Role of Spermidine, a Host-bacterial metabolite, in attenuating Persistent Gastrointestinal Mediated Neurotoxicity in Gulf War Illness Mouse model

Post three decades of Persian Gulf War, Gulf War (GW) veterans suffers from gut dysbiosis persistently resulting in extreme gastrointestinal (GI) and neuroinflammation resulting in cognitive and behavioral impairments. Through a metabolomics analysis, we identified spermidine, a metabolite produced by host-associated bacteria, as a key mediator of microbiome metabolism within the host. Spermidine is a natural polyamine, synthesized through a metabolic pathway involving the amino acid ornithine and has been reported to exert anti-inflammatory and anti-aging properties. Further, spermidine is reported to produce Kynurenine, an Aryl-Hydrocarbon Receptor (AhR) ligand, thereby initiating AhR activation, leading to ameliorating intestinal barrier integrity. Gut barrier disruption with alterations in tight junction (TJ) proteins is widely reported in Gulf War Illness (GWI), leading to persistent GI inflammation, which in turn drives neuroinflammation through blood-brain barrier (BBB) disruption. Therefore, we decided to investigate the therapeutic role of spermidine in attenuating GI mediated neuroinflammation in persistent GWI mouse model. Wild-type C57BL/6J mice were orally gavaged with Pyridostigmine bromide and Permethrin, for two weeks. A subset of these GWI-induced mice was then treated orally with spermidine for five days per week over five months. Our results indicated that spermidine supplementation mitigated the disrupted intestinal gut barrier integrity by restoring the levels of TJ proteins- Occludin and Claudin-2 and decreased the release of pro-inflammatory cytokines- IL-1β and IL-6. Further, spermidine ameliorated intestinal inflammation by decreasing the release of HMGB1 in systemic circulation from intestinal epithelial lining of the small intestine by the activation of AhR/NRF-2/HO-1 pathway. Certain damage-associated molecular patterns (DAMPs), such as HMGB1, can function in an autocrine manner. In this context, we also investigated spermidine’s effect in mitigating intestinal inflammation by inhibiting HMGB1- RAGE activation and attenuating NFκB signaling through the decreased phosphorylation of the p65 subunit. The reduction in circulating HMGB1 levels results in decreased disruption of the blood-brain barrier (BBB) and a reduction in microglial cell activation, thereby mitigating neuroinflammation. These findings highlight the potential therapeutic efficacy of spermidine in ameliorating the inflammatory manifestations of GWI, offering significant insights into the complex molecular mechanisms underlying its effects. This study was supported by VA Merit Award I01CX001923-01 awarded to Dr. Saurabh Chatterjee This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.