The central problem the review confronts is one of fidelity. Traditional animal models of inflammatory bowel disease, for example, rely on chemically induced colitis in rodents, which captures only fragments of the human condition and often fails to predict how patients will respond to drugs. Population-based analyses of the global burden of digestive diseases across 204 countries, and systematic assessments of lifetime gastrointestinal cancer risks across 185 countries, underscore how large the unmet clinical need is. At the same time, statistics on clinical drug development suggest that roughly ninety percent of programmes fail, a figure that many in the field attribute in part to the poor predictive power of preclinical models. The translational gap between animal efficacy data and human outcomes has become one of the most cited justifications for developing human-relevant in vitro systems.

Microphysiological systems address that gap by reconstructing the architecture and dynamics of human tissue at miniature scale. Organoids are self-organising three-dimensional cultures derived from adult stem cells or induced pluripotent stem cells, and they can recapitulate the cellular diversity of the epithelium from which they originate, including absorptive enterocytes, goblet cells, Paneth cells, enteroendocrine cells and tuft cells. Organ-on-a-chip devices go a step further by embedding such cultures within microfluidic channels where engineers can control fluid shear stress, apply cyclic mechanical deformation that mimics peristalsis, maintain anaerobic conditions compatible with obligate gut anaerobes, and co-culture the epithelium with immune cells, fibroblasts, endothelial cells and living microbiomes. The combination of cellular, spatial and mechanical fidelity is what distinguishes these platforms from static cultures.

The review traces the evolution of these technologies from early proof-of-concept devices to today’s increasingly sophisticated models. Landmark studies demonstrated that a human gut-on-a-chip could sustain intestinal bacterial overgrowth and inflammation under controlled flow and deformation, and that a microfluidic interface could model the human–microbe boundary directly. Subsequent work achieved something once thought impossible outside the body: culturing a complex human gut microbiome under anaerobic conditions within an intestine-on-a-chip, allowing investigators to observe host–microbiome crosstalk in real time. In parallel, scaffold-guided organoid morphogenesis produced homeostatic mini-intestines with villus-like architecture, while automated microcavity arrays brought high-throughput organoid culture within reach, addressing one of the field’s persistent scalability problems.

Applications across the length of the gastrointestinal tract now form a substantial body of evidence. In the oral cavity, gingival tissue models have been developed that sustain inflammation and recovery over multi-week experiments, capturing crevicular fluid flow and host–oral microbiome interactions relevant to periodontitis, a condition whose immune cell networks are otherwise difficult to study in isolation. In the oesophagus, organ chips have been used to model epithelial–stromal interactions in Barrett’s oesophagus, the premalignant condition that precedes oesophageal adenocarcinoma, while oesophageal organoid cultures have revealed functional interplay between Notch signalling and inflammatory cytokines and have recapitulated the heterogeneity of oesophageal adenocarcinoma for clonality studies and precision therapeutics. Patient-derived oesophageal adenocarcinoma organ chips are now being positioned as platforms for functional precision oncology.

In the stomach, bioinspired stomach-on-a-chip devices reproduce luminal flow and peristaltic-like motility, and organoid-based microphysiological systems have been engineered to recapitulate the dynamic mucosal defence mechanisms of the gastric lining. A particularly striking recent advance involves Helicobacter pylori, the bacterium responsible for most peptic ulcers and a major risk factor for gastric cancer. Accessible homeostatic gastric organoids have revealed cell-type-specific host–pathogen interactions during infection, and multi-regional gastric assembloids have enabled functional parietal cell maturation and patient-specific modelling of antral foveolar hyperplasia. Because H. pylori deregulates T and B cell signalling to achieve immune evasion, models that pair human epithelium with immune components are especially valuable for dissecting how infection progresses toward metaplasia and malignancy.

