Current advances in restoring intestinal barrier homeostasis by natural medicines

The intestinal mucosa serves as a critical interface separating the internal environment of the human body from the external milieu, with its barrier function determining the appropriate entry of luminal contents. Dysfunction of this barrier is closely associated with the development of intestinal disorders, such as inflammatory bowel disease and irritable bowel syndrome, as well as a spectrum of extraintestinal diseases. Both Eastern and Western traditional medicine regard the intestine as central to overall health, and since most natural medicines are administered orally, they are likely to interact with the intestinal mucosa and could potentially influence intestinal barrier homeostasis.

This review summarizes the mechanisms by which natural medicine (including compounds and extracts) restores the homeostasis of the intestinal barrier, and further elucidates their therapeutic implications for ameliorating both local intestinal pathologies and systemic extraintestinal diseases.

This review is based on a comprehensive synthesis of recent literature regarding the restoration of intestinal barrier homeostasis. The focus is on the mechanisms through which natural medicines, including herbal extracts and traditional Chinese medicine (TCM) formulations, influence intestinal epithelial cells, immune regulation, and gut microbiota balance, as well as the role of the "Gut-X axis" in modulating extraintestinal diseases. Relevant studies published in English between January 1, 2020, and September 30, 2025, were identified through a systematic search of databases such as PubMed, Web of Science, Scopus, and Google Scholar. Only original preclinical research, including in vitro, ex vivo, and animal model studies, was considered. Keywords related to natural medicines, intestinal barrier integrity, TCM, herbal extracts, formulations, and relevant mechanisms (e.g., inflammation, microbiota regulation, epithelial integrity) were used for the search. Studies were assessed for relevance, and key data on therapeutic effects and mechanisms were extracted for further analysis.

The analysis demonstrates the multi-targeted efficacy of natural medicines in restoring intestinal barrier homeostasis, specifically in: enhancing epithelial integrity; regulating intracellular programs such as apoptosis and autophagy; balancing immune responses; remodeling the gut microbiota-metabolite profile; and exerting therapeutic impact across established "Gut-X axes" (specifically the Gut-Lung, Gut-Liver, Gut-Brain, Gut-Endocrine, and Gut-Heart axes).

The multi-targeted nature of natural medicines mirrors the complexity of intestinal barrier regulation, yet also presents a challenge for mechanistic delineation. Overcoming the inherent limitations of current research necessitates a paradigm shift towards a systems medicine approach. This transition is essential to systematically decode the sophisticated pharmacology of natural medicines and elucidate their synergistic actions on the intestinal barrier.