A diet-associated microbial metabolite pathway involving Flavonifractor plautii, 4-hydroxyphenylacetic acid (4-HPAA), and SIRT1 signaling links polyphenol-rich dietary intervention to macrophage immunometabolic regulation and intestinal barrier protection in Crohn's disease models.
Key Findings
Results
An Aronia berry polyphenol-rich diet alleviated colitis, reduced mucosal injury, and improved epithelial barrier integrity in mouse models of Crohn's disease.
IL-10-/- and TNBS-induced colitis mouse models were used to evaluate the effects of dietary intervention.
The diet reduced mucosal injury and improved epithelial barrier integrity in both models.
The study used integrated metagenomic, metabolomic, and transcriptomic analyses combined with in vivo and in vitro mechanistic experiments.
Results
Multi-omics analyses identified Flavonifractor plautii enrichment and increased microbiota-derived 4-hydroxyphenylacetic acid (4-HPAA) levels as major diet-associated changes.
Metagenomic analysis was used to identify diet-responsive microbial taxa.
Metabolomic analysis identified 4-HPAA as a key diet-associated metabolite.
F. plautii was identified as the primary bacterial taxon enriched in response to the polyphenol-rich diet.
The enrichment of F. plautii and elevated 4-HPAA were the two major diet-associated changes detected by multi-omics.
Results
F. plautii supplementation was associated with increased 4-HPAA production, and 4-HPAA administration partially reproduced the intestinal protective phenotype in vivo.
Bacterial strain supplementation experiments were conducted to assess F. plautii's role in 4-HPAA production.
4-HPAA administration as a candidate metabolite was evaluated in vivo.
4-HPAA only partially reproduced the intestinal protective phenotype, suggesting additional mechanisms may be involved.
The findings establish a functional link between F. plautii colonization and 4-HPAA-mediated intestinal protection.
Results
4-HPAA suppressed pro-inflammatory macrophage activation and promoted oxidative metabolic remodeling in macrophages.
In vitro mechanistic experiments were used to assess 4-HPAA effects on macrophages.
4-HPAA promoted oxidative metabolic remodeling, suggesting a shift in macrophage immunometabolism.
Pro-inflammatory activation was suppressed by 4-HPAA treatment in macrophage models.
The metabolic remodeling is described as a 'reprogramming' of macrophage immunometabolism.
The mechanism involves 4-HPAA reducing ubiquitination-mediated proteasomal degradation of SIRT1 protein.
SIRT1 stabilization led to activation of the SIRT1-PGC-1α signaling pathway.
This mechanistic link connects a gut microbiota-derived metabolite to an epigenetic/metabolic regulatory axis in macrophages.
Results
Myeloid SIRT1 deficiency attenuated the effects of 4-HPAA on macrophage polarization, inflammatory cytokine expression, and epithelial barrier-associated proteins.
Myeloid-specific SIRT1-deficient models were used to confirm the SIRT1-dependent mechanism.
Loss of SIRT1 in myeloid cells reduced 4-HPAA's ability to modulate macrophage polarization.
4-HPAA's effects on inflammatory cytokine expression were attenuated in myeloid SIRT1-deficient conditions.
Epithelial barrier-associated protein expression was also affected by myeloid SIRT1 deficiency, indicating a macrophage-to-epithelium signaling axis.
What This Means
This research suggests that eating a diet rich in polyphenols — compounds found in foods like Aronia berries — can help reduce intestinal inflammation associated with Crohn's disease by changing the composition of gut bacteria and the molecules they produce. In mouse models of Crohn's disease, animals fed a polyphenol-rich diet showed less colon damage, better gut lining integrity, and reduced inflammation. Using advanced molecular analysis tools, the researchers traced these benefits to a specific gut bacterium called Flavonifractor plautii, which increased in abundance on the polyphenol diet and produced higher levels of a molecule called 4-hydroxyphenylacetic acid (4-HPAA).
This research suggests that 4-HPAA acts as a key messenger between gut bacteria and the immune system. Specifically, 4-HPAA was found to calm overactive immune cells called macrophages — which play a central role in the chronic inflammation seen in Crohn's disease — by stabilizing a protein called SIRT1. Normally, SIRT1 gets broken down in inflamed macrophages, but 4-HPAA blocks this breakdown, allowing SIRT1 to activate a protective signaling pathway (SIRT1-PGC-1α) that shifts macrophages away from an inflammatory state and toward a more restorative, energy-efficient mode. When the researchers removed SIRT1 specifically from immune cells, the protective effects of 4-HPAA were largely lost, confirming that SIRT1 is essential to this process.
This research suggests that the chain of events — polyphenol-rich diet → F. plautii enrichment → 4-HPAA production → SIRT1 stabilization → reduced macrophage inflammation → improved gut barrier — represents a new biological pathway connecting diet, gut bacteria, and immune regulation in Crohn's disease. These findings may have practical implications for developing dietary or microbiome-based strategies to complement existing treatments for Crohn's disease and related inflammatory bowel conditions, though further research in humans would be needed to confirm these effects.
Cheng C, Cheng S, Jiang W, Fu S, Shang Y, Tang X, et al.. (2026). Microbiota-derived 4-HPAA alleviates Crohn's disease by stabilizing SIRT1 and reprogramming macrophage immunometabolism.. Apoptosis : an international journal on programmed cell death. https://doi.org/10.1007/s10495-026-02417-9