A49 LACTOBACILLI DEGRADE WHEAT AMYLASE TRYPSIN INHIBITORS (ATI) TO AMELIORATE GUT DYSFUNCTION INDUCED BY IMMUNOGENIC WHEAT PROTEINS
Bibliographic record
Abstract
Wheat-related disorders involve a wide spectrum of conditions, triggered by the ingestion of gluten-containing cereals. The induction of gluten-specific immune responses in celiac disease is well established. However, the contribution of gluten and/or non-gluten proteins in the generation of symptoms in other wheat-related disorders is controversial. Amylase trypsin inhibitors (ATIs) are pest-resistant molecules in modern wheat with TLR4-activating capacities. We investigated the role of ATIs in the generation of gut barrier dysfunction and dysmotility in wild-type mice as well as in the severity of gluten-induced immunopathology in genetically predisposed mice. We also determined the metabolic capacity of core microbial groups to degrade ATIs, and examined how this impacts ATIs or gluten-induced gut dysfunction. To determine if ATIs could induce gut dysfunction in non-genetically susceptible mice, C57BL/6 or Myd88-/- mice were placed on a wheat free diet (WFD) or ATI diet for 1 week. To study the adjuvant effect of ATIs, NOD/DQ8 mice sensitized with cholera toxin and gliadin received a diet containing: 1) ATIs with no gluten (ATIs), 2) gluten depleted of ATIs (G-ATIs), or 3) depleted gluten supplemented with ATIs (G+ATIs), for 2 weeks. Non-sensitized NOD/DQ8 (controls) received a WFD for 2 weeks. To study the metabolic capacity of microbes to degrade ATIs in vivo, Lactobacillus strains isolated from the human intestine and with different hydrolytic capacity against ATI were pooled and supplemented to mice by oral gavage daily during dietary intervention. CD3+ intraepithelial lymphocytes (IELs) were measured by immunohistochemistry, intestinal permeability by Ussing chambers, gene expression by Nanostring Technology and 16S rRNA profiling of cecal microbial content via Illumina MiSeq. We show that ATIs not only induce innate immune responses through the TLR4-MD2-CD14 pathway, but also barrier dysfunction in C57BL/6 mice in the absence of overt mucosal damage. When combined with gluten in mice with a permissive celiac genetic background (NOD-DQ8 transgenic), ATI exacerbate gluten-induced immunopathology increasing intestinal permeability, IEL proliferation and upregulation of pro-inflammatory genes. We also demonstrate that ATIs can be degraded by certain commensal bacteria such as Lactobacillus, thereby reducing their immune-stimulatory capacity in mouse models. ATIs may play a role in wheat-related disorders. Microbiome-modulating strategies based on the use of strains with specific ATIs-degrading capacity may be effective in patients with wheat-sensitive disorders. CAG, CIHR
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".