REGULATION OF HUMAN INTESTINAL ORGANOID REACTIVE OXYGEN SPECIES PRODUCTION AND MITOCHONDRIAL FUNCTION BY DUOX2 GENETIC VARIATION AND MICROBIAL PRODUCTS
نویسندگان
چکیده
Abstract Introduction The DUOX2 intestinal epithelial NADPH oxidase is upregulated in Crohn’s Disease (CD), and mutations are associated with increased CD risk. Oxidative stress loss of mitochondrial function disrupt the barrier promoting inflammatory responses to commensals. relative impact microbial products this regard poorly understood. Hypothesis We hypothesized that genetic variation would be differences cellular reactive oxygen species (ROS) production a Human Intestinal Organoid (HIO) model system. Methods Induced pluripotent stem cell lines derived from pediatric patients without combined missense mutations(R701Q, P982A, H678R) were used generate wild type (WT) DUOX2mut HIOs. Reactive was measured using two-color ROS-ID® Total ROS/Superoxide detection kit, membrane potential (MMP) JC1 staining by flow cytometry HIO EpCAM+ cells CD90+ stromal cells. Expression genes which varied mutation carriage patent ileal biopsies RT-PCR. complex I II activity an Oroboros respirometer. Results Epithelial ROS reduced under basal conditions; difference not observed following pyocyanin stimulation (Fig. 1A). A profound suppression butyrate treatment. Butyrate did alter production. Under these conditions, induction abrogated WT, but 1B). expression core regulating respiratory chain DNA synthesis (COX5B, NDUFA1, POLG2, SLC25A27) HIF1A implicated function, independent genotype (p<0.05). 2A), 2B), conditions. This specific, as vary genotype. Conclusions confirmed effects exposure on Genotype dependent largely butyrate, although inhibition induced intact function. Data suggest previously unanticipated effect MMP respiration. may have implications for mechanisms regulates commensals CD.
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ژورنال
عنوان ژورنال: Inflammatory Bowel Diseases
سال: 2021
ISSN: ['1078-0998', '1536-4844']
DOI: https://doi.org/10.1093/ibd/izaa347.073