Patient-derived organoids: A new platform for mechanism research and drug development of gastric intestinal metaplasia

Abstract

In a recent study published in the World Journal of Gastrointestinal Oncology, Liu et al identified taurine as a potential drug for suppressing gastric intestinal metaplasia (GIM) in patient-derived organoids and Atp4a-/- mice. Gastric cancer is one of the leading causes of cancer-related deaths worldwide. GIM is a reversible stage in the Correa cascade of gastric carcinogenesis, which is a research hotspot. Previous research models, which included animals and cells, to some extent limited the progress of GIM. Currently, the rapid development of organoid technology has significantly overcome the limitations of the research models in GIM. Organoid technology provides a novel research model for GIM studies that can preserve molecular characteristics of GIM patients with high similarity, thereby offering experimental evidence to support individualized diagnosis and treatment in the clinic. Here, we discuss research models, current therapeutic drugs, and treatment prospects for GIM. Our view is that future research should focus on patient-derived organoids to conduct more accurate studies of GIM pathogenesis and to advance drug development.

Key Words: Gastric intestinal metaplasia; Patient-derived organoids; Helicobacter pylori infection; Bile acids; Transgenic mice

Core Tip: Gastric intestinal metaplasia (GIM) is a precancerous lesion in the process of gastric carcinogenesis. Organoid technology has overcome the limitations of previous models by preserving patient-specific molecular features. A recent study identified taurine as a potential drug for suppressing GIM in patient-derived organoids and mouse models. Future research should prioritize the use of patient-derived organoids to study GIM pathogenesis and advance drug development more precisely.

This editorial refers to “Taurine suppresses gastric intestinal metaplasia in patient-derived organoids and Atp4a (-/-) mice” by Liu et al, 2026; https://doi.org/10.4251/wjgo.v18.i2.114161.

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INTRODUCTION

Gastric cancer (GC) is one of the major causes of cancer-related deaths. In 2022, the incidence of newly diagnosed GC ranked fifth among all malignant tumors globally, while its mortality rate ranked fourth[1]. The development of GC follows the Correa cascade, progressing from chronic gastritis, atrophy, gastric intestinal metaplasia (GIM), and dysplasia[2]. As a precancerous lesion of GC, GIM is closely related to the occurrence of GC. Interventions for GIM mainly include eradicating Helicobacter pylori (H. pylori) and regular endoscopic follow-up. However, eradicating H. pylori does not completely prevent progression from GIM to dysplasia[3], and there remains a lack of realistic research models and effective treatment options for GIM.

Liu et al[4] in World Journal of Gastrointestinal Oncology found that taurine treatment significantly attenuated GIM progression in an Atp4a-/- mouse model and in patient-derived GIM organoids (GIMOs). These findings highlight the importance of patient-derived organoids (PDOs) for mechanism research and new drug development, enabling more accurate studies of GIM pathogenesis and advancing drug development.

THE COMMON RESEARCH MODELS OF GIM

The etiology of GIM is related to H. pylori infection and bile reflux[3]. Persistent chronic inflammation promotes abnormal activation of caudal-type homeobox protein 2 (CDX2), causing the gastric mucosal epithelium to transform into intestinal epithelium[5]. The pathways involved include the Hippo signaling pathway, the nuclear factor kappa B (NF-κB) signaling pathway, the signal transducers and activators of transcription 3 signaling pathway, the mammalian target of rapamycin signaling pathway, and the Wnt signaling pathway[6], which are characterized by elevated expression of intestinal markers such as CDX1, CDX2, mucin (MUC) 2, and trefoil factor 3[7]. Pathological classification is divided into complete intestinal metaplasia and incomplete-type GIM (Inc IM). It is generally believed that Inc IM carries a higher risk of GC[8].

GIM lacks cell models that can directly reflect the clinical characteristics. Scholars often use GES-1 cells to induce inflammation to mimic the damaged state of gastric mucosal cells[9] or use GC cells, such as AGS and MKN45, in studies[5]. The animal GIM models include H. pylori infection, bile acid gavage, bile acid reflux surgery, and chemical carcinogen induction. Alternatively, ATPase H+/K+ transporting subunit alpha (Atp4a) knockout[10] or CDX2 overexpression[11] transgenic mice can spontaneously develop GIM. The latest findings reported by Liu et al[4] confirmed that pathological changes, including glandular hypertrophy and vacuolar dilation, could occur in Atp4a^-/- mice.

