Oral Alcohol‐Triggered In Situ‐Forming Hydrogel Reduces Gastrointestinal Alcohol Absorption and Mitigates Alcohol‐Induced Organic Injury

ABSTRACT Alcohol‐related organic injury represents a major global public health challenge. Developing a novel strategy for preventing alcohol injury poses significant challenges. Herein, this study reports a “source interception” strategy based on an oral alcohol‐triggered hydrogel (SP@Gel) in the gastrointestinal tract fabricated from natural food‐derived components which undergoes the mitigation of alcohol‐induced injury. First, SP@Gel acts as a molecular sponge and forms a physical barrier to sequester alcohol absorption, substantially decreases blood alcohol and acetaldehyde levels, protects the intestinal mucosa injury in alcohol‐exposed mice. SP@Gel also reduces the increase in hepatic steatosis and oxidative stress induced by alcohol exposure. Next, SP@Gel regulates the intestinal microbiota and maintains metabolic balance. Integrated 16S rRNA sequencing and serum metabolomics reveal that these benefits are associated with the maintenance of gut microbial homeostasis and key metabolites, particularly bile acids. Energy metabolism analysis further demonstrates that SP@Gel alleviates alcohol‐induced metabolic disturbances, preserving oxygen consumption and energy expenditure, and preventing the pathological shift in substrate utilization from pathological lipid oxidation toward physiological carbohydrate oxidation. Collectively, this work establishes a new preventative interception concept for the global public health challenge of alcohol‐induced injury, moving beyond traditional metabolic approaches to offer a safe, efficient, and physiologically precise strategy.