Western diet weakens the gut’s nervous system through iron-dependent damage

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Jun 10 2026

A new study suggests that saturated fat exposure may damage the gut’s own nervous system by triggering iron-dependent neuronal injury, offering a mechanistic clue to diet-related digestive problems.

Study: Western diet induces iron-dependent enteric neurodegeneration via ferroptosis. Image Credit: Yuriy Golub / Shutterstock

In a recent study published in the Journal of Clinical Investigation, a group of researchers investigated whether a Western diet in mice and palmitic acid exposure in murine and ex vivo human enteric nervous system models trigger ferroptosis-mediated enteric nervous system damage and impaired gut function.

Background

What if the foods commonly linked to obesity could also damage the nervous system inside the gut? The enteric nervous system, also known as the “second brain,” controls digestion, intestinal motility, secretion, and immune communication. Digestive issues like constipation and bloating are increasingly reported in people consuming Western-style diets rich in saturated fats.

Research shows that typical Western-style diets are associated with metabolic disorders, inflammation, and nerve damage. However, the biological mechanisms underlying how excess dietary fat affects enteric neurons remain unclear. Further research is needed to identify the pathways driving this damage.

About the Study

The researchers studied the effect of fat on the enteric nervous system using laboratory, animal, and human tissue models. They fed male and female mice a standard diet or a high-fat "Western" diet enriched in saturated fatty acids, including palmitic acid, for 12 weeks. They also tested whether boosting nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidant-regulating protein, could reduce nerve damage.

Colonic motility was evaluated using a bead expulsion assay to assess intestinal transit time. Colonic tissue was collected and analyzed for markers of iron deposits, oxidative stress, lipid peroxidation, and neuronal cell death. Quantitative real-time polymerase chain reaction (qPCR), immunofluorescence imaging, western blotting, ribonucleic acid (RNA) sequencing, and other methods were used to assess cellular changes.

The researchers used murine fetal enteric neurons and adult primary-cultured enteric neurons in the experiment. The cultured neurons were exposed to palmitic acid (a saturated fatty acid and a major circulating fatty acid relevant to Western-style dietary fat exposure) to assess how this would affect intracellular iron concentration, mitochondrial function, reactive oxygen species production, calcium signaling, and cell viability. The researchers also used ferrostatin-1, a ferroptosis inhibitor, to determine whether the observed effects were due to ferroptosis.

They cultured myenteric ganglia from humans that had undergone colectomy procedures and also subjected them to the same palmitic acid exposure to measure how palmitic acid affected human enteric neurons versus mouse enteric neurons. They then used advanced imaging and molecular techniques to evaluate cell survival, iron regulation, and supporting cell responses.

Study Results

The study found that exposure to palmitic acid resulted in numerous effects consistent with ferroptosis. Enteric neurons treated with palmitic acid showed increased expression of transferrin receptor 1 (TfR1) and ferritin heavy chain 1 (FTH1), both of which facilitate iron uptake and storage. In addition, there was a decrease in protective pathways that regulate iron export and antioxidant defense mechanisms.

Neuronal markers like class III β-tubulin and neuronal nitric oxide synthase were decreased, suggesting that neuronal cells were losing their normal cellular characteristics. High levels of lipid peroxidation and accumulation of 4-hydroxynonenal showed that oxidative damage was affecting the enteric nervous system. In contrast, ferrostatin-1 reduced iron accumulation within cells, lowered oxidative stress, and prevented cellular death, providing evidence that ferroptosis was responsible for the injury.

Increased levels of palmitic acid correlated with increased levels of oxidative species produced by the mitochondria, altered the structural integrity of the mitochondria, increased the amount of iron in the mitochondria, and decreased the expression of the mitochondrial genes that are responsible for producing energy. Additionally, there was a significant reduction in proteins that inhibit ferroptosis, such as glutathione peroxidase 4 and ferroptosis suppressor protein 1. This reduced protection against oxidative injury and increased the rate of degenerative changes in the neurons.

Functional experiments showed palmitic acid had two specific effects. Neurons showed changes in calcium signaling after a brief exposure. However, after prolonged exposure, neurons became unable to produce normal calcium responses to electrical field stimulation and showed substantial neuronal cell death and loss of neuronal marker expression. These changes after long-term exposure appear to be due to ferroptosis rather than temporary physiological effects, since administration of ferrostatin-1 reduced the long-term effects resulting from chronic lipid exposure. By contrast, ferrostatin-1 did not alter the short-term calcium-signaling effects of palmitic acid, indicating that acute and chronic exposure acted through different mechanisms.

Mice fed a Western diet showed delayed colonic transit, suggesting altered gastrointestinal motility. Furthermore, the mice showed increased iron accumulation, increased markers of ferroptosis, decreased neuronal nitric oxide synthase expression, and evidence of enteric neurodegeneration. When Nrf2 signaling was enhanced, it improved antioxidant defense, reduced iron dysregulation, enhanced neuronal health, and prevented Western diet-induced delayed colonic transit in the mouse model.

Similar findings were observed in human tissues: human myenteric ganglia exposed to palmitic acid showed extensive neuronal death, increased expression of TfR1 and FTH1, and activation of enteric glial cells. In 2 of 14 patient-derived preparations, there was considerable structural damage to the human myenteric ganglia, indicating that palmitic acid exposure induced neuronal ferroptotic signatures, glial activation, and, in some samples, broader structural injury within the human enteric nervous system.

Conclusion

Researchers found that exposure to a Western diet in mice and to palmitic acid in cell and ex vivo human tissue models promoted enteric neurodegeneration through ferroptosis. These changes disrupt gastrointestinal motility and may help explain the digestive symptoms often seen with obesity and metabolic disorders.

The researchers also demonstrated that activating Nrf2 can protect enteric neurons, restore antioxidant levels, and improve gut health in experimental models. Moreover, the discovery of ferroptosis as a new cause of damage to the intestinal nervous system creates opportunities for the future development of treatments to prevent diet-related gastrointestinal problems. However, because the study was conducted mainly in mouse models, cultured murine neurons, and ex vivo human myenteric ganglia, the findings support a mechanistic pathway rather than proving that Western diets directly cause enteric neurodegeneration in humans.

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