Human Intestinal Organoids as a Model for Acute GI-ARS

Gastrointestinal acute radiation syndrome (GI-ARS) is a consequence of exposure to high doses of ionizing radiation and is characterized by extensive damage to the intestinal epithelium that leads to loss of barrier function, sepsis, and in some cases mortality. Currently there is a critical need to develop new physiologically relevant human models to study GI-ARS and to evaluate potential medical countermeasures (MCMs). This project aims to establish human intestinal organoids (HIOs) as a robust in vitro model for GI-ARS using high- content imaging approaches to assess the therapeutic potential of a microbial based MCM. Optimization of radiation dosing will be performed using a large cohort of HIOs that allow assessment of sex, age, and intestinal region on the response to radiation to be interrogated. A library of biomarkers of radiation damage will be assembled using novel screening approaches that combine multi-omics analysis, bioinformatic pipelines, and network analysis. Following biomarker identification, Cell Painting, a high content morphological profiling technique, will be implemented to characterize the cellular response to radiation treatment in a high throughput manner using a scanning disc confocal microscope and customized analyses package. The generation of detailed cellular and subcellular phenotypic profiles that associate with radiation will be used to enable rapid, quantitative assessment of therapeutic efficacy of a microbial based MCM. The MCMs to be tested are Limosilactobacillus reuteri 6475 (LR6475) organisms as a modality to deliver key growth factors necessary to promote regeneration and repair of the intestinal epithelium that target the intestinal stem cell. At the completion of the proposed studies, HIO will be validated as a translatable model for GI-ARS and a novel imaging based phenotypic screening pipeline for radiation injury and MCM evaluation will be established. This work will significantly advance efforts in radiation countermeasure development, facilitate future therapeutic screening and support preparedness for radiological emergencies. Project Number: 1U01AI195485-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: SARAH BLUTT (+1 co-PI) | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $560,175 | Activity Code: U01 | Study Section: Special Emphasis Panel[ZRG1 DCAI-R (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1U01AI19548501