Gut-On-Chip Systems: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Moran Morelli.

New mechanistic models, such as organ-on-a-chip provide a more accurate representation of human physiology and could help bridge the gap between clinical and pre-clinical studies. Gut-on-chip models allow researchers to better understand the underlying mechanisms of disease and the effect of different microbial compositions on the gut. They can help to move the field from correlation to causation and accelerate the development of new treatments for diseases associated with changes in the gut microbiome. Here we discuss the main properties of these systems to study host-microbial interactions.

  • gut-on-a-chip
  • microfluidics
  • host–microbial interactions
  • organoids

1. Material

Polydimethylsiloxane (PDMS) is the most widely used material to produce microfluidic systems [14][1]. Its ease of production and ability to be molded into different shapes revolutionized microfluidics and made it accessible to most labs. PDMS is an elastomeric polymer with various advantageous traits for biomedical use, such as biocompatibility, gas permeability, optical transparency, chemical stability, and tunable elasticity and wettability [14,15][1][2].
Despite these advantages, PDMS has some limitations. It can absorb small hydrophobic molecules from- or release free oligomers into- the culture medium, which can affect experimental outcomes [14,15,16][1][2][3]. Mathematical models have been developed to simulate drug concentrations in PDMS microfluidic chips [17][4]. Several coating methods have emerged to overcome small molecule partitioning into PDMS, but studies showed that absorption was variable, time-dependent, and not determined exclusively by hydrophobicity [18,19][5][6]. While such methods can mitigate the absorption of hydrophobic molecules and the release of free oligomers into the culture medium, they often slow the fabrication process and diminish elasticity, transparency, and biocompatibility [15][2].
Although PDMS has led to a wide range of developments for biomedical applications, further work is still needed to improve current surface treatments and the scalability of the production of PDMS-based devices [14][1]. These points will have to be addressed to transfer microfluidic technology from laboratories to industry and, therefore, to the biotechnology market. For this reason, more and more researchers are turning to PDMS-free alternatives for the construction of organ-on-a-chip models [20,21,22,23,24][7][8][9][10][11].

2. Flow

Flow is an inherent property of microfluidic gut-on-chip models, where perfusion of the cell culture medium at defined flow rates is achieved through a variety of methods such as syringes [25,26[12][13][14],27], pumps [21,22,28,29][8][9][15][16] or gravity [23,30,31,32][10][17][18][19]. The perfusion of cells can replicate in vivo fluid flow, exposing cells to the corresponding shear stresses and increasing physiological relevance.
Several examples of improved cell differentiation have been reported in different microfluidic devices [33,34,35][20][21][22]. When comparing Caco-2 cells cultured in static or dynamic conditions, fluidic culture accelerated the formation of leak-tight gut tubules [23][10], improved morphogenesis [20[7][12][22],25,35], and enhanced barrier integrity [20,21,23,36][7][8][10][23]. It also increased CYP3A4 activity [31[18][22],35], glucose absorption [37][24], and mucus secretion [36][23]. Kulthong et al. showed that Caco-2 cultured in static or dynamic conditions showed different responses to nanomaterials [38][25]. Workman and colleagues found that the culture of IPSCs-organoids under a continuous flow resulted in the formation of a polarized epithelium containing all differentiated subtypes and stem cells [34][21].
At the transcriptome level, intestinal cells showed different profiles in static or dynamic conditions [39][26]. Kasendra et al. showed that the transcriptome of duodenal organoids, when cultured in a microfluidic device, more closely mimicked human duodenum compared to the organoids used to prepare the chips [40,41][27][28].
Flow also prolongs epithelial integrity by removing dead cells and improving access to nutrients [42,43][29][30]. This is especially useful in models of host-microbial interactions, where microbial overgrowth is an important limitation [44][31]. Using a microfluidic device with the flow and cyclic strain, Kim and coworkers co-cultured Caco-2 and L. rhamnosus GG (LGG) for up to a week without impairing barrier integrity. In contrast, loss of barrier function and cell death was observed after only 48 h in a transwell system [25][12].
While it is now clear that fluid flow and corresponding shear stresses can improve physiological relevance, only a few studies have explored which flow profiles are best for intestinal epithelial cell differentiation. Using a two-channel system, Shin et al. showed that basolateral flow was crucial for epithelial morphogenesis [45][32]. Langerak and colleagues showed that pump-driven flow improved cell differentiation compared to gravity-driven flow [46][33]. Fois et al. compared a dynamic flow rate to a constant flow rate and showed that the dynamic flow rate had no biological benefit but a reduced reagent consumption, which is an essential parameter for scalability [47][34]. Further work will have to investigate the effect of flow parameters such as shear stress, dynamic or constant flow, and—in the case of multicompartment platforms—apical and basolateral flow profiles.

