2. Academic Validation
  3. Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells

Gut Bacteria-derived Membrane Vesicles Induce Colonic Dysplasia by Inducing DNA Damage in Colon Epithelial Cells

  • Cell Mol Gastroenterol Hepatol. 2024 Feb 1:S2352-345X(24)00010-9. doi: 10.1016/j.jcmgh.2024.01.010.
Yu Miyakawa 1,  Motoyuki Otsuka 2,  Chikako Shibata 1,  Takahiro Seimiya 1,  Keisuke Yamamoto 1,  Rei Ishibashi 1,  Takahiro Kishikawa 1,  Eri Tanaka 1,  Takayuki Isagawa 3,  Norihiko Takeda 4,  Noriaki Kamio 5,  Kenichi Imai 5,  Mitsuhiro Fujishiro 1
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 2 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Gastroenterology and Hepatology, Academic Field of Medicine, Density and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address: otsukamo-tky@umin.ac.jp.
  • 3 Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
  • 4 Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 5 Department of Microbiology and Immunology, Nihon University School of Dentistry, Tokyo, Japan.
PMID: 38309455 DOI: 10.1016/j.jcmgh.2024.01.010
Abstract

Background & aims: Colorectal Cancer (CRC) is the third most common Cancer in the world. Gut microbiota has recently been implicated in the development of CRC. Actinomyces odontolyticus is one of the most abundant bacteria in the gut of patients with very early stages of CRC. A odontolyticus is an anaerobic bacterium existing principally in the oral cavity, similar to Fusobacterium nucleatum, which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of A odontolyticus on colonic oncogenesis.

Methods: We examined the induction of intracellular signaling by A odontolyticus in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut Organoid model and mouse colon tissues in vivo.

Results: A odontolyticus secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive Reactive Oxygen Species (ROS) in colon epithelial cells. We found that A odontolyticus secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by A odontolyticus-derived MVs was confirmed in the gut Organoid model and also in mouse colon tissues.

Conclusions: A odontolyticus secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.

Keywords

A odontolyticus; Colon Cancer; DNA Damage; Mitochondria; NF-κB.

Figures
Products