Potential Role of HFE‐Mediated Iron Overload and Low Ferroxidase Activity in the Pathogenesis of Refractory SIBO and Autonomic Dysregulation

Background: The clinical management of refractory Small Intestinal Bacterial Overgrowth (SIBO) and persistent gastrointestinal dysmotility represents a significant challenge, as these symptoms are often resistant to standard antibiotic treatments. While frequently categorized as functional disorders, the chronicity and systemic nature of these presentations suggest a possible underlying involvement of the autonomic nervous system. We explore the hypothesis that systemic iron dysregulation, rather than isolated dysbiosis, may contribute to these neuro and gastrointestinal manifestations. Hypothesis: We propose that iron overload mediated by HFE mutations, potentially exacerbated by low ferroxidase activity (ceruloplasmin), may lead to the accumulation of non-transferrin-bound iron (NTBI) in its reactive ferrous state (Fe2+). In this framework, we examine whether a lack of efficient iron chaperoning creates a pro-oxidative environment that could interfere with normal autonomic function. Mechanism: The suggested mechanism involves the Fenton reaction, where excess Fe2+ facilitates the generation of hydroxyl radicals. It is hypothesized that this localized oxidative stress may affect the unmyelinated neurons of the myenteric plexus, potentially leading to autonomic dysregulation. Such an environment could impair intestinal motility, thereby creating a substrate for recurrent and refractory SIBO. Furthermore, this iron dysregulation may act as a nutrient for pathogenic microbiota. This availability supports bacterial proliferation and biofilm formation, further contributing to the refractory nature of SIBO. Clinical Relevance: This model suggests that in patients with overlapping HFE variants and low ceruloplasmin, refractory SIBO may be a symptom of a broader metabolic dysregulation. Consequently, therapeutic strategies could consider the management of the systemic iron burden. Therapeutic phlebotomy is discussed as a potential intervention to reduce reactive iron levels, which might mitigate oxidative stress and support the stabilization of autonomic gastrointestinal function.