P114 Role of NLRX1 Agonist NX-13 in Reducing Visceral Hypersensitivity in Preclinical Gastrointestinal Inflammation
Bibliographic record
Abstract
Abstract Background NLRX1 activation reduces inflammation by decreasing oxidative stress and altering cellular metabolism within multiple cell types implicated in ulcerative colitis (UC). Colitis animal models demonstrated reduced disease severity and a phase 1b clinical trial showed signs of rapid symptom and endoscopic improvement in patients with active UC.1, 2 Abdominal pain driven by visceral hypersensitivity may persist in patients even after inflammation has resolved, negatively affecting their quality of life.3, 4 Therapeutic agents which address inflammation, epithelial healing, and visceral hypersensitivity concurrently may provide greater symptomatic relief and improved quality of life as many patients, even in remission, still complain of abdominal pain. We here describe the effects of oral NX-13 in a rat model of visceral hypersensitivity. Methods Rats (n=8) were dosed daily for a period of 3 days with NX-13 or vehicle. Under anesthesia, electrodes were positioned to monitor oblique abdominal muscle contraction and a colonic balloon catheter was inserted intra-anally. Visceral pain was assessed at baseline and 3 h post lipopolysaccharide injection (1 mg/kg subcutaneous) through measuring of visceromotor response (VMR) via electromyogram (EMG) recording and visual assessment of abdominal withdrawal reflex (AWR). Data are represented as median (IQR) and statistical significance determined by non-parametric Mann-Whitney U test. Results Compared to the vehicle control, oral NX-13 delayed the onset of muscle contraction in response to colonic distension in LPS-treated rats. Further, NX-13 treated rats experienced reduced contraction intensity and reduced sustained abdominal muscle contraction period compared to the vehicle control. Specifically, NX-13 decreased the number of AWR during colonic expansion compared to the control group (p=0.01, Fig1A). Moreover, NX-13 desensitized the VMR response by numerically increasing the minimum volume of the colonic distension balloon required to induce significant VMR. The mean minimum volume of water injected required to induce significant VMR increased 23%, from 650 μL in the vehicle group to 800 μL in the NX-13 treated rats (p=0.16, Fig1B). Lastly, NX-13 visually reduced the maximum abdominal EMG amplitude during colonic distention (p=0.19, Fig1C). Conclusion Adequate management of persistent pain in IBD patients with or without active bowel inflammation remains an unmet need in the treatment of IBD. The potential for NX-13 to specifically reduce visceral hypersensitivity and abdominal pain will be evaluated further in the ongoing phase 2 human NEXUS trial in patients with UC. 1Leber et al. J Immunol 203(12) 2Peyrin-Biroulet et al. JCC (17)Supp 3Abreu et al. JCC (14)Supp 4Wils et al. J Clin Med 11(15)
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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) | 0.001 | 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".