Western diet induces iron-dependent enteric neurodegeneration via ferroptosis.

Summary

A Western diet and palmitic acid triggered ferroptosis in enteric neurons, leading to delayed colonic transit. Genetic activation of Nfe2l2 or pharmacologic inhibition with ferrostatin-1 rescued mitochondrial integrity, neuronal viability, and motility phenotypes across mouse, cellular, and human ex vivo systems.

Key Findings

• Western-diet–fed mice showed delayed colonic transit, increased TfR1/FTH-1, and selective nNOS neuron vulnerability, reversed by Nfe2l2 overexpression.
• Palmitic acid induced labile and mitochondrial iron accumulation, lipid peroxidation (4-HNE), mitochondrial depolarization, Ca2+ dysregulation, and ROS in enteric neurons.
• Ferrostatin-1 preserved mitochondrial integrity, neuronal viability, and ENS function in vitro and ex vivo.
• Human myenteric ganglia exposed to palmitic acid exhibited iron loading and ferroptosis, supporting translational relevance.

Clinical Implications

While preclinical, findings suggest perioperative nutrition and ferroptosis-targeted strategies (e.g., Nrf2 activation, ferroptosis inhibitors) may mitigate postoperative ileus or dysmotility in high-risk patients consuming Western diets.

Limitations

• Preclinical design limits immediate clinical generalizability and dosing guidance.
• Dietary and metabolic heterogeneity in humans may modulate ferroptosis susceptibility beyond modeled conditions.

Future Directions

Test ferroptosis-modulating interventions (e.g., Nrf2 activators, iron chelators) in perioperative models of ileus and in early-phase clinical trials targeting diet-associated dysmotility.