3. Mechanical Forces

The intestine undergoes ring and segmental contractions, which serve a propulsive function. Their frequency range from 2 to 20 per minute, with high frequencies towards the duodenum and low frequencies towards the colon [48,49,50,51][35][36][37][38]. Increasing evidence suggests that these mechanical forces also influence homeostasis and intestinal development. For example, alterations in gut motility play a role in inflammation and several disorders, such as inflammatory bowel disease (IBD) [48,52][35][39]. Moreover, several studies showed that intestinal mobility and gut microbiota were inter-regulated [8,53,54,55,56][40][41][42][43][44].
A limited number of studies have explored the impact of mechanical forces on intestinal epithelial cells (IECs) development, homeostasis, and interaction with microbes. Kim et al. used a system of vacuum chambers and cyclic suction to mechanically deform Caco-2 and mimic peristalsis. Cyclic strain did not affect cell morphology nor trans-epithelial electrical resistance (TEER) values but increased paracellular permeability and aminopeptidase activity [25][12]. Later, they observed that the cessation of cyclic strain—but not flow—was sufficient to induce the overgrowth of GFP-labelled E. coli on Caco-2 cells [57][45]. Using a similar device, Grassart and coworkers observed that cyclic strain enhanced Shigella invasion in Caco-2 cells, indicating that the bacteria took advantage of the gut micro-architecture to increase its virulence [58][46]. In a similar study, Bouquet-Pujadas et al. studied the effect of peristalsis on the invasion of two enteroinvasive microbes: S. flexneri and E. histolytica. They observed that the virulence of both pathogens was increased by peristalsis, even though the invasion mechanisms of each pathogen were different [59][47].
In jejunal organoids, cyclic stretch did not affect the response to a bacterial virulence factor [60][48]. In colon organoids cultured in a microfluidic device, stretching did not have a clear impact on the polarization of IECs but enhanced the terms relating to the transport of water, ions, and lipoproteins at the transcriptome level [61][49]. Adding mechanical stretch on top of flow did not contribute to the further differentiation of jejunal organoids [33][20].
Jing and colleagues used a 3-channel system and a multi-channel pneumatic pump to regulate air pressure to the fluid medium, allowing for the generation of a periodic and physiologically relevant pressure difference between the middle channel and the two adjacent channels. They observed that periodic peristalsis promoted the growth and differentiation of epithelial cells compared to static transwell models [28][15]. However, because this study compared a microfluidic device with flow and peristalsis to a static transwell model, it was impossible to assess whether the results obtained were a direct consequence of peristalsis alone.
A recent computational study showed that, together with pore size, peristalsis was one of the critical factors affecting shear stress on the membrane surface of gut-on-chip systems, indicating that these factors could play a pivotal role in cell differentiation [62][50]. Although increasing evidence shows that mechanical forces influence the biology of intestinal mucosal cells [48[35][51],63], not many models have explored this perspective. To this day, the standard method to include peristalsis is the use of a cyclic strain through vacuum chambers [25][12], which was initially designed to mimic breathing in lung models and might, therefore, not fully mimic peristalsis [33][20]. The effect of different types of mechanical stimuli on intestinal cultures will have to be investigated to determine whether current approaches faithfully replicate in vivo situations.

