Drug-induced gastrointestinal toxicity: from pathophysiological mechanisms to human-relevant preclinical models

Drug-induced gastrointestinal toxicity (DiGIT) represents a major dose-limiting adverse effect that severely compromises patient outcomes and therapeutic efficacy across global populations. Frequently triggered by chemotherapeutic agents and non-steroidal anti-inflammatory drugs (NSAIDs), DiGIT spans a clinical spectrum from mild dyspepsia to life-threatening complications, including severe mucositis, ulceration, and gastrointestinal (GI) bleeding. Because the GI tract serves as a primary site of drug exposure, its rapidly proliferating epithelial architecture, mucosal immune interface, and complex microbiota, essential components of intestinal homeostasis, are particularly susceptible to off-target therapeutic damage. This review provides a comprehensive analysis of DiGIT across the upper and lower GI tracts, examining the distinct toxicity profiles of NSAIDs and chemotherapy. We detail the underlying pathophysiological mechanisms, focusing on drug-induced epithelial damage, innate immune system activation, and microbiome dysbiosis, alongside current supportive management strategies. Finally, we highlight the preclinical landscape of in vitro toxicity testing, outlining how emerging, physiologically representative bioengineered models can better evaluate GI safety, streamline risk assessment, and improve candidate drug success.