An Organ-on-Chip Platform for Simulating Drug Metabolism Along the Gut-Liver Axis.

The human microbiome significantly influences drug metabolism through the gut-liver axis, leading to modified drug responses and potential toxicity. Due to the complex nature of the human gut environment, the understanding of microbiome-driven impacts on these processes is limited. To address this, a multiorgan-on-a-chip (MOoC) platform that combines the human microbial-crosstalk (HuMiX) gut-on-chip (GoC) and the Dynamic42 liver-on-chip (LoC), mimicking the bidirectional interconnection between the gut and liver known as the gut-liver axis, is introduced. This platform supports the viability and functionality of intestinal and liver cells. In a proof-of-concept study, the metabolism of irinotecan, a widely used colorectal cancer drug, is imitated within the MOoC. Utilizing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), irinotecan metabolites are tracked, confirming the platform's ability to represent drug metabolism along the gut-liver axis. Further, using the authors' gut-liver platform, it is shown that the colorectal cancer-associated gut bacterium, Escherichia coli, modifies irinotecan metabolism through the transformation of its inactive metabolite SN-38G into its toxic metabolite SN-38. This platform serves as a robust tool for investigating the intricate interplay between gut microbes and pharmaceuticals, offering a representative alternative to animal models and providing novel drug development strategies.

Agitated ants: regulation and self-organization of incipient nest excavation via collisional cues.

Ants are millimetres in scale yet collectively create metre-scale nests in diverse substrates. To discover principles by which ant collectives self-organize to excavate crowded, narrow tunnels, we studied incipient excavation in small groups of fire ants in quasi-two-dimensional arenas. Excavation rates displayed three stages: initially excavation occurred at a constant rate, followed by a rapid decay, and finally a slower decay scaling in time as t-1/2. We used a cellular automata model to understand such scaling and motivate how rate modulation emerges without global control. In the model, ants estimated their collision frequency with other ants, but otherwise did not communicate. To capture early excavation rates, we introduced the concept of 'agitation'-a tendency of individuals to avoid rest if collisions are frequent. The model reproduced the observed multi-stage excavation dynamics; analysis revealed how parameters affected features of multi-stage progression. Moreover, a scaling argument without ant-ant interactions captures tunnel growth power-law at long times. Our study demonstrates how individual ants may use local collisional cues to achieve functional global self-organization. Such contact-based decisions could be leveraged by other living and non-living collectives to perform tasks in confined and crowded environments.

Human macrophage polarization determines bacterial persistence of Staphylococcus aureus in a liver-on-chip-based infection model.

Infections with Staphylococcus aureus (S. aureus) have been reported from various organs ranging from asymptomatic colonization to severe infections and sepsis. Although considered an extracellular pathogen, S. aureus can invade and persist in professional phagocytes such as monocytes and macrophages. Its capability to persist and manipulate macrophages is considered a critical step to evade host antimicrobial reactions. We leveraged a recently established human liver-on-chip model to demonstrate that S. aureus specifically targets macrophages as essential niche facilitating bacterial persistence and phenotype switching to small colony variants (SCVs). In vitro, M2 polarization was found to favor SCV-formation and was associated with increased intracellular bacterial loads in macrophages, increased cell death, and impaired recruitment of circulating monocytes to sites of infection. These findings expand the knowledge about macrophage activation in the liver and its impact on bacterial persistence and dissemination in the course of infection.

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics.

Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (glucose, lipid, protein and drug) by recreating organ-level function. This review provides a resource for scientists aiming to study human metabolism by providing an overview of MOCs recapitulating aspects of metabolism, by addressing the technical aspects of MOC development and by providing guidelines for correlation with in silico models. The current state and challenges are presented for two application areas: (i) disease modelling and (ii) pharmacokinetics/pharmacodynamics. Additionally, the guidelines to integrate the MOC data into in silico models could strengthen the predictive power of the technology. Finally, the translational aspects of metabolizing MOCs are addressed, including adoption for personalized medicine and prospects for the clinic. Predictive MOCs could enable a significantly reduced dependence on animal models and open doors towards economical non-clinical testing and understanding of disease mechanisms.

Emulating the gut-liver axis: Dissecting the microbiome's effect on drug metabolism using multiorgan-on-chip models.

The homeostatic relationship between the gut, its microbiome, and the liver is crucial for the regulation of drug metabolism processes. Gut microbes are known to influence human health and disease by enhancing food metabolism and providing a first line of defense against pathogens. In addition to this, the gut microbiome also plays a key role in the processing of exogenous pharmaceutical compounds. Modeling the highly variable luminal gut environment and understanding how gut microbes can modulate drug availability or induce liver toxicity remains a challenge. However, microfluidics-based technologies such as organ-on-chips could overcome current challenges in drug toxicity assessment assays because these technologies are able to better recapitulate complex human responses. Efforts are being made to create in vitro multiorgan platforms, tailored for an individual patient's microbial background. These platforms could be used as a tool to predict the effect of the gut microbiome on pharmacokinetics in a personalized way.