4. Oxygen-Gradient

A descending oxygen gradient is present along the length of the intestine and across its wall. In the small and large intestines, the lumen is in a state of physiological hypoxia and is home to trillions of microbes, most of which are strict anaerobes. Although there is a strong need to develop more representative models of the intestine, mimicking physiologic intestinal hypoxia in vitro remains challenging because human cells require oxygen while standard cell culture methods are performed in an aerobic environment.
The first microfluidic model allowing the co-culture of human cells and anaerobic microbes in separated compartments was reported in 2016 and called human-microbial cross-talk (HuMiX). Shah et al. successfully co-cultured Caco-2 with L. rhamnosus or the strict anaerobe B. caccae for 48 h and showed a differential response between the two species. Oxygen sensing was performed using 5 mm-wide optical sensors [21][8].
Furthermore, Shin and colleagues developed the anoxic–oxic interface-on-a-chip using an anoxic medium to generate a controlled oxygen gradient, which allowed the culture of Caco-2 to be in direct contact with two obligate anaerobes for up to a week [64][52]. They performed in situ measurements using dendrimer-encapsulated nanoparticles (Pt-DENs) [65][53]. In a later iteration, they developed the physiodynamic mucosal interface-on-a-chip (PMI chip), containing a convoluted microchannel, in which they co-cultured Caco-2 with human fecal microbiome [66][54].
In addition, Jalili-Firoozinezhad et al. incorporated physiologic oxygen gradients into a gut-on-a-chip and co-cultured Caco-2 or primary ileal organoids in direct contact with complex fecal-derived microbiota for five days. The authors measured real-time oxygen concentration using fluorescent sensors [67][55].
Finally, De Gregorio and coworkers reproduced the architecture and vertical topography of the microbiota in an immune-competent gut-microbiota axis model (MihI-oC) with a complex serosal environment composed of a responsive extracellular matrix (ECM) and the release of immune mediators from various cell types (epithelial, stromal, blood, microbes). The authors measured oxygen using an optical detector (OXY-4 PreSens) [68][56].
One of the main limitations of previously described anaerobic gut-on-chip models is that none showed whether intestinal epithelial cells were in normoxic conditions. To address this issue, Wang et al. described a standalone microfluidic device with fluorescent oxygen sensors and partitioned the oxygen environment to allow cells to remain under normoxic conditions while bacteria were under anoxic conditions. To verify the oxygen status, the authors used three complementary methods––(i) an in-situ oxygen sensor was used to measure oxygen levels in the device, (ii) pimonidazole was used to measure oxygen levels of the intestinal cells, and (iii) a GFP facultative anaerobe was used to measure oxygen levels of the bacteria [69][57]. The combination of these methods enabled a more comprehensive monitoring of oxygen concentrations within the device and allowed for the regulation of oxygen tension to meet the needs of both host cells and anaerobic bacteria; this is an improvement upon the monitoring methods described in previous reports.
In the last five years, the emergence of new models recapitulating physiologic hypoxia has allowed the co-culture of strict anaerobes with human cells. The improvement and miniaturization of oxygen sensors enabled the development of new platforms with integrated oxygen sensors and higher throughput [22,70][9][58]. Microfluidic models play a pivotal role in improving the simulation of the intestinal oxygen gradient and recapitulating physiological conditions to co-culture aerobic and anaerobic micro-organisms and better mimic host-microbial interactions.

5. Micro-Architecture

When viewed from inside the lumen, the epithelium of the colon appears flat, while the epithelium of the small intestine displays finger-like projections referred to as villi. Both the small intestine and colon have invaginations called crypts, which contain stem cells at the bottom and differentiated cells at the top [71][59]. Several microfluidic models were used to study the spatial arrangement of intestinal cells and their role in homeostasis and host-microbial interactions.
Kim et al. showed that Caco-2 spontaneously formed villi-like undulating structures when exposed to a peristalsis-like motion and fluid flow. Such arrangements were similar to the microenvironment of the intestine, with proliferative niches located in the crypts and differentiating cells moving along the crypt-villi axis to differentiate into all subtypes of intestinal epithelial cells [35][22]. They later showed that microbial cells predominantly colonize intervillous spaces [57][45]. Using a similar model Grassart and colleagues showed that crypt-like structures were critical for Shigella adhesion [58][46]. Similar crypt-villi-like structures were observed in other gut-on-a-chip models using Caco-2 [20][7], duodenal organoids [40[27][28],41], and IPSCs organoids [34][21], but not in jejunal organoids [33][20].
Other groups used microfabricated scaffolds to mimic intestinal micro-architecture. Wang et al. showed that chemical gradients applied to an epithelial monolayer and cultured on a microfabricated scaffold recapitulate in vivo responses of intestinal crypts [72][60]. Nikolaev et al. used laser-cut scaffolds to develop a gut-on-a-chip model to re-create the spatial arrangement of the crypt-villus axis, which remained stable for several days in culture and allowed long-term host–microbial studies [42][29]. Shin and colleagues co-cultured fecal microbiota and Caco-2 cells in a convoluted channel with multiaxial deformations, which induced dynamic cell trains and enhanced luminal particle mixing [66][54]. Using a collagen-scaffold mimicking intestinal villus, Shim et al. observed improved metabolic activity in cells cultured in 3D on the scaffold, compared to cells in 2D. However, they also observed a higher permeability and lower villi height, indicating that the potential increased shear stress at the top of the villi could be detrimental to the cells [31][18]. By pouring collagen into a PDMS mold, Verhulsel and coworkers developed a model with the topography and dimensions of the mouse gut, in which they co-cultured primary mouse epithelial cells and fibroblasts in conditions closely resembling the in vivo intestinal epithelium [43][30].
Two-dimensional models are incapable of fully recreating the micro-architecture of tissues. With the advent of 3D cell culture models, it became possible to replicate the micro-architecture of the intestine and examine the spatial arrangement of cells in homeostasis or disease. Further development in microfabrication techniques, such as 3D printing, would allow the combination of micro-scaffold with extracellular matrices to better mimic the gut microenvironment and create more relevant intestinal models.

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