A16 ALTERATIONS TO BOTH INTESTINAL BARRIER INTEGRITY AND THE MICROBIOTA CONSPIRE DURING AGING TO PROMOTE DISEASE PROGRESSION IN A MOUSE MODEL OF MULTIPLE SCLEROSIS
Bibliographic record
Abstract
Abstract Background Multiple sclerosis (MS) is a chronic, inflammatory condition impacted by both genetic and environmental factors. Aged individuals have an increased risk of progressive multiple sclerosis (pMS), as well as altered microbiota community composition and elevated levels of circulating gut microbiota-derived metabolites due to compromised gut barrier function. Fecal microbiota transplantation (FMT) studies confirm that an MS-associated microbiome can potentiate disease onset and enhance neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Aims 1) Assess whether an aged microbiota alone is sufficient to promote age-associated progressive-like disease in our mouse model of EAE 2) Determine whether altered intestinal barrier integrity results in central nervous system-specific immune changes and/or disease course during EAE Methods To assess the impact of an aged microbiota on EAE outcomes we performed age-disparate human-derived FMT from young vs aged healthy co-habiting, first degree relatives into recipient mice. Then, to further interrogate the role of the gut-brain axis in the association of age and pMS we isolated the compromised intestinal barrier seen in aged individuals as a variable via two methods – Muc2-/- mice, which exhibit a defective mucus barrier, and DSS treated mice. Results Following adoptive transfer of young EAE-primed T cells, ‘young’ FMT recipients exhibited disease resolution while an ‘aged’ FMT lead to severe, non-remitting EAE relative to both controls and ‘young’ FMT recipients. This difference in outcomes was not seen in all donor pairs, suggesting that worsened EAE is not a universal feature of the aged microbiota. We collected cecal material, blood, and central nervous system (CNS) tissue from an age-differential FMT mouse pair and performed metabolomic analysis. We found robust differences in the metabolomic profile of young vs aged FMT recipients before and after EAE induction. Further, in both models of altered barrier integrity, we observed altered myeloid cell trafficking to and immune activation in the CNS, suggesting that the intestinal barrier itself plays a critical role in immune activation during EAE. Conclusions These findings suggest specific age-related microbiota-derived metabolites, which have increased access to the host system due to a leaky intestinal barrier, may be associated with increased risk of progressive disease and may represent promising therapeutic targets for MS. Funding Agencies CIHRMS Canada
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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) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".