Dysregulated Glycerophospholipid Metabolism and ChAT Overexpression in Wrap-Restraint Stress-Induced IBS Mice: A Multi-Omics Approach to Gut-Brain Axis Disruption and Potential Therapeutic Targets

Abstract

Abstract Background: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects a significant portion of the global population. Despite extensive research in recent years, the pathophysiology of IBS remains poorly understood, and there is currently no definitive cure for the condition. However, recent advances in high-throughput technologies such as genomics, transcriptomics, proteomics, and metabolomics have allowed for exploration of IBS at the multi-omics level. These approaches enable us to examine IBS from multiple perspectives and identify potential biomarkers and therapeutic targets for the condition. Methods:This study employed a comprehensive multi-omics investigation on the IBS model induced by “wrap-restraint stress”, revealing significant abnormalities in systemic glycerophospholipid metabolism within the gut-brain axis. Results:Metabolomics analysis demonstrated decreased phosphatidylcholine (PC) content and increased lysophosphatidylcholine (lyso-PC) levels in multiple tissues of IBS mice. Concurrently, transcriptomic analysis indicated increased transcription of Choline acetyltransferase (ChAT), a crucial enzyme involved in the acetylcholine synthesis pathway. To explore potential therapies, we administered α-NETA, a ChAT inhibitor, to IBS mice in subsequent experiments. Remarkably, α-NETA treatment improved various IBS-like symptoms, including increased body weight, decreased visceral sensitivity, reduced fecal water content, and alleviated anxiety-like behaviors. Additionally, α-NETA administration significantly elevated PC levels in multiple tissues while reducing the levels of Cytosolic phospholipase A2 (cPLA2), an enzyme responsible for PC degradation into lyso-PC. Conclusions: Our findings suggest that elevated levels of acetylcholine induced by ChAT overexpression and enhanced activity induce gut-brain axis disturbances and a variety of IBS-like symptoms in mice. This study highlights the therapeutic potential of targeting glycerophospholipid metabolism and ChAT as a promising approach for managing IBS.