Lipidomic Trajectories Characterize Delayed Mucosal Wound Healing in Quiescent Ulcerative Colitis and Identify Potential Novel Therapeutic Targets

Abstract

Improving the long-term prognosis of ulcerative colitis (UC) requires sustained deep mucosal colonic healing with histologic remission, making the study of colonic tissue regeneration essential. In experimental colitis models, lipid metabolites are recognized as pivotal components of this process. This study aimed to describe the kinetics of wound healing and lipid metabolites engaged in regeneration in the normal colonic mucosa and how they are affected in UC to reveal new therapeutic targets. Experimental colonic wounds were created endoscopically in quiescent UC (n=21) and controls (n=9), and the healing process was surveilled by serial endoscopies and cross-sectional wound biopsies post-wounding. Biopsies were analyzed by liquid chromatography coupled with mass spectrometry. Endoscopic wound scores were significantly higher in UC at day two (p=0.001) and seven (p<0.0001) post-wounding, demonstrating a prolonged wound healing process. The wound scores were correlated with lipid mediators crucial for normal regeneration and sustained UC-specific changes in key phospholipids and eicosanoids, i.e., lysophosphatidylcholine, phosphatidylcholine, lysophosphatidic acid, phosphatidylglycerol, phosphatidylinositol, prostaglandin D2, and prostaglandin E1, were observed. A prolonged wound healing process is identified in quiescent UC with altered disease specific lipidomic trajectories providing potential novel therapeutic avenues for stimulating mucosal regeneration as an add-on to the traditional immune suppression treatment.

Integrated Metabolomics and Gut Microbiome Analysis Reveals the Efficacy of a Phytochemical Constituent in the Management of Ulcerative Colitis

“…[38] Low levels of LysoPC and PC observed in TNBS-induced rats may result from inadequate mucosal restoration, but may also be causal as different types of LysoPC have different or even opposite functions. [39] While palmitoyl-LysoPC (16:0) and arachidonoyl-LysoPC (20:4) have been shown to be pro-inflammatory, stearoyl-LysoPC (18:0) has been reported to have an anti-inflammatory function by inhibiting inflammatory cytokines such as TNF-𝛼, IL-6, and IL-1𝛽. [37,40] Therefore, regulating the homeostasis of LysoPC and PC is of great importance in the treatment of UC.…”

Mucosal and Plasma Metabolomes in New-onset Paediatric Inflammatory Bowel Disease: Correlations with Disease Characteristics and Plasma Inflammation Protein Markers

“… 12 Interestingly, a disturbed colonic wound healing process has also been associated with mucosal lipidomic alterations, including decreased levels of LP and other bioactive phospholipids, in patients with quiescent UC. 44 In a study of stool samples from adult UC patients, Zou et al . demonstrated an association between low levels of LPE [16:0 and 18:1] and inflammation.…”

Fatty acids and lipid mediators in inflammatory bowel disease: from mechanism to treatment

“…Due to its significant role in inflammation, the major urinary metabolite of PGE is considered to be a predictive biomarker of mucosal healing and relapse ( 190 ). Furthermore, in a lipidomics study of UC patients, PGE1 and PGD2 are critical factors influencing mucosal healing ( 191 ). Inhibition of LTB4 might hold potential therapeutic implications for UC ( 192 ).…”