What the study found
The study found that a Western diet and palmitic acid, a saturated fatty acid, were associated with iron-dependent ferroptotic injury in the enteric nervous system, the network of nerves that controls the gut. In mice and human myenteric ganglia, this was linked to enteric neuron damage and impaired colonic motility.
Why the authors say this matters
The authors conclude that these findings support a translational relevance to diet-associated enteric neuropathy, meaning nerve damage in the gut linked to diet. They suggest that nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression and ferrostatin 1 may be relevant because they reversed or protected against the changes they observed.
What the researchers tested
The researchers used mouse diets, cell-based systems, and human myenteric ganglia, which are clusters of nerve cells in the gut wall. Mice were fed a control diet or a Western diet for 12 weeks, with or without AAV9-MaCPNS2 delivery of Nfe2l2/Nrf2 to enteric neurons, and colonic motility was measured with a bead expulsion assay. They also examined immortalized murine fetal enteric neurons, primary enteric neurons, murine myenteric plexuses, and human networks of myenteric ganglia using RNA sequencing and multiple readouts of ferroptosis.
What worked and what didn't
In Western diet-fed mice, colonic transit was delayed, TfR1 and FTH1 increased, and nNOS neurons were more vulnerable; these changes were reversed by Nrf2 overexpression. In palmitic acid-treated murine enteric neurons, RNA sequencing showed disrupted neurotransmitter signaling, reduced mitochondrial and antioxidant programs, and increased iron import and lipid peroxidation signatures. Palmitic acid also increased labile Fe2+, mitochondrial reactive oxygen species, membrane depolarization, Ca2+ dysregulation, 4-hydroxynonenal, and mitoferrin 2, while ferrostatin 1 preserved mitochondrial integrity, viability, and enteric nervous system function.
What to keep in mind
The abstract does not describe detailed limitations. The findings come from murine models, in vitro systems, and human myenteric ganglia, so the study’s evidence is based on these experimental settings rather than a full clinical trial.
Key points
- Western diet feeding in mice was associated with delayed colonic transit and changes consistent with enteric nerve injury.
- Palmitic acid increased markers linked to iron loading, lipid peroxidation, and mitochondrial stress in enteric neurons.
- Nrf2 overexpression reversed the Western diet-related changes seen in mice.
- Ferrostatin 1 protected mitochondrial integrity, cell viability, and enteric nervous system function in the experimental systems tested.
- Human myenteric ganglia showed palmitic acid-induced enteric neuronal iron loading and ferroptosis.
Disclosure
- Research title:
- Western diet linked to iron-dependent enteric neuron damage
- Authors:
- Arun Balasubramaniam, Dmitrii Pavlov, Yunpeng Du, Jeremy Reeves, Alan Harzman, Yunshan Liu, Francesca Cingolani, Xinxu Yuan, Jay M. Patel, Simon M. Mwangi, Peijian He, C. Michael Hart, Wenhui Hu, Fievos L. Christofi, Shanthi Srinivasan
- Institutions:
- Atlanta VA Health Care System, Atlanta VA Health Care System, Atlanta VA Health Care System, Atlanta VA Health Care System, Atlanta VA Health Care System, Atlanta VA Health Care System, Atlanta VA Health Care System, Emory University, Emory University, Emory University, Emory University, Emory University, Emory University, Emory University, The Ohio State University, Virginia Commonwealth University, Virginia Commonwealth University
- Publication date:
- 2026-04-21
- DOI:
- 10.1172/jci196113
- OpenAlex record:
- View
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