The Role of Lysophosphatidic Acid in Enteric Glial Modulation of Visceral Nociception

Visceral pain is the most common gastrointestinal issue and a hallmark feature of inflammatory bowel disease and irritable bowel syndrome. Visceral hypersensitivity is a major mechanism that contributes to pain but the processes leading to visceral hypersensitivity are not understood. Enteric glia surround sensory nerve terminals in the intestine and exhibit bi-directional communication with nociceptors. Our recent discoveries show that enteric glia are highly responsive to the bioactive lipid lysophosphatidic acid (LPA), which is known to contribute to neuropathic pain. How LPA interacts with enteric glia to modulate nociception remains poorly understood. We hypothesized that LPA contributes to visceral hypersensitivity through mechanisms involving enteric glial LPAR1 that sensitize Trpv1+ nociceptors. Mass spectrometry analysis of multiple LPA species in colonic tissue from male and female control and 2,4-dintriobenzenesulfonic acid (DNBS)-treated acute colitis mice showed that LPA is elevated during inflammation with high expression of 18:0 LPA, followed by 16:0 and 18:2. Inflamed male mice exhibited a greater increase in multiple LPA species as compared to females, with 18:0 LPA being most abundant. In vitro Ca 2+ imaging was conducted in colonic myenteric plexus whole mounts from Trpv1 Cre;GCaMP6f mice that express the genetically encoded Ca 2+ sensor GCaMP6f in Trpv1+ neurons to determine if LPA activates or sensitizes Trpv1+ neurons. GCaMP6f fluorescence in Trpv1+ nerve terminals was measured at baseline, following exposure to 1 μM of Trpv1 agonist capsaicin, following 1 μM LPA challenge, and in response to 1 μM capsaicin following exposure to 1 μM LPA. ΔF/F 0 was quantified based on number of frames and maximum response peaks were analyzed. Control experiments with focal application of Krebs ruled out potential mechanical activation of nociceptors during the application of drugs. Focal application of LPA alone did not stimulate nociceptor Ca 2+ responses. In contrast, the Trpv1 agonist capsaicin evoked nociceptor Ca 2+ responses that were 0.095 ΔF/F in amplitude. Pre-incubating samples with LPA for 30 minutes increased average nociceptor Ca 2+ responses to capsaicin by 55% to 0.148 ΔF/F. However, this effect did not reach statistical significance due to variability and limited sample size (p = 0.2051, unpaired t-test). Based on these results, LPA may serve as a candidate mediator of glial-driven visceral hypersensitivity, but further studies are needed to understand how glial LPAR1 signaling contributes to gut health and disease. This work was supported by NIH grants R01DK120862 and R01DK103723 from the NIDDK to B.D.G. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.