The Bidirectional Impact of Arginine-Vasopressin Receptor 1a (Avpr1a/AVPR1A) and the Gut Microbiome on Visceral Hypersensitivity

Visceral hypersensitivity (VH) is commonly cited as a driver of chronic abdominal pain in disorders of gut-brain interactions (DGBI) where persistent and/or recurrent abdominal pain is a primary symptom regardless of any alterations in bowel habits. Development of VH is influenced by genetic, environmental, and gut microbial colonization factors, yet specific mechanisms that generate VH are incompletely understood. Correspondingly, current pain treatments for DGBI, including irritable bowel syndrome (IBS), primarily focus on symptom management and severity rather than targeting the pathophysiological mechanisms underlying pain. We have begun to examine the role of genetic susceptibility and microbiome response dynamics in VH development using intracolonic zymosan (ZYM), which is a preclinical model of post-inflammatory IBS. Preliminary data reveals differential susceptibility between ZYM-induced VH in two closely related C57BL/6 sub strains; one from Taconic Biosciences (C57BL/6NTac) and the other from Jackson Laboratory (C57BL/6J). Using genomic comparisons, we have identified a VH candidate gene that encodes the arginine-vasopressin receptor 1A (Avpr1a/AVPR1A) protein. We have subsequently observed dynamic strain differences in the location and composition of the gut microbiome in response to ZYM corresponding to VH susceptibility. Further, we’ve identified colon-specific alterations in enteric neuron response properties that covary with gene expression and the pattern of microbial colonization corresponding to VH development. Through manipulation of the expression of Avpr1a and of the microbiome in the colon, we can develop novel tissue-specific pharmacological interventions designed to the target the mechanisms underlying chronic VH.