However, animal GIM models have the disadvantages of a long experimental cycle and interspecies differences. Mice with gene editing exhibit extensive genetic variation in the gastric mucosa that does not reflect the chronic pathological characteristics of clinical GIM; furthermore, it is difficult to explain the stem cell origin of GIM.

THE CURRENT RESEARCH STATUS OF GIMOS

Organoid technology can construct three-dimensional structures that resemble in vivo organs by isolating stem cells, exposing them to specific niche growth factors, and supporting them with an extracellular matrix mimetic[12]. PDOs obtained through endoscopic sampling cause less patient trauma, retain the molecular characteristics of patients’ clinical lesions to the greatest extent, and align with the Food and Drug Administration’s call to address the ethical use of experimental animals and reduce animal experiments. GIMOs are currently the most appropriate research model for GIM diseases[13].

Organoid culture combined with multi-omics approaches can reveal the molecular characteristics and distinct cell populations of intestinal metaplasia. The largest GIMOs biobank to date was established by scholars from Hong Kong, China[14]. Twenty-eight GIMOs derived from GIM mucosa obtained from patients undergoing total gastrectomy for GC were characterized along with normal gastric and colonic mucosa using multi-omics approaches. Exhibiting high heterogeneity, GIMOs co-express characteristic molecules of gastric and intestinal mucosa. With their strong differentiation plasticity, they can model various clinical stages of GIM. Kim et al[8] reported extensive intergenic hypermethylation in Inc IM using spatial transcriptomics. Spatial localization in microsatellite-stable GC samples showed a significant enrichment of Inc IM cells. Wei et al[15] demonstrated that overexpression of olfactomedin 4 and myosin heavy chain 9 in GIMOs accelerates glycogen synthase kinase 3 beta ubiquitination, elevates β-catenin levels via the Wnt pathway, and enhances GIM proliferation and invasion.

Utilizing gene overexpression and pharmacological interventions, GIMOs can be induced from normal gastric organoids. Koide et al[16] differentiated human induced pluripotent stem cells into gastric organoids, and then overexpressed CDX2 by using the Tet-On system to induce intestinal phenotypes to establish GIMOs. Using nitrosoguanidine, Li et al[17] treated gastric mucosal organoids derived from C57BL/6J mice, which induced a marked upregulation of intestinal markers (CDX2 and MUC2) alongside a downregulation of gastric markers (ATP4B and MUC6), supporting the hypothesis that GIM originates from MIST1+ stem cells. Shibata et al[18] treated mice with N-methyl-N-nitroso-urea, then cultured GIMOs from the mucosa. When transplanted into xenograft models, these organoids formed tumors, indicating that GIMOs preserve key characteristics of the original tissue. Jin et al[19] constructed gastric organoids from FVB/N mice and treated them with deoxycholic acid, and found that bile acids significantly enhanced the co-expression of p-signal transducers and activators of transcription 3 and KLF transcription factor 5 in the cell nucleus, promoting the occurrence of GIM.

The gastric mucosal microenvironment comprises gastric mucosal cells, immune cells, and the microbial community on the mucosa. The co-culture system established in a Transwell chamber more accurately reflects the state of the gastric mucosa. Ding et al[20] constructed a co-culture system comprising dendritic cells, two-dimensional gastric epithelial layers, and H. pylori. They observed that stronger responses to damage-associated molecular patterns and higher toll-like receptor 9 expression were associated with increased susceptibility to H. pylori-related tumorigenesis[20]. This effect was linked to the creation of an NF-κB binding site in the minor C allele of toll-like receptor 9. Liu et al[21] isolated GIM stem cells from GIM patients using electronic endoscopy and then cultured them in a GIM air-liquid interface model, which can be used for in-depth research on the mucosal barrier.

