Enterotoxigenic Bacteroidesfragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p

Gastroenterology. 2021 Nov;161(5):1552-1566.e12. doi: 10.1053/j.gastro.2021.08.003. Epub 2021 Aug 8.

Abstract

Background & aims: Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear.

Methods: microRNA sequencing was used to detect the differentially expressed microRNAs in both ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit 8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo.

Results: ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF-down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC.

Conclusions: Exosomal miR-149-3p derived from ETBF-treated cells facilitated T-helper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. Targeting the ETBF/miR-149-3p pathway presents a promising approach to treat patients with intestinal inflammation and CRC with a high amount of ETBF.

Keywords: Carcinogenesis; Exosome; Intestinal Inflammation; PHF5A; Th17 Cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteroides fragilis / pathogenicity*
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Colitis, Ulcerative / genetics
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / microbiology*
  • Colitis, Ulcerative / pathology
  • Colon / metabolism
  • Colon / microbiology*
  • Colon / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / microbiology*
  • Colorectal Neoplasms / pathology
  • Crohn Disease / genetics
  • Crohn Disease / metabolism
  • Crohn Disease / microbiology*
  • Crohn Disease / pathology
  • Disease Models, Animal
  • Exosomes / genetics
  • Exosomes / metabolism
  • Exosomes / microbiology*
  • HCT116 Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Host-Pathogen Interactions
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • MIRN149 microRNA, human
  • MIRN149 microRNA, mouse
  • MicroRNAs
  • PHF5A protein, human
  • RNA-Binding Proteins
  • Trans-Activators
  • METTL14 protein, human
  • Methyltransferases
  • Histone Acetyltransferases
  • KAT2A protein, human