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Expansion of Bacteriophages Is Linked to Aggravated Intestinal Inflammation and Colitis.

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PubMed ID: 30763538

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Gogokhia L, Buhrke K, Bell R, Hoffman B, Brown DG, Hanke-Gogokhia C, Ajami NJ, Wong MC, Ghazaryan A, Valentine JF, Porter N, Martens E, O'Connell R, Jacob V, Scherl E, Crawford C, Stephens WZ, Casjens SR, Longman RS, Round JL

Cell Host Microbe. 02 2019

COMMENT: Previous studies have shown that Bacteriophages are members of the resident gastrointestinal (GI) microbiota, and their composition is significantly different in individuals with inflammatory bowel disease (IBD) compared to healthy controls. Individuals with Crohn’s disease (CD) and ulcerative colitis (UC) display an increase in Caudovirales. Although these viruses do not directly infect the mammalian host, they possess many molecules that could potentially stimulate the immune system. In addition, it has been found that Adherent invasive Escherichia coli (AIEC) and Fusobacterium nucleatum are found on tumors in individuals with intestinal cancer. This work investigates the molecular pathway by which bacteriophages influence mammalian immunity within the GI tract.

Objectives

To determine whether bacteriophages could be employed to target Adherent invasive Escherichia coli (AIEC) in colorectal cancer, we sought to isolate phages against AIEC from the human microbiota...We sought to use purified phages to prevent tumor growth in a mouse model of bacteria-aggravated colorectal cancer.

Since bacteriophages do not infect eukaryotic cells, we sought to understand the mechanism by which they could stimulate IFN-γ using in vitro approaches.

We examined if differences in the intestinal bacteriophage community impact the clinical success of fecal microbiota transplantation (FMT) in active UC patients. To this end, we performed total nucleic acid sequencing to detect the viral community in 20 individuals with active UC prior to and 4 weeks after receiving FMT.

Main results

We identified and sequenced several AIEC-specific bacteriophages from an individual with IBD and chose three that were easily propagated and purified..All of these phages belong to the order Caudovirales, consistent with this order of bacteriophages being increased in individuals with CD.

Mutations in tumor suppressor adenomatous polyposis coli (APC) are a major initiating factor in the etiology of colorectal cancer in humans (Barker et al., 2009). Disease in this model is significantly worsened by colonization with AIEC strains.....Importantly, bacteriophage treatment of AIEC-colonized APCmin animals reduced E. coli colonization...,this reduction in E. coli NC101 colonization was associated with decreased tumor size and enhanced survival.

These results demonstrate that continuous treatment with bacteriophages isolated from the human GI tract can effectively reduce target bacteria in the intestine and protect from an invasive bacteria-exacerbated colorectal cancer.

Analysis of the gene expression profiling data showed that despite the global downregulation of genes associated with cancer, a large set of immune system transcripts and pathways were upregulated in phage-treated animals compared to control.

Data demonstrate that bacteriophages within the gut can stimulate both phage-specific as well as non-specific immune responses and can thus enhance immunity against other organisms present within the gut.

Data indicate that local increases in bacteriophage abundance, as seen in patients with IBD, might also function to exacerbate the inflammation within the intestine and contribute to disease severity.

Caudovirales bacteriophages are even more significantly enriched in individuals who fail to respond to a fecal transplant, which supports the notion that elevated Caudovirales phages might predict FMT failure and need for additional maintenance FMT delivery or escalation of treatment.

Conclusions

We report the use of E. coli-specific bacteriophages to significantly reduce colonization by carcinogenic bacteria and increase survival of animals predisposed to colorectal cancer development.

Consistent with our findings in mice, we identify a positive correlation between mucosal IFN-γ production and total viral abundance.

Given the specificity of bacteriophages for their bacterial targets and their influence on the mammalian intestine, future work is warranted to dissect how these complex interactions can be manipulated for therapeutic benefit.

Contributor

Diana López-Farfán