Organs-on-a-Chip Recapitulating the Gut–Islets Axis for Endocrine Hormone Secretion Regulator Evaluation

Background
The gut–islets axis connects nutrient sensing in the intestine with insulin secretion from the pancreas and plays an essential role in glucose regulation. GLP-1 released by intestinal L cells can enhance β-cell insulin secretion, and bile acids have recently been shown to influence this process through receptors such as TGR5 and FXR. However, the interaction between gut-derived signals and islet responses is highly dynamic and difficult to reproduce with standard cell culture systems. Most in vitro models lack the three-dimensional structure and fluid environment needed to reflect physiological conditions. A platform that can better mimic gut–islets communication and allow controlled testing of metabolic regulators would therefore be valuable for studying glucose homeostasis and related diseases.

Research Progress
To address the limitations of conventional in vitro models, the research team developed a microfluidic platform that supports the three-dimensional growth of both intestinal L cells and pancreatic β cells. Using a porous hydrogel scaffold produced through droplet microfluidics, the cells were able to form uniform spheroids that remained stable and functional under continuous perfusion. This setup provided a more physiologically relevant environment for studying hormone secretion. Building on this structure, the team integrated a branching microchannel network capable of generating stable concentration gradients, allowing different bile acid levels to be tested in parallel. By connecting L-cell and β-cell compartments in sequence, the chip was able to reproduce a key feature of the gut–islets axis: bile acid–induced GLP-1 release and the resulting enhancement of insulin secretion. Among the bile acids examined, HCA produced the strongest effect on GLP-1 and showed a clear impact on downstream β-cell responses. The consistency of these results with known in vivo trends suggests that the platform can provide a reliable way to evaluate metabolic regulators under controlled conditions.

Future Prospects
The organ-on-a-chip platform offers a practical approach for examining communication between the gut and the islets under controlled conditions, and its applications can be expanded in several meaningful ways. Introducing additional cell types, such as liver cells or microbial components, would enable the system to represent more complex aspects of metabolic regulation. Its capacity to form stable chemical gradients and track hormone responses also makes it well suited for testing bile acid derivatives and other metabolic regulators. In the future, incorporating patient-derived cells may help establish personalized models that reflect individual differences in hormone secretion or drug sensitivity. As advances continue in microfluidic engineering, biomaterials, and analytical methods, such integrated platforms are expected to play an increasingly important role in studying metabolic diseases and supporting the development of new therapeutic strategies.

The complete study is accessible via DOI:10.34133/research.0923

https://spj.science.org/doi/10.34133/research.0923

Title: Organs-on-a-Chip Recapitulating the Gut–Islets Axis for Endocrine Hormone Secretion Regulator Evaluation
Authors: JI SUN , ZHUHAO WU, JINGBO LI, LUORAN SHANG , YUANJIN ZHAO, AND LING LI
Journal: 9 Oct 2025 Vol 8 Article ID: 0923
DOI:10.34133/research.0923

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Fig. 1. Cell viability of the cell spheroids on the microfluidic chip. (A) Photograph of the chip. (B and C) Images showing the gradient generator and culture chamber of the chip. Scale bars, 5 mm. (D) Schematic diagram of cell seeding in the chip. (E) Cell viability of β-cell spheroids and L-cell spheroids (n = 3). (F and G) Fluorescence images of (F) β-cell spheroids and (G) L-cell spheroids were labeled with calcein AM (green) and PI (red) on days 1, 3, 5, and 7. Scale bars, 50 μm.
Fig. 2. Function evaluation of the simulated gut–islets axis on the microfluidic chip. (A) Schematic diagram of the assembled microfluidic chip, L-cell and β-cell seeding, and function evaluation. (B) Expression of pancreatic function-related genes in β-cells after a 5-d culture on the chip (n = 3). P value: 0.0105, 0.0056, and 0.0014. (C) β-Cell insulin secretion under varying conditions (n = 3). P value: 0.0196, 0.0107, 0.0366, and 0.0173. (D) Immunofluorescence image of insulin staining in β-cell spheroids on chip under high-glucose treatment. Scale bar, 50 μm. *P < 0.05, **P < 0.01.
Fig. 3. Evaluation results of BAs on organ-on-a-chip. (A) Schematic diagram of BA evaluation. (B) Photograph of the assembled microfluidic chip. (C) Optical microscopic image showing rhodamine B distribution in the microchannels of the microfluidic chip (100 μM rhodamine solution was pumped through the right inlet at 0.1 μl/min flow rate, and phosphate-buffered saline solution was pumped through the left inlet at the same flow rate). (D) Fluorescent intensity of rhodamine B measured at the terminal branches of microfluidic channels 1 to 4 (n = 3). (E) GLP-1 secretion of L-cell spheroids incubated in gradient concentration of HCA on chip (n = 3). P value: <0.0001, 0.0004, and 0.0173. (F) GLP-1 secretion of L-cell spheroids incubated in the concentration of BAs in channel 4 (n = 3). P value: 0.0201 and 0.0157. (G) Insulin secretion of β-cell spheroids on the integrated microfluidic chips (n = 3). P value: 0.0069 and 0.0024. (H) Insulin secretion of β-cell spheroids in channel 4 (n = 3). P value: 0.0498, 0.0356, and 0.0192. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

18.12.2025 Science and Technology Review Publishing House

Regions: Asia, China

Keywords: Health, Medical, People in health research, Science, Life Sciences

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