Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis

Lasha Gogokhia, Kate Buhrke, Rickesha Bell, Brenden Hoffman, D. Garrett Brown, Christin Hanke-Gogokhia, Nadim J. Ajami, Matthew C. Wong, Arevik Ghazaryan, John F. Valentine, Nathan Porter, Eric Martens, Ryan O'Connell, Vinita Jacob, Ellen Scherl, Carl Crawford, W. Zac Stephens, Sherwood R. Casjens, Randy S. Longman, June L. Round

Research output: Contribution to journalArticlepeer-review

364 Scopus citations

Abstract

Bacteriophages are the most abundant members of the microbiota and have the potential to shape gut bacterial communities. Changes to bacteriophage composition are associated with disease, but how phages impact mammalian health remains unclear. We noted an induction of host immunity when experimentally treating bacterially driven cancer, leading us to test whether bacteriophages alter immune responses. Treating germ-free mice with bacteriophages leads to immune cell expansion in the gut. Lactobacillus, Escherichia, and Bacteroides bacteriophages and phage DNA stimulated IFN-γ via the nucleotide-sensing receptor TLR9. The resultant immune responses were both phage and bacteria specific. Additionally, increasing bacteriophage levels exacerbated colitis via TLR9 and IFN-γ. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-γ positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-γ compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health.

Original languageEnglish
Pages (from-to)285-299.e8
JournalCell Host and Microbe
Volume25
Issue number2
DOIs
StatePublished - 13 Feb 2019
Externally publishedYes

Keywords

  • FMT
  • IFN-y
  • T cells
  • TLR9
  • Th1
  • bacteriophages
  • colitis
  • dendritic cells

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