Protective Effects of Natural Products, Functional Foods, and Probiotics on NSAID-Induced Small Intestinal Injury: A Systematic Review with Mechanistic Considerations of Oxidative Stress and Microbiome Modulation.

NSAID-induced small intestinal injury is a clinically significant complication among chronic NSAID and aspirin users, yet effective treatment options remain limited. This systematic review evaluated natural products, functional foods, and probiotics for preventing or treating NSAID-induced small intestinal injury. PubMed, Embase, CENTRAL, and CNKI were searched from inception to January 2026 for randomized studies involving adults with NSAID- or aspirin-induced enteropathy assessed using capsule endoscopy or intestinal permeability testing. Risk of bias was assessed using RoB 2 and ROBINS-I. Due to substantial clinical and methodological heterogeneity, meta-analysis was not performed, and findings were synthesized narratively. Twenty-two studies were included: 21 randomized controlled trials and one quasi-randomized study. Geranylgeranylacetone demonstrated protective effects in three of four capsule endoscopy studies. Lactoferrin, zinc carnosine, and fish protein hydrolysate reduced indomethacin-induced intestinal hyperpermeability. Probiotic effects appeared outcome-dependent, with more consistent benefits observed for capsule endoscopy-based mucosal injury outcomes than for intestinal permeability outcomes. Among randomized trials, three were rated as having low risk of bias, 15 had some concerns, and three had high risk. Overall, preliminary evidence suggests that selected natural-origin interventions may protect against NSAID/aspirin-induced small intestinal injury. However, because the certainty of evidence was generally low or very low, these findings should be interpreted as hypothesis-generating and require confirmation in larger, methodologically rigorous trials.