC2 and CLDN1, reducing their expression and altering the mucus barrier that selects for SCFA-producing taxa [2].
3. HIF-1α drives expression of LDHA and PDK1, increasing lactate excretion and lowering luminal pH, conditions that inhibit butyrate synthesis pathways in Firmicutes [3].
4. Reduced butyrate diminishes HDAC inhibition in colonocytes, leading to hyperacetylated NF-κB and heightened TNF-α/IL-6 secretion, which further stimulates immune IL-1α release [4].

Testable predictions

• Prediction 1: In aged mice, colonic epithelial HIF-1α protein levels will correlate inversely with fecal butyrate concentration and positively with IL-1α in lamina propria mononuclear cells.
• Prediction 2: Pharmacological blockade of IL-1R (using anakinra) or epithelial-specific HIF-1α deletion will restore F. prausnitzii abundance, increase butyrate, and improve barrier function (lower FITC-dextran flux) without altering overall microbial diversity.
• Prediction 3: Transplanting microbiota from IL-1R-blocked aged mice into germ-free young recipients will not recapitulate the barrier defect, indicating that the immune-epithelial axis, not the microbiota alone, drives the phenotype.

Experimental approach

1. Correlative analysis: Measure HIF-1α (Western blot/IHC), IL-1α (ELISA), butyrate (GC-MS), and tight-junction protein expression in colon samples from young (3 mo) and aged (24 mo) mice (n = 8 per group).
2. Intervention: Treat aged mice with anakinra (100 mg/kg i.p. every 48 h for 4 weeks) or use Villin-CreERT2;Hif1a^fl/fl mice induced at 20 mo. Compare to vehicle-treated controls.
3. Readouts: 16S rRNA sequencing for F. prausnitzii/Roseburia relative abundance, fecal SCFA quantification, FITC-dextran permeability assay, and serum TNF-α/IL-6 levels.
4. Microbiota transfer: Collect feces from treated aged donors, transplant into germ-free recipients, and assess barrier integrity after 2 weeks.

Falsifiability

If IL-1R blockade or epithelial HIF-1α loss fails to increase butyrate producers, improve barrier function, or reduce systemic cytokines despite confirmed target engagement, the hypothesis is refuted. Likewise, if microbiota transfer from treated donors still transmits the barrier defect to germ-free hosts, the immune-epithelial mechanism is insufficient.

Broader implication

This model positions the immune system not merely as a passive victim of inflammaging but as an active sculptor of the epithelial metabolic landscape that governs microbiota-derived healthspan factors. Targeting the IL-1α/HIF-1α axis could decouple immune aging from microbiome decay, potentially delaying multiple age-related pathologies.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC8054695/ [2] https://pubmed.ncbi.nlm.nih.gov/40943196/ [3] https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1452917/full [4] https://www.tandfonline.com/doi/full/10.1080/19490976.2024.2389319