The small intestine and colon have seen perhaps the most intense model-building activity. Primary human small intestine-on-a-chip platforms built from biopsy-derived organoids, and induced pluripotent stem cell-derived intestine chips containing self-organising epithelial, mesenchymal and neural cells, have expanded the repertoire of available systems. Nutritional deficiency induced in an intestine-on-a-chip has recapitulated the injury hallmarks of environmental enteric dysfunction, a condition affecting children in low-resource settings that is nearly impossible to model in animals. In celiac disease research, a human autoimmune organoid model revealed a role for interleukin-7 in the disease process, while complementary work has shown that gliadin-dependent unfolded protein responses directly trigger transglutaminase expression, pro-inflammatory cytokine release, permeability dysregulation and reduced CFTR expression in patient epithelial cells.

Inflammatory bowel disease and colorectal cancer receive the most detailed treatment in the review, reflecting both their clinical weight and the maturity of the modelling effort. A newly reported human inflammatory bowel disease-on-a-chip can model disease progression, cancer initiation and even sex-specific effects, addressing a dimension of gastrointestinal physiology that has long been underappreciated. Gut–liver physiomimetic systems have exposed paradoxical effects of short-chain fatty acids on inflammation, and macrophage-augmented intestinal organoids now model virus–host interactions in enteric viral disease. On the cancer side, colorectal cancer organoids have been interrogated by multi-omics to identify mediators of progression following SMAD4 inactivation, oncogenic signalling has been linked to specific differentiation states, and colon tumour organoids have been enabled to undergo peristalsis on microfluidic chips. Microfluidic co-culture models from the review’s own authors examine colonocyte–microbiota interactions and the interplay between dietary fibre, macrophages and colonocytes in colorectal cancer, connecting diet — a known modulator of carcinogenesis — to tumour biology in a controlled setting.

The authors are candid about what these systems still cannot do. Complexity remains a limiting factor: most chips contain a fraction of the cell types present in real mucosa, and the full immune compartment, the enteric nervous system and the spatially organised microbiota of the gut wall are only partially represented. Translation from device to clinic is still early, and scalability — producing enough replicate, standardised tissues for industrial drug screening — continues to challenge the field. Radiation injury studies in gut-on-a-chip platforms illustrate both the promise and the difficulty: such models reproduce cell death patterns and allow countermeasure drug testing, but correlating chip-scale dosimetry with clinical radiotherapy remains an open problem. Interconnected multi-organ systems that link gut chips to liver, brain or vascular modules through robotic fluidic coupling point toward a future in which the gut–liver and microbiota–gut–brain axes can be studied pharmacokinetically, but these assemblies add engineering complexity of their own.

The trajectory the review sketches is nonetheless ambitious. Emerging directions include bioprinted patient-derived organoid arrays that capture both intrinsic and extrinsic tumour features for personalised medicine, artificial intelligence applied to microbiome research and to the analysis of spatially resolved transcriptomics, intelligent intestine-on-a-chip devices that screen probiotics automatically, and organoid platforms for studying ageing signatures in the intestinal epithelium. The authors argue that by bridging microengineering innovation with clinical gastroenterology, next-generation human-relevant models can inform mechanistic discovery, guide targeted therapeutic development and support precision medicine in gastrointestinal disease. For a field in which most patients with inflammatory bowel disease still cycle through therapies by trial and error, and in which gastrointestinal cancers remain among the leading causes of cancer death worldwide, the prospect of testing drugs on miniature replicas of a patient’s own diseased tissue represents one of the most consequential shifts in preclinical medicine now underway.

Subject of Research: Microphysiological systems, including organoids and organ-on-a-chip devices, for modelling human gastrointestinal diseases

Article Title: Microphysiological models of human gastrointestinal diseases

Article References: Peñarete-Acosta, D., Noe, P., Kellogg, T., Li, S., Radolf, J. D., Hyams, J. S., & Jalili, S. (2026). Microphysiological models of human gastrointestinal diseases. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-026-01805-5

Image Credits: AI Generated

DOI: 10.1038/s41551-026-01805-5

Keywords: organoids, organ-on-a-chip, gastrointestinal disease, inflammatory bowel disease, colorectal cancer, gut microbiome, microphysiological systems, Helicobacter pylori, precision medicine, biomedical engineering, mucosal immunity, drug development