Abstract
Background/Objectives: Nicotine-free electronic cigarettes (NFECs) are becoming increasingly popular, especially among youth and non-smokers, yet their effects on the gastrointestinal tract (GIT) remain poorly understood. This systematic review synthesizes available in vitro, in vivo, and limited human evidence on NFEC-associated changes in gastrointestinal health and function. Methods: Literature searches were conducted in Medline, Web of Science, Cochrane, and Scopus in July 2025, following PRISMA guidelines. Eligible studies examined NFEC effects on any GIT segment, including the oral cavity, liver, intestines, and microbiome. Data on study design, exposure characteristics, and main outcomes were extracted and narratively synthesized. Results: Of 111 identified records, 94 full-text articles were retrieved, and 21 studies met the inclusion criteria. Most were preclinical, with only one human pilot study. Evidence from oral cell and microbial models suggests that NFEC aerosols can induce pro-inflammatory cytokine production, impair cell viability, and disrupt microbial metabolism through their base constituents (propylene glycol, vegetable glycerine, and flavourings). Animal studies indicate possible hepatic oxidative stress, altered lipid metabolism, and gut barrier dysfunction, with some data suggesting more pronounced steatosis in nicotine-free exposures compared to nicotine-containing counterparts. Microbiome studies report reduced tight junction expression and altered neutrophil function. Conclusions: Current evidence is limited and predominantly preclinical but indicates that NFEC exposure can affect multiple aspects of gastrointestinal health. Robust longitudinal and interventional human studies are urgently needed to determine the clinical relevance of these findings and to inform regulation and public health policy.