Glucosylceramide production maintains colon integrity in response to Bacteroides fragilis toxin-induced colon epithelial cell signaling

Details

• Alternative Title:
  FASEB J
• Personal Author:
  Patterson, Logan ; Allen, Jawara ; Posey, Isabella ; Shaw, Jeremy Joseph Porter ; Costa-Pinheiro, Pedro ; Walker, Susan J. ; Gademsey, Alexis ; Wu, Xinqun ; Wu, Shaoguang ; Zachos, Nicholas C. ; Fox, Todd E. ; Sears, Cynthia L. ; Kester, Mark
• Description:
  Enterotoxigenic Bacteroides fragilis (ETBF) is a commensal bacterium of great importance to human health due to its ability to induce colitis and cause colon tumor formation in mice through the production of B. fragilis toxin (BFT). The formation of tumors is dependent on a pro-inflammatory signaling cascade, which begins with the disruption of epithelial barrier integrity through cleavage of E-cadherin. Here, we show that BFT increases levels of glucosylceramide, a vital intestinal sphingolipid, both in mice and in colon organoids (colonoids) generated from the distal colons of mice. When colonoids are treated with BFT in the presence of an inhibitor of glucosylceramide synthase (GCS), the enzyme responsible for generating glucosylceramide, colonoids become highly permeable, lose structural integrity, and eventually burst, releasing their contents into the extracellular matrix. By increasing glucosylceramide levels in colonoids via an inhibitor of glucocerebrosidase (GBA, the enzyme that degrades glucosylceramide), colonoid permeability was reduced, and bursting was significantly decreased. In the presence of BFT, pharmacological inhibition of GCS caused levels of tight junction protein 1 (TJP1) to decrease. However, when GBA was inhibited, TJP1 levels remained stable, suggesting that BFT-induced production of glucosylceramide helps to stabilize tight junctions. Taken together, our data demonstrate a glucosylceramide-dependent mechanism by which the colon epithelium responds to BFT.
• Subjects:
  Animals Article Bacterial Toxins Bacteroides Fragilis Bacteroides Fragilis Toxin Colitis Colon Epithelial Cells Glucosylceramidase Glucosylceramides Glucosyltransferases Intestinal Mucosa Metalloendopeptidases Mice Mice, Inbred C57BL Organoids Permeability Signal Transduction Tight Junctions Zonula Occludens-1 Protein

  More +
• Source:
  FASEB J. 34(12):15922-15945
• Pubmed ID:
  33047400
• Pubmed Central ID:
  PMC8140605
• Document Type:
  Journal Article
• Funding:
  T32 GM136577/GM/NIGMS NIH HHSUnited States/ ; P30 DK089502/DK/NIDDK NIH HHSUnited States/ ; S10 OD025244/OD/NIH HHSUnited States/ ; S10 OD025244/CD/ODCDC CDC HHSUnited States/ ; S10 OD021723/OD/NIH HHSUnited States/ ; NIH DK-089502/Integrated Physiology and Imaging Cores of the Hopkins Conte Digestive Disease Basic and Translational Research Core Center/ ; F99 CA245802/CA/NCI NIH HHSUnited States/
• Volume:
  34
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:bd128d67ed5bb1dae96207063b9ec8b6390b03e77f1ab86c4fb3042807cbe300
• Download URL:
  https://stacks.cdc.gov/view/cdc/106472/cdc_106472_DS1.pdf
• File Type:
  [PDF - 2.56 MB ]