Role of epithelial reactive oxygen production for interactions with the microbiome
Background and current state of research
Reactive oxygen species (ROS) serve as one line of defense against pathogenic infection due to their high antibacterial activity. However, chronic or overactivation of ROS production also leads to tissue and DNA damage and thereby to susceptibility for inflammation and cancer. In previous work we identified the microbiome as potent regulator of intestinal epithelial ROS responses (Sommer & Bäckhed 2015 Mucosal Immunology; Sommer et al. 2015 Genome Biology). This led us to hypothesize that intestinal ROS production critically determines host-microbiome interactions and thereby intestinal physiology.
Our goal is to decipher the function of epithelial ROS production for the selection of the microbiome and how defects in this process may affect susceptibility to intestinal inflammation, cancer and metabolic disease.
How to get there
We will investigate the phenotype and disease susceptibility along with the microbiome of mice lacking the key ROS-producing enzyme DUOX2 in the intestinal epithelium. Additionally, we also screened DUOX2-microbiome interactions in human IBD patients.
DUOX2-produced reactive oxygen species (ROS) control intestinal microbiome composition and its epithelial deletion protects from experimental colitis in mice. In humans, IBD patients with high DUOX2 expression display a dysbiotic microbiome. Therefore, dysregulated DUOX2-microbiome interactions associate with intestinal inflammation in both mice and humans. For more details see our latest published manuscript: Link to article
Epithelial Dual Oxidase 2 shapes the mucosal microbiome and contributes to inflam-matory susceptibility. Castrillón-Betancur JC, López-Agudelo VA, Sommer N, Cleeves S, Bernardes JP, Weber-Stiehl S, Rosen-stiel P, Sommer F. Antioxidants. 2023;12(10),1889; DOI: https://doi.org/10.3390/antiox12101889
Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut. Duan J, Matute JD, Unger LW, Hanley T, Schnell A, Lin X, Krupka N, Griebel P, Lambden C, Sit B, Grootjans J, Pyzik M, Sommer F, Kaiser S, Falk-Paulsen M, Grasberger H, Kao JY, Fuhrer T, Li H, Paik D, Lee Y, Refetoff S, Glickman JN, Paton AW, Bry L, Paton JC, Sauer U, Macpherson AJ, Rosenstiel P, Kuchroo VK, Waldor MK, Huh JR, Kaser A, Blumberg RS. Immunity. 2023 Mar 7:S1074-7613(23)00092-4. doi: 10.1016/j.immuni.2023.02.018. PMID: 36917985.
The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium. Sommer F, Bäckhed F. Mucosal Immunol. 2015 Mar;8(2):372-9. doi: 10.1038/mi.2014.74. Epub 2014 Aug 27. PMID: 25160818.
Site-specific programming of the host epithelial transcriptome by the gut microbiota. Sommer F, Nookaew I, Sommer N, Fogelstrand P, Bäckhed F. Genome Biol. 2015 Mar 28;16:62. doi: 10.1186/s13059-015-0614-4. PubMed PMID: 25887251; PubMed Central PMCID: PMC4404278.
Juan Camilo Castrillon-Betancur