A40 GUT MICROBIOTA PROMOTES NUTRIENT AVAILABLITY AND PATHOGENESIS OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
Bibliographic record
Abstract
Abstract Background Our gut microbiota plays an important role in protecting the gastrointestinal (GI) tract from invading enteric pathogens. Much of this colonization resistance is mediated by limiting nutrient availability, however, enteric pathogens have evolved strategies to subvert this competition, utilizing commensal metabolites to facilitate their infection. Access to nutrients is not only crucial for a pathogen’s metabolic fitness, but can also drive the expression of virulence factors, a process high in energy demands. In addition, enteric pathogens, such as the attaching and effacing (A/E) bacterium Citrobacter rodentium, must cross the colonic mucus layer that normally prevents their direct access to the underlying epithelium. Intestinal mucus is comprised of highly glycosylated mucins, with the sugar sialic acid frequently occupying the terminal position of their O-glycan side chains. We hypothesize that C. rodentium utilizes commensal-liberated mucin sugars, such as sialic acid, as nutrients and signals to promote its virulence. Purpose This study investigates the mechanisms by which A/E pathogens reach the colonic mucosal surface, and the role played by commensal microbes in facilitating the infection. Method Expression of virulence factors secreted by C. rodentium in the presence or absence of sialic acid was analyzed by SDS-PAGE and mass spectrometry. Next, we infected specific-pathogen free (SPF), germfree (GF), and previously GF C57Bl/6 mice mono-colonized with Bacteroides thetaotaomicron, a mucus-degrading commensal, to examine their susceptibility to C. rodentium and to measure the levels of free sialic acid in their feces. Result(s) Sensing of sialic acid by C. rodentium, was found to induce the secretion of several key virulence proteins, enhancing the pathogen’s migration across the colonic mucus layer and adhesion to the underlying epithelium. Access to sialic acid within the gut environment was enhanced in the presence of microbiota, as the levels of free sialic acid were low in GF mice. Interestingly, despite GF mice carrying very high C. rodentium burdens, passage across the mucus layer and infection of their colonic epithelium was impaired as compared to SPF mice. Notably, B. thetaotaomicron was found to degrade whole mucus in vitro, facilitating its consumption by C. rodentium for growth, while B. thetaotaomicron mono-colonized GF mice showed increased susceptibility to colonic infection by C. rodentium. Conclusion(s) We demonstrate that although commensal microbes promote colonization resistance, as an A/E pathogen infection establishes, specific commensal bacteria accelerate infection in the GI tract by releasing an important nutrient, ie. sialic acid, from mucus. Access to sialic acid promotes C. rodentium virulence by inducing the key virulence factors that facilitate its translocation across the mucus layer as well as adhesion to the epithelium, thereby expediting disease progression. Please acknowledge all funding agencies by checking the applicable boxes below CCC, CIHR, Other Please indicate your source of funding; CH.I.L.D. Foundation Disclosure of Interest None Declared
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".