Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis

Abstract

Graphical Abstract Highlights d Bacteriophages target specific bacteria and mitigate bacterially driven colon cancer d Phages activate phage-specific and non-specific IFN-g mediated immune responses via TLR9 d Phages exacerbate colitis, and TLR9/IFNg blockade abrogates phage-mediated inflammation d UC patient responses to fecal microbiota therapy correlate with Caurovirales abundance SUMMARY 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-g 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-g. Similarly, ulcerative colitis (UC) patients responsive to fecal microbiota transplantation (FMT) have reduced phages compared to non-responders, and mucosal IFN-g positively correlates with bacteriophage levels. Bacteriophages from active UC patients induced more IFN-g compared to healthy individuals. Collectively, these results indicate that bacteriophages can alter mucosal immunity to impact mammalian health. Duerkop, B.A., and Hooper, L.V. (2013). Resident viruses and their interactions with the immune system. Nat. Immunol. 14, 654-659.

The gut microbiota and its interactions with cardiovascular disease

“…Bacteriophages, the most abundant members of the microbiota, activate IFN‐γ‐mediated immune responses via TLR9. Consistently, TLR9/IFN‐ γ blockade abrogates phage‐mediated inflammation (Gogokhia, et al , ). Elevated levels of circulating inflammatory cytokines, such as TNFα, IL‐6 and CRP (C‐reactive protein), are potent inducers of intestinal permeability (Sandek, et al , ; Al‐Sadi, et al , ; Al‐Sadi, et al , ), which can promote a vicious feed‐forward cycle of heightened endotoxin translocation and inflammatory cytokine accumulation in the circulation (Fig.…”

5 challenges in understanding the role of the virome in health and disease

“…For phages, presuming they act by modulating the bacterial community, the animal model must harbor the relevant bacterial host species, and thus the bacterial microbiome may need to be manipulated as well. Notably, some recent studies have suggested that phages may also interact directly with eukaryotic host cells [28,29]. Overall, significant effort and resources must be expended to establish robust animal-infection models suitable to define the role of the virome.…”

Immunological mechanisms underpinning faecal microbiota transplantation for the treatment of inflammatory bowel disease

“…A seminal study that incorporated an open‐label pilot of FMT explored the role of bacteriophages in altering mucosal immune responses. In this study, 20 patients with active UC treated with a single colonoscopic infusion of FMT showed a positive correlation between CD4 + T cell production of IFN‐γ from rectal mucosal biopsies and the relative abundance of total gut viral reads, specifically the bacteriophage Caudiovirales . They found that this bacteriophage was significantly enriched in patients who failed to respond to FMT.…”