Despite the significant advancements brought by immune checkpoint inhibitors (ICIs) in melanoma treatment, patient responses are widely varied. Researchers suspect that the gut microbiome plays a significant role in influencing these responses. The study introduces an innovative microfluidic chip model that mimics the human gut’s architecture and functionality, including fecal microbiome interactions and peristaltic movements. This model aims to understand how the gut microbiome affects the effectiveness of ICIs in melanoma treatment.
“In this Article, we present a system that mimics the architecture and functionality of the human intestine and that is suitable for studying microbiome–host interactions. It relies on intestinal cells co-cultured with microvascular endothelial cells on a compartmentalized microfluidic 3D system actuated with a peristaltic-like motion. We employ it to dissect the effects, in their intestine, of the microbiota of patients with melanoma who are responsive or non-responsive to immunotherapy, and provide mechanistic insights “, the authors explained.
“a, The device is composed of an intestinal epithelial channel and a vascular endothelial channel separated by ECM-like gel; a superimposed actuation chamber allows cyclic controlled deformation of the construct that mimics peristalsis. PDMS, polydimethylsiloxane. b, Microfluidic device and external actuation system. c, Brightfield and live/dead fluorescence image of hiPSCs-derived organoids in plate. d, Representative confocal images (n = 13 in 2 independent experiments) of intestinal cells from disaggregated hiPSCs-derived organoids after 9 days of culture on chip. DAPI (blue), ZO-1 (green), Ki67 (cyan) and villin (magenta). e,f, Epithelial cells polarization from disaggregated organoids. Representative confocal image and fluorescence intensity plot on z axis of nuclei (DAPI, blue) and apical occludins (ZO-1, green) in combination either with villin (magenta, e) or MUC5AC (red, f). g, Representative confocal images (n > 4 in 2 independent experiments) of the different intestinal cell lineages from disaggregated hiPSCs-derived organoids after 9 days of culture on chip. MUC5AC (red), MUC2 (yellow), E-cadherin (white), ZO-1 (green), chromogranin A (cyan, Chromo A) and lysozyme (magenta). Chromo A, chromogranin A. h,i, Fluorescence microscopy images (h) and quantification (i) of Ki67 (cyan), villin (magenta), MUC5AC (red) and MUC2 (yellow) in static versus actuated chips. Mechanical actuation resulted in increased proliferation (Ki67, nstatic = 4, nactuated = 4, P = 0.0368), maturation (villin, nstatic = 3, nactuated = 3, P = 0.0035) and mucus production (MUC5AC, nstatic = 2, nactuated = 4; MUC2, nstatic = 1, nactuated = 2). Bars represent mean ± s.d., two-tailed unpaired t-test. *P ≤ 0.05; **P ≤ 0.01. A, area; Stat, static chips; Act, actuated chips. j, Representative brightfield images (n > 8 in 2 independent experiments) of epithelial cells from disaggregated hiPSCs-derived organoids cultured in static versus actuated conditions highlighting the formation of 3D villi-like structures. k, Representative confocal images (n = 13 in 2 independent experiments) and 3D reconstruction of villi-like structure on chip. Dashed lines indicate the axis along with the (x,z) and (z,y) confocal images used for the reconstructions where taken.” Reproduced from Ballerini, M., Galiè, S., Tyagi, P. et al. A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma. Nat. Biomed. Eng (2025). under a CC BY 4.0 Attribution 4.0 International license
The proposed gut-on-a-chip microfluidic device consists of two main channels microfabricated using PDMS: a vascular channel lined with human microvascular endothelial cells and an intestinal channel housing intestinal organoids from human induced pluripotent stem cells, separated by a collagen matrix. This setup not only enables detailed studies under dynamic conditions akin to the human gastrointestinal environment but also facilitates the exploration of microbiome-host interactions that influence treatment outcomes.
Researchers incorporated fecal samples from melanoma patients into the intestinal microfluidic channel of the gut-on-a-chip. Multiomic analyses revealed specific epithelium-related biomarkers and microbial factors associated with patient responses to ICIs. The chip’s environment allowed for the observation that the microbiome of patients who did not respond to treatment had diminished capabilities in buffering cellular stress and regeneration, hinting at potential pathways for enhancing therapeutic efficacy.
This gut-on-a-chip microfluidic model showcases a breakthrough in predicting and understanding the variable responses of melanoma patients to immunotherapy. By integrating human-like mechanical and microbial interactions, it holds promise for identifying prognostic biomarkers and therapeutic targets that could lead to more personalized and effective cancer treatments.
“Overall, the gut-on-a-chip can be employed to quantitatively investigate the molecular effects associated with bacterial components and to develop them into more effective and safe therapies.“, the authors concluded
Figures are reproduced from Ballerini, M., Galiè, S., Tyagi, P. et al. A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-024-01318-z under a CC BY 4.0 Attribution 4.0 International license.
Read the original article: A gut-on-a-chip incorporating human faecal samples and peristalsis predicts responses to immune checkpoint inhibitors for melanoma
For more insights into the world of microfluidics and its burgeoning applications in biomedical research, stay tuned to our blog and explore the limitless possibilities that this technology unfolds. If you need high quality microfluidics chip for your experiments, do not hesitate to contact us.
Traditional developmental toxicity (DevTox) studies largely rely on mammalian models to assess chemical impacts on…
Circulating tumor cells (CTCs) hold the potential for cancer diagnosis and monitoring, offering a non-invasive…
Leukocyte differentiation and counting are critical for clinical diagnostics but are hindered by the low…
Screening for microbial proteolytic activity is essential in various biotechnological applications, including bioenergy, food processing,…
Understanding how cellular components, especially chromatin and nuclear condensates, respond to mechanical forces during confined…
In droplet microfluidics, high-throughput screening is critical for analyzing large cellular or molecular libraries at…