Ahmad Arzouni

Neuroglobin (NGB), initially identified for its oxygen-binding capacity in neuronal tissues, has emerged as a multifunctional protein involved in neuroprotection, oxidative stress regulation, and mitochondrial homeostasis. Although its functions have been extensively studied in the central nervous system (CNS), its potential role in the gut–brain axis (GBA) remains largely unexplored. The GBA integrates neural, endocrine, immune, and metabolic signaling between the gastrointestinal tract and the brain, and growing evidence from microbiome, neurobiology, endocrinology, and nutrition research suggests that several pathways involved in GBA signaling may also influence NGB expression or activity. However, direct experimental evidence, particularly from in vivo studies, remains limited. This hypothesis-driven review integrates evidence from diverse fields to explore the possibility that NGB may represent a molecular link between gut-derived signals and neuroprotective mechanisms. We summarize current knowledge of NGB biology and discuss indirect evidence indicating that microbial metabolites, dietary phytochemicals, and hormonal mediators, including estradiol, may converge on pathways associated with NGB regulation. Based on these observations, we propose a conceptual framework in which NGB could participate in gut–brain communication while emphasizing that this hypothesis requires experimental validation. By bringing together findings that have not previously been considered within a unified context, this review highlights key knowledge gaps, opens new perspectives on the potential involvement of NGB in the GBA, and provides a foundation for future mechanistic studies in neurodegenerative and neuroinflammatory disorders.