Protease-Induced Excitation of Dorsal Root Ganglion Neurons in Response to Acute Perturbation of the Gut Microbiota Is Associated With Visceral and Somatic Hypersensitivity

• DOI: 10.1016/j.jcmgh.2024.03.006
• Publication Date: 2024-03-16T07:36:18Z
• Authors: Corey C. Baker; Jessica L. Sessen...; Hannah M. Wood; Yang Yu; Quentin Tsang; Taylor A. Alward; Nestor N. Jimenez...; Amal Abu Omar; Abby McDonnel; Julia P. Segal; Calvin P. Sjaarda; Nigel W. Bunnett; Brian L. Schmidt; Alberto Caminero; Nadejda Boev; Courtney A. Banne...; Nader Ghasemlou; Prameet M. Sheth; Stephen J. Vanner; David E. Reed; Alan E. Lomax
• Keywords: Dysbiosis; Visceral pain; Dorsal root ganglion

Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory disease.Germ-free mice more prone to abdominal than conventionally-housed mice, reconstitution the microbiota in germ-free reduces sensitivity.However, mechanisms underlying modulation remain elusive.We hypothesized disruption intestinal modulates excitability peripheral nociceptive neurons.In vivo vitro assays visceral sensation were performed on treated non-absorbable antibiotic vancomycin (50 µg/mL drinking water) for 7 days water-treated control mice.Bacterial dysbiosis was verified by 16s rRNA analysis stool composition.Treatment led an increased sensitivity colonic distension vitro, hyperexcitability dorsal root ganglion (DRG) neurons compared controls.Interestingly, DRG not restricted those innervated gut, suggesting widespread effect gut circuits.Consistent this, sensitive thermal stimuli applied hind paws.Incubation from naïve serum vancomycintreated neuron excitability, alters circulating mediators influence nociception.The cysteine protease inhibitor E64 (30 nM) protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 µM) each blocked increase response vancomycin-treated as did knockout PAR-2 NaV1.8-expressing neurons.Stool supernatant, but via activation PAR-2.Together, these data suggest identify proteases potential mediator this effect.