Excitation of Vagal Afferent Neurons by Fecal Supernatant from Inflammatory Bowel Disease Patients
Bibliographic record
Abstract
Background The gut‐ microbiota‐brain axis has received increasing attention recently due to evidence that colonic microbes can affect brain function and behavior. Recent studies have demonstrated that vagal afferent neurons may be an important conduit between the gut microbiota and the brain, as it is capable of detecting mediators released from the gut microbiota. However, it is unknown whether i) the gut microbiota from healthy human stool donors affects nodose ganglion (NG) neurophysiology or ii) gut microbial dysbiosis during inflammatory bowel disease (IBD) impacts the function of vagal afferent neurons. Hypothesis Remodeling of gut microbiota during IBD increases secretion of mediators that change the excitability of vagal afferent neurons. Methods To examine the effect of IBD patients’ fecal supernatant (FS; 1:20 dilution) on the excitability of mouse vagal afferent neurons, NG neurons from C57/Bl6 mice were collected, dissociated, and incubated overnight with FS from 5 active Crohn’s disease (CD) patients, 7 active ulcerative colitis (UC) patients, and 5 healthy volunteers (HV). Current and voltage‐clamp recordings were used to assess changes in neuronal excitability and ion channel function. Results CD and UC FS significantly increased the excitability of NG neurons through a reduction in the rheobase of 40% (CD:60 cells vs . control: 54 cells), P <0.0001, Mann‐Whitney test) and 23% (n= 50 cells vs . control: 46 cells, P = 0.0038, Mann‐Whitney test) compared to their individual vehicle control neurons, respectively. This decrease in rheobase was accompanied by a two‐fold increase in the number of action potentials elicited at twice rheobase ( P <0.01, Mann‐Whitney test). However, neither resting membrane potential, nor input resistance was altered in NG neurons treated with IBD FS compared with vehicle control neurons. HV FS had no effect on NG excitability. CD and UC FS significantly reduced voltage‐gated K + currents ( P= 0.0075 and P <0.0001, two‐way ANOVA followed by Sidak's multiple comparison test, respectively), but had no effect on voltage‐gated Na + currents. The excitatory effect of CD and UC FS of NG neurons was blocked by the cysteine protease inhibitor (E64) (30 nM), but not the serine protease inhibitor (FUT175) (10 μM). In all CD patients, pre‐incubation of E64 blocked the increase in excitability by CD patient FS (CD rheobase:40.6 ± 3.6 pA vs .CD+ E64 rheobase: 73.9 ± 4.5 pA) ( P<0.0001 , one‐way ANOVA followed by Tukey's multiple comparison). However, E64 was only able to block the excitatory effect of FS from 5 out of 7 UC patients FS (UC rheobase:43.8 ± 4.7 pA vs . UC+ E64 rheobase: 83.5 ± 4.3 pA) ( P =0.0092, one‐way ANOVA followed by Tukey's multiple comparison). The protease‐activated receptor 2 (PAR2) antagonist GB83 (10 μM) also blocked the effect of the CD and UC patient supernatant on NG neurons ( P=0.0081 and P =0.0116, Kruskal‐Wallis test, respectively). Conclusion FS from active IBD patients contain mediators that can excite NG neurons. Cysteine proteases directly mediates the effect of IBD FS on NG neurons by activation of PAR‐2. Signaling pathways downstream of PAR‐2 activation lead to inhibition of voltage‐gated K + currents.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".