GIMOs can indicate the direction of treatment for GIM. He et al[22] demonstrated that the telomerase reverse transcriptase/Wnt/β-catenin was activated in gastric organoids infected with cytotoxin-associated gene A protein-HA lentivirus. The antiparasitic drug nidazopyridine could inhibit the Wnt/β-catenin pathway and reduce precancerous lesions in GC. Wang et al[23] improved gastric metaplastic lesions in mice and inhibited GC organoid growth by targeting lipid accumulation. Li et al’s research[24] demonstrated that chloroquine treatment improves the GIMOs status induced by H. pylori + neuromedin U by reversing autophagy dysfunction, restoring leucine-rich repeat-containing G protein-coupled receptor 5 + stem cell volume, enhancing trefoil factor 20 expression, and reducing inflammation.

FUTURE THERAPEUTIC DIRECTIONS IN GIM

For GIM treatment, patients usually undergo staging to identify GC risk using the Operative Link on the GIM Assessment system, and regular endoscopic monitoring is performed to detect GC. The treatment of GIM includes eradicating H. pylori, promoting gastric motility to reduce bile reflux, using ursodeoxycholic acid to improve bile composition, and using gastric mucosal protectants, among other measures.

It is worth noting that some natural and Chinese herbal medicines have also shown therapeutic effects for GIM. Traditional Chinese medicine (TCM) compound prescriptions and Chinese patent medicines offer significant therapeutic efficacy, few adverse reactions, and broad applicability in the treatment of GIM. In the clinic, endoscopic and pathological biopsies have confirmed that TCM can reverse the Correa cascade reaction and control the development of GIM[25]. In basic research, the TCM Wei-Fu-Chun tablet alleviates inflammation by inhibiting the NF-κB pathway and downregulating CDX2 expression, thereby improving GIM[26]; Yue et al[27] found that TCM Wei-Fu-Chun exerts therapeutic effects on gastric fundic gland polyps by promoting ferroptosis; the TCM Wei-Wei decoction enhanced the expression of ATP4A and progastricsin and reversed the development of GC[28]; the TCM Huang-Jin-Shuang-Shen Decoction targeted the abnormally activated Wnt/β-catenin pathway mediated by stearoyl-CoA desaturase to inhibit the proliferation of GC-related stem cells and improve the mucosal pathological state[29].

The high-throughput drug screening technology that combines organoids with microfluidic chips has been widely recognized[30]. For instance, de Poel et al[31] used an organoid-based high-throughput screening platform to evaluate 1400 Food and Drug Administration-approved drugs for cystic fibrosis patients carrying rare gene mutations, demonstrating the therapeutic potential of phosphodiesterase 4 inhibitors and cystic fibrosis transmembrane conductance regulator modulators. Yan et al[32] developed a microfluidic organoid chip capable of generating logarithmic drug concentration gradients. By overlapping two-layer grid structures, the sensitivities of two drugs can be tested simultaneously across 36 concentration combinations in a single run, greatly improving drug-screening efficiency. GIMOs can retain epigenetic characteristics similar to those in situ. Thus, in the future, GIMOs combined with microfluidic chip technology are very promising for improving drug-screening efficiency and facilitating individualized clinical diagnosis and treatment.

CONCLUSION

The findings reported by Liu et al[4] have laid a strong foundation for further study of GIMOs as powerful research models for mechanism exploration and drug development. In the future, organoid technology should be vigorously promoted to gradually replace animal experiments, elucidate the key mechanisms underlying GIM inflammation and cancer transformation in the human population, and provide an experimental basis for individualized patient diagnosis and treatment. For instance, the proliferation rate and morphology of PDOs can be combined with Operative Link on GIM Assessment to assess cancerization risk.

The molecular phenotype of the PDO can be linked to electronic endoscopic staining and magnifying endoscopy. High-throughput drug screening can be combined with technologies such as microfluidic organoid chips to predict clinical efficacy. In addition, a co-culture model of gastric organoids and microorganisms can simulate the stomach’s microecology and support the development of gastric probiotics. GIM still requires in-depth studies with larger sample sizes to find effective therapies to reduce the incidence of GC in the population. Organoid technology provides the most suitable in vitro research model for individualized diagnosis and treatment of GIM.