Acute radiation syndrome (ARS) caused by exposure to high levels of g-radiation is associated with injury to the gastrointestinal system, which can be life-threatening [1]. Due to the lack of preclinical models that are representative of human pathophysiology, a limited number of drugs have been approved as radiation medical countermeasures (MCMs), and almost all of these are aimed at treating neutropenia. Therefore, there is still a great need for therapies that address the gastrointestinal manifestations of ARS. To meet this challenge, we modeled acute radiation injury using human intestine using organ-on-a-chip (Organ Chip) microfluidic culture technology that can recapitulate organ-level physiology and pathophysiology with high fidelity. Human Intestine Chips were created by lining two-channel microfluidic chips with ileum organoid-derived epithelial cells isolated from healthy patients in one channel and interfacing them with small intestine-derived microvascular endothelial cells across a porous membrane in the second parallel channel. A hypoxia gradient was also generated on-chip to enable co-culture of the human cells with patient-derived complex microbiome (i.e., that contain anaerobes and aerobes) in the presence or absence of a commercially available probiotic consortium (VSL#3) for extended times [2]. Exposure of the Intestine Chips to g radiation (8 Gy) induced villus blunting, expression of DNA damage marker, H2AX, and production of pro-inflammatory cytokines (NGAL, MCP-1, IL-8) in both the epithelium and endothelium. Inclusion of a complex gut microbiome in the chip prior to radiation exposure further increased villus blunting and H2AX expression in both the epithelium and endothelium, while also suppressing expression of the DNA damage repair protein, 53bp1, in the endothelium. Importantly, administration of the VSL#3 probiotic formulation to the epithelial lumen of the Intestine Chip containing complex gut microbiome prior to radiation exposure significantly suppress radiation injury as measured by decreased villus blunting, lower H2AX expression, and suppressed pro-inflammatory cytokine production. Interestingly, however, while the probiotic treatment decreased production of NGAL and MCP-1 by both the epithelium and endothelium, IL-8 production was only reduced in the epithelium. This work suggests that host-microbiome interactions may influence radiation-induced damage in the human intestine and that an existing low-cost, commercially available probiotic could potentially be repurposed as a radiation MCM therapeutic.
References:
[1] Hauer-Jensen, et al. (2014). Nature Rev. Gas. & Hep., 11(8), 470-479.
[2] Jalili-Firoozinezhad, S., et al. (2019). Nature biomedical engineering, 3(7), 520-531.

Thomas Mathiassen

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MICROBIOME-MODULATED ACUTE RADIATION SYNDROME IN HUMAN INTESTINE ORGAN CHIPS

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