Dysregulation of Bile Acids, