Controlling systemic disease from the gut: intestinal ROS as an upstream driver of systemic inflammation

Oxidative stress has long been implicated in the pathogenesis of a wide range of chronic diseases; however, systemic antioxidant therapies have yielded limited clinical benefits, partly due to their non-selective distribution and interference with physiological redox signaling. Increasing evidence suggests that the intestine plays a central role in amplifying systemic inflammation, yet the causal contribution of intestinal reactive oxygen species (ROS) has remained unclear. In this review, we summarize a series of studies demonstrating that selective scavenging of intestinal ROS, achieved by orally administered, non-absorbable antioxidant nanoparticles, exerts profound effects on whole-body pathophysiology without systemic drug exposure. These gut-localized antioxidants remain confined to the intestinal lumen, effectively suppressing oxidative damage to the intestinal barrier while avoiding adverse effects associated with intracellular or mitochondrial ROS depletion. Experimental evidence across multiple disease models shows that attenuation of intestinal oxidative stress prevents systemic inflammation, reduces circulating pro-inflammatory cytokines such as interleukin-6, and improves diverse pathological outcomes, including exercise-induced organ damage, depression-like behaviors via the gut–brain axis, and muscle wasting in cancer cachexia. Collectively, these findings establish intestinal oxidative stress as an upstream driver of systemic disease progression and highlight gut-confined antioxidant intervention as a safe and mechanistically distinct therapeutic strategy. This concept provides a new framework for re-evaluating oral antioxidant therapy from the perspective of intestinal redox control and its clinical implications.