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Western diet induces iron-dependent enteric neurodegeneration via ferroptosis
The consumption of Western diets (WD), characterized by high levels of saturated fats such as palmitic acid (PA), raises concerns about their role in enteric neurodegeneration and associated motility disorders. A research study examined the potential of WD and PA to trigger iron-dependent ferroptotic injury within the enteric nervous system (ENS) using murine models, in vitro systems, and human myenteric ganglia.
In this study, mice were placed on either a control diet (CD) or a WD for a duration of 12 weeks, with variations including the systemic AAV9-MaCPNS2 delivery of Nfe2l2 to the enteric neurons. Colonic motility was measured through bead expulsion assays. To assess ferroptosis, researchers used multiple indicators, including iron dysregulation markers transferrin receptor 1 (TfR1) and ferritin heavy chain 1 (FTH1), as well as indicators of lipid peroxidation, namely C11-BODIPY and 4-hydroxynonenal (4-HNE). Other critical assessments included the suppression of glutathione peroxidase 4 (GPX4) and pharmacological inhibition with ferrostatin 1 (Fer-1) in primary enteric neurons, murine myenteric plexuses, and human myenteric ganglia networks (nhMPG).
The findings revealed that mice on a WD displayed delayed colonic transit, increased levels of TfR1 and FTH1, and heightened vulnerability of nNOS neurons. Notably, overexpression of the nuclear factor erythroid 2–related factor 2 (Nfe2l2, also known as Nrf2) effectively reversed these detrimental changes. RNA-sequencing analysis of immortalized murine fetal enteric neurons (IM-FENs) treated with PA indicated disruptions in neurotransmitter signaling, diminished mitochondrial and antioxidant functions, and elevated signatures of iron import and lipid peroxidation.
Additionally, PA exposure increased labile iron (Fe2+) levels, mitochondrial reactive oxygen species (ROS), membrane depolarization, and calcium dysregulation, along with heightened production of 4-HNE and mitoferrin 2 (Mfrn2). Conversely, treatment with Fer-1 preserved mitochondrial integrity, viability, and overall ENS function. In the context of human nhMPG, PA not only induced iron loading in enteric neurons but also facilitated ferroptosis, underscoring the translational relevance of these findings to diet-related enteric neuropathy. [NPID: Western diet, saturated fats, enteric nervous system, gut motility, ferroptosis].
Year: 2026
