A56 ACTIVATION OF COLONIC AFFERERNT NERVES BY DEOXYCHOLIC ACID
Bibliographic record
Abstract
In addition to their well-known role in lipid digestion and absorption, bile acids function as signaling molecules. Increased bile acids are delivered to the colon in a subpopulation of patients with irritable bowel syndrome (IBS); however, it is unknown whether this contributes to visceral hypersensitivity leading to abdominal pain. To examine mechanisms underlying the activation of extrinsic afferents innervating mouse colon and their cell bodies by deoxycholic acid (DCA), a major secondary bile acid. All experiments were performed on male C57BL/6 mice. In vitro preparations of the proximal colon (innervated by a mixture of vagal and spinal afferents) and distal colon (spinal afferents only) were employed to perform extracellular recordings of mesenteric afferent axons. Neuronal excitability of cultured dorsal root ganglion (DRG) and nodose ganglion (NG) neurons was examined by measuring rheobase using perforated patch clamp techniques. Colonic 5-HT release was assessed using an ELISA kit. Intraluminal application of DCA (100 μM-1 mM) increased basal afferent firing frequency dose-dependently in both proximal (P<0.01, paired t-test, N=8) and distal colon (P<0.01, paired t-test, N=8). This increase in response to DCA (1 mM) in proximal colon was blocked by a 5-HT3 receptor antagonist granisetron (1 μM, P<0.01, paired t-test, N=10), implying an indirect activation via mucosal 5-HT release. Conversely, increased basal firing via DCA in distal colonic afferents was not blocked by granisetron (P=0.266, paired t-test, N=8). Consistently, DCA stimulated more 5-HT release in proximal colon than distal (P<0.05, unpaired t-test, N=5). Mechanosensitivity of distal colonic afferents was significantly augmented following 30-min perfusion of 1 mM DCA (P<0.05, two-way ANOVA with Bonferroni test, N=7), and this potentiation was not affected by pre-treatment with granisetron (P<0.05, N=7). A lower concentration of DCA at 100 μM was not able to potentiate mechanosensitivity (P=0.909, N=6). DCA (100 μM) increased excitability (i.e. decreased rheobase) of DRG neurons (P<0.01, paired t-test, n=11) whereas it decreased excitability (i.e. increased rheobase) of NG neurons (P<0.01, paired t-test, n=12). Together, these data suggest that DCA directly activates spinal afferents innervating mouse colon whereas it activates vagal afferents indirectly via mucosal 5-HT release. Furthermore, continual exposure to DCA sensitizes spinal afferent nerves to mechanical distention and may be a mechanism underlying visceral hypersensitivity. Queen’s University
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".