A1 BACTERIAL LYSOPHOSPHATIDYLCHOLINE (LPC) AND LYSOPHOSPHATIDIC ACID (LPA) INDUCE VISCERAL HYPERSENSITIVITY THROUGH TRANSIENT RECEPTOR POTENTIAL CANONICAL 5 (TRPC5) AND LYSOPHOSPHATIDIC ACID RECEPTOR 1 (LPAR1) AND 3 (LPAR3) DEPENDENT-MECHANISMS
Bibliographic record
Abstract
Abstract Background Abdominal pain is the key symptom in Irritable Bowel Syndrome (IBS). Its pathophysiology is not fully understood, but low-grade inflammation and gut microbiota-diet interactions have been implicated. LPC and LPA are phospholipids generated by inflammatory processes in mammals, which are known to induce neurogenic pain through multiple channels and G-protein-coupled receptors. It is unknown whether bacteria can produce LPC/LPA and through which pathways they signal to the host. Aims To investigate whether bacterial LPC and LPA induce visceral hypersensitivity and identify the underlying mechanisms. Methods Germ-free NIH Swiss and Swiss Webster mice (n=117) were colonized for 5 weeks with fecal microbiota from IBS patients with either low or high fecal LPC/LPA levels, or microbiota from healthy controls. The mice were fed either regular chow or a diet enriched with phosphatidylcholine (PC) (2g/kg) a precursor of LPC and LPA. Visceral sensitivity was assessed by visceromotor responses (VMRs) to colorectal distension. Dorsal root ganglion (DRG) neurons from C57BL/6 mice were pretreated with a TRPC5 inhibitor (AC1903; 30 μM), an LPAR1 antagonist (AM095; 10 μM), or an LPAR1 and LPAR3 antagonist (Ki16425; 10 μM) or their vehicle (0.1% DMSO), and then treated with LPC (10 μM) or LPA (10 μM), respectively. Calcium mobilization was measured by a Cytation C10 imaging reader using a fluorescent probe Fluo-4 (1 mM). C57BL/6 mice received intracolonic infusion with a vehicle or a mix of LPC (600 μM) /LPA (25 μM), one group of mice was pretreated with AC1903 (30 μM) and Ki16425 (10 μM) prior to LPC/LPA administration, CRD was performed 90 minutes later. Results Mice with fecal microbiota from IBS patients with high fecal LPC/LPA displayed visceral hypersensitivity compared to mice with microbiota from healthy controls or from patients with low fecal LPC/LPA. These increased responses were seen only in mice fed PC-enriched diet, but not with regular chow. Both LPC and LPA administration increased the percentage of responding DRG neurons compared to the vehicle. The pretreatment with AC1903, AM095 or Ki16425 decreased the percentage of responding neurons when treated with LPC or LPA, respectively, compared to the vehicle. Intracolonic administration of LPC and LPA induced a significant increase in visceral sensitivity compared to the vehicle-treated mice. This increase was prevented in mice pretreated with an intracolonic injection of AC1903 and Ki16425. Conclusions Bacterial LPC and LPA induce neuronal activation and visceral hypersensitivity through TRPC5 and LPAR1/LPAR3-dependent mechanisms, respectively. Funding Agencies CIHRWeston Family Foundation
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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) | 0.000 | 0.001 |
| 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 | 0.001 |
| 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".