EF-05 Androgens regulate microbiota composition, function and protective properties in lupus-prone mice
Bibliographic record
Abstract
Background Dysbiosis (alterations in microbiota composition) is associated with autoimmune diseases, including lupus. Factors that are thought to influence gut microbiota include diet, age and more recently, sex. Like humans, female NZBxNZWF1 (BWF1) mice spontaneously develop lupus-like disease, and exhibit much greater incidence of disease than males. Castration of male BWF1 mice increases disease onset/incidence and decreases survival suggesting that male sex steroids, androgens, play an important role in protection of males from disease. Methods Intact female and male, or castrated and sham-castrated male BWF1 mice were used in this study. Cecal contents (microbiota) from different groups were transferred into female BWF1 mice shortly after weaning (∼26 days) and either disease or in vitro cell function (cell culture, flow cytometry) was evaluated. Feces were collected from adult mice and analyzed for either microbiota composition (deep sequencing of 16S gene) or metabolomic profiles (mass spectrometry). Results We have found that the composition of gut microbiota and metabolomic/lipidomic profiles differ between mature female and male BWF1 mice. Transfer of male microbiota to female BWF1 mice suppresses disease and increases survival. Further, we found that male microbiota may protect, in part, via an effect on tolerogenic CD103+ dendritic cells (CD103DC) that induce peripheral Tregs (pTregs) through TGFβ and retinoic acid (RA) production. Female BWF1 CD103DC have a decreased ability to induce pTregs and express retinaldehyde dehydrogenase, (RALDH2), an enzyme involved in RA synthesis. Transfer of male microbiota to female BWF1 mice reconstitutes both RALDH2 expression and the ability of the CD103DC to induce pTregs. Interestingly, castration of male mice significantly alters gut microbiota composition and metabolomic/lipidomic profiles by comparison to males, diminishes CD103DC function and decreases the ability of the microbiota to protect female mice from disease. The mechanisms underlying male microbiota-mediated protection from disease are unknown, but may be mediated through the production of metabolites. We have identified several metabolites that are increased in male compared to both female and castrated male feces that function as retinoid X receptor agonists and enhance RALDH2 activity and increase pTregs in vivo. Conclusions Our data suggest that androgens alter the composition and function of the gut microbiota in males, and the metabolites produced by the male microbiota may have potential for development into therapeutic strategies for the treatment of disease. Acknowledgements Funded by Lupus Research Institute, Alliance for Lupus Research and National Institutes of Health.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".