Leveraging Organ-on-Chip Models to Investigate Host-Microbiota Dynamics and Targeted Therapies for Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is an idiopathic gastrointestinal disease with drastically increasing incidence rates. Due to its multifactorial etiology, a precise investigation of the pathogenesis is extremely difficult. Although reductionist cell culture models and more complex disease models in animals have clarified the understanding of individual disease mechanisms and contributing factors of IBD in the past, it remains challenging to bridge research and clinical practice. Conventional 2D cell culture models cannot replicate complex host-microbiota interactions and stable long-term microbial culture. Further, extrapolating data from animal models to patients remains challenging due to genetic and environmental diversity leading to differences in immune responses. Human intestine organ-on-chip (OoC) models have emerged as an alternative in vitro model approach to investigate IBD. OoC models not only recapitulate the human intestinal microenvironment more accurately than 2D cultures yet may also be advantageous for the identification of important disease-driving factors and pharmacological interventions targets due to the possibility of emulating different complexities. The predispositions and biological hallmarks of IBD focusing on host-microbiota interactions at the intestinal mucosal barrier are elucidated here. Additionally, the potential of OoCs to explore microbiota-related therapies and personalized medicine for IBD treatment is discussed.

Keywords: IBD treatment; host–microbiota interactions; inflammatory bowel disease; intestine‐on‐chip.

Figure 1

Dysregulated host–microbiota interactions in IBD pathophysiology. An overview of the complex and dynamic interplay between host cells and luminal microbiota, which is affected by factors such as genetic predisposition or environmental influences (medication, chemicals, stress, lifestyle, and infections). IBD is associated with changes in microbial composition and metabolic activity within the luminal compartment of the intestine. Disruption of the mucosal epithelium is indicated by a reduced mucus layer due to goblet cell malfunction, decreased secretion of antimicrobial peptides following Paneth cell abnormalities, and compromised junctional complex integrity. In response to dysbiosis and epithelial barrier dysfunction, microbiota and microbial products can invade into the lamina propria resulting in an activation of the mucosal immune system. Interactions of translocated microbiota and resident immune cells such as macrophages and dendritic cells further exacerbate a disbalance in regulatory and effector T cell populations and lead to increased immune cell infiltration from the peripheral vasculature. This results in an amplified cycle of chronic inflammation in the intestinal mucosa. Created with BioRender.com.

Figure 2

OoC as a model platform to recapitulate IBD disease phenotypes in vitro. Schematic representation of an IoC model consisting of two individual cultivation compartments separated by a porous membrane as scaffold for cell adhesion. The depicted model consists of a vascular cell layer (endothelial and immune cells) and an idealized 3D epithelial cell layer. The IoC simultaneously allows to independently culture different cell types of the intestine and to dynamically perfuse these cellular compartments. This is not only important to generate a 3D tissue morphology with crypt‐ and villus‐like structures but also as a next step for maintenance of inoculated microbiota without accumulation of cellular debris and bacterial overgrowth. By applying different triggers such as proinflammatory cytokines (TNF‐α, IL‐1β, and IFN‐γ), pathogenic bacteria or bacterial lipopolysaccharide (LPS), nutritional deprivation, and chemical dextran sodium sulfate (DSS) into the indicated compartments (black arrows), IBD‐like phenotypes with clinical hallmarks can be induced. Created with BioRender.com.

Figure 3

Exemplary OoC models for modeling and investigating IBD. A) Schematic illustration of a multicellular three‐lane IoC in the OrganoPlate (Mimetas). The cells were seeded in the adjacent perfusion channels, with an extracellular matrix (ECM) channel in between. The epithelium consisted of Caco‐2 and HT29‐MTX‐E12 cells, whereas the vascular compartment included THP‐1 monocytes and MUTZ‐3 dendritic cells. Both channels were perfused with a proinflammatory cocktail of TNF‐α, IL‐1β to induce IBD‐like conditions. Reproduced with permission.^{[ 242 ]} Copyright 2020, Elsevier. B) Experimental setup of a two‐compartment IoC consisting of Caco‐2 (top) and human umbilical vein endothelial cells (HUVECs, bottom) separated by a porous membrane. Cells were subjected to perfusion on both sides and vacuum pressure for stretch motions. IBD‐like conditions were induced by application of proinflammatory cytokines in different concentrations and either in the HUVEC compartment or in both the Caco‐2 and the HUVEC compartment. Intestinal barrier dysfunction was measured by parallel administration of a permeability tracer. Reproduced under terms of the CC‐BY license.^{[ 241 ]} Copyright 2023, The Authors, published by Public Library of Science (PLOS). C) Perfused IoC model containing intestinal epithelial cells and endothelial cells with circulating immune cells (PBMCs). LPS was used to mimic the presence of the microbiome in the intestinal lumen and to stimulate PBMC attachment and infiltration to induce inflammation. Reproduced with permission.^{[ 245 ]} Copyright 2016, National Academy of Sciences. D) Representation of an IoC incorporating intestinal epithelial cells and circulating PBMC. The combination of LPS and DSS in the presence of circulating PBMCs induces a colitis‐like phenotype by disrupting the 3D tissue architecture, leading to villus atrophy. Reproduced with permission.^{[ 246 ]} Copyright 2018, National Academy of Sciences. E) Outline of an intestinal OoC model consisting of enterocytes, HUVECs, and macrophages. The gut microbiome is partly recapitulated through the presence of pathogenic E. coli 11775, which results in intestinal inflammation in the model. Reproduced under terms of the CC‐BY license.^{[ 247 ]} Copyright 2022, The Authors, published by Frontiers. F) Promotion of an inflammatory disease state by nutritional deprivation (‐N/‐T) in an IoC model. Reproduced under terms of the CC Attribution 4.0 International License^{[ 248 ]} Copyright 2022, The Authors, published by Springer Nature. G) Emulating biopsy‐derived human colonoids into an OoC model with adjacent microvascular endothelial cells. Both compartments are separated by a membrane and are constantly perfused and stretched through a vacuum channel. Exposure to IFN‐γ or IL‐22 increases intestinal barrier permeability, resulting in a leaky gut. Reproduced with permission.^{[ 249 ]} Copyright 2021, Elsevier.

Figure 4

Novel treatment strategies for IBD using IoC platforms. A) Schematic overview of treatment strategies in OoC IBD models to improve the intestinal microecology. OoC models can interfere with IBD conditions with different strategies. Prebiotics such as dietary fibers from nutrition act as substrates for beneficial bacteria in the intestine to promote their growth, thereby restoring the microbial balance. Probiotics such as Lactobacillus, Bifidobacterium, and synthetically engineered strains are administered within OoCs as therapeutic agents to reduce inflammation and to restore the intestinal barrier integrity. Postbiotics, for example SCFAs, secondary bile acids, and tryptophan metabolites, are produced by living microbiota via metabolization and exert anti‐inflammatory and regenerative functions, which can be evaluated in OoCs. B) OoC platforms can facilitate the transition toward personalized medicine in IBD treatment. Incorporating patient‐derived cell sources such as immune cells from the blood or intestinal epithelial cells from biopsies enhances the physiological complexity of the model and their predictability. OoCs further allow testing of fecal microbiota transfer as personalized treatment for IBD or the perfusion of fecal filtrate suspensions to investigate metabolite profiles. Created with BioRender.com.