A149 LYTIC PHAGE REDUCES COLITIS SEVERITY IN MICE COLONIZED WITH IBD-ASSOCIATED <i>E. COLI</i> NRG857C
Bibliographic record
Abstract
Abstract Background Current therapies for inflammatory bowel disease (IBD) suppress inflammation rather than inhibiting the underlying drivers. Treatment failures can lead to dose escalation and risk of adverse effects. Bacteria with pathogenic potential, like adherent-invasive Escherichia coli (AIEC), have been postulated as one possible microbial driver in Crohn’s disease (CD), however, targeting these bacteria with precision in IBD remains challenging. Most antibiotics have broad-spectrum activity and disturb the background microbiome, which may exacerbate inflammation. Aims We aimed to assess whether and how bacteriophage, specific for a CD-associated bacterium, improves colitis severity in gnotobiotic mouse models. Methods Adult germ-free C57BL/6 mice were colonized with altered Schaedler-flora (ASF) and E. coli NRG857c (NRG), a CD-associated isolate. After 3 weeks, mice were treated with an NRG-specific lytic phage (1x109 PFU/dose; daily or TIW) or vehicle (PBS) for 2 weeks (n=6/group) and then exposed to 1 cycle of dextran sulfate sodium (2%; DSS) in drinking water. Additional PBS-treated mice (n=6) not exposed to DSS served as controls. Phage treatment was also tested in a spontaneous model of colitis using C57BL/6NTac-Il10em8Tac (IL-10-/-) mice, treated weekly with phage. In both models, mice were monitored daily for weight, stool consistency, and occult blood. Fecal contents were cultured to determine bacterial load, and the expression of NRG fimS was quantified using qPCR as an assessment of bacterial virulence. At endpoint, colon tissues were collected for histological and immunohistochemistry analysis to quantify colitis severity and NRG infiltration, respectively. Results In ASF and NRG colonized mice, phage treatment reduced clinical symptoms (p&lt; 0.001, p&lt;0.001) and histological scores (p&lt; 0.0001, p&lt; 0.001) of chemical and spontaneous colitis respectively. A1-log reduction in NRG bacterial load was observed in phage-treated mice (p&lt; 0.001), and reisolated NRG exhibited a reduced FimS ON/OFF ratio (p-value &lt; 0.01). Immunohistochemistry revealed reduced infiltration of NRG into the lamina propria following phage treatment, with greater accumulation in the epithelium. Conclusions Our results demonstrate that lytic phage targeting a CD-associated bacterium attenuates colitis in two gnotobiotic mouse models. Whereas this model did not lead to complete eradication of the disease-driving agent, phage treatment was associated with a reduction in a known AIEC virulence factor, attenuating colitis severity. The data suggest alternative mechanisms should be considered when translating phage therapy to treat IBD in clinical trials. Funding Agencies CIHRFarncombe Innovation Fund
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".