A6 MECHANISMS UNDERLYING GUT DYSFUNCTION FOLLOWING C. <i>DIFFICILE</i> INFECTION AND IMPLICATIONS FOR TREATMENT
Bibliographic record
Abstract
Abstract Background Recent evidence suggests an increasing prevalence of gut dysfunction following C. difficile infection (CDI). The accompanying prolonged antibiotic (AB) exposure likely contributes to chronic gut dysfunction and our ability to induce gut dysfunction in germ free (GF) mice colonized with microbiota from a patient with severe slow transit post CDI (PCDI) supports this notion (10.1093/jcag/gwz047.117). Furthermore, we were able to restore gut function following fecal microbial transfer from healthy murine donors. Our studies have implicated a role for macrophages in the destruction of the Interstitial Cell of Cajal (ICC) network underlying slow colonic transit in the humanized mouse model. These findings prompted us to evaluate microbiota-directed therapy in normalising gut function in this model. Aims 1)To investigate whether dietary psyllium rescues the development of slow colonic transit (SCT) through modulating host function via microbiota mediated immune mechanisms; and 2)To evaluate the mechanisms underlying the beneficial effects of psyllium Methods GF mice were colonized with either microbiota from the PCDI patient or healthy control (HC) for 3 weeks following which PCDI mice were treated with either a control diet or a 15% psyllium diet (PSY). Colonic motility was assessed before and after the diet intervention using the bead expulsion test. Stool samples were collected for microbial profiling, and short and branched-chain fatty acids (SCFA/BCFA) analysis. Colonic muscle layers encompassing myenteric plexus (MP) were collected for gene expression analysis and to evaluate activated macrophages and ICC degeneration using immunohistochemistry. Results Microbiota from a PCDI patient induced a SCT phenotype in GF mice (n=13) as compared to mice colonized with HC microbiota (p=0.0002). Psyllium rescued this SCT phenotype in mice (PCDI(n=7) vs.PSY(n=6):p=0.0014). The psyllium-induced rescue was accompanied by normalization of the ICC network and morphological alterations in infiltrating macrophages. This was supported by changes in immune-related gene expression in the MP including CD11b, NOS, Myd88, Mapk1 and NF-κB. Additionally, bacterial composition was different between PCDI and PSY group (p=0.003). SCFAs like acetic and propionic acid were increased, while BCFA like isobutyric and isovaleric acid were decreased following PSY treatment. These alterations in SCFA/BCFA were supported by fluctuations in specific bacteria like Butyricimonas, Phascolarctobacterium and Allistipes. Conclusions Our results provide evidence that chronic gut dysfunction following CDI and AB exposure is microbiota-driven. Furthermore, microbiota-directed therapy using psyllium could serve as a novel therapeutic strategy to normalize gut function via microbiota-mediated restoration of immune homeostasis in these patients. Funding Agencies W. Garfield Weston Foundation
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".