Comparative gastrointestinal organoid models across species: A Zoobiquity approach for precision medicine

Abstract

Gastrointestinal (GI) health underpins systemic well-being, yet the complexity of gut physiology poses significant challenges to understanding disease mechanisms and developing effective, personalized therapies. Traditional models often fail to capture the intricate interplay between epithelial, mesenchymal, immune, and neuronal cells that govern gut homeostasis and disease. Over the past five years, advances in organoid technology have created physiologically relevant, three-dimensional GI models that replicate native tissue architecture and function. These models have revolutionized the study of autoimmune disorders, homeostatic dysfunction, and pathogen infections, such as norovirus and Salmonella, which affect millions of humans and animals globally. In this review, we explore how organoids, derived from intestinal and pluripotent stem cells, are transforming our understanding of GI development, disease etiology, and therapeutic innovation. Through the "Zoobiquity" paradigm and "One Health" framework, we highlight the integration of companion animal organoids, which provide invaluable insights into shared disease mechanisms and preclinical therapeutic development. Despite their promise, challenges remain in achieving organoid maturation, expanding immune and neuronal integration, and bridging the gap between organoid responses and in vivo outcomes. By refining these cutting-edge platforms, we can advance human and veterinary medicine alike, fostering a holistic approach to health and disease.

Keywords: Companion animal models; Comparative biology; Disease modeling; Gastrointestinal organoids; Intestinal stem cells; Zoobiquity; iPS cells.

Fig. 1

Summary of intestinal organoid development from intestinal stem cells (ISCs) or pluripotent stem cells (PSCs). Primary organoids are first established as enteroids or colonoids from ISCs, embedded in Matrigel, and as Matrigel-free mini-gut structures from PSCs. Advanced “engineered organoids” are generated through modifications such as apical polarity engineering (e.g., apical-in or apical-out orientations) and the incorporation of additional cell types, including immune cells (e.g., intraepithelial lymphocytes and macrophages) and neural components. These engineered models enable the study of complex interactions between the intestinal epithelium, immune system, and neural system, simulating in vivo-like microenvironments.

Fig. 2

Overview of intestinal organoid applications and the Zoobiquity approach in organoid studies. Organoids derived from adult stem cells (ASCs) or PSCs can be used for modeling host-pathogen interactions, refractory intestinal diseases, and genetic disorders. Pathogens such as viruses, bacteria, parasites, and disease-related factors (e.g., cytokines and hypoxia) can be applied to these systems for in-depth analyses. Organoids also provide platforms for gene editing, patient-derived models, and translational feedback to clinical settings. The Zoobiquity framework bridges human and veterinary medicine, emphasizing shared diseases (e.g., zoonoses, IBD) and facilitating comparative studies integrating organoid-based insights with whole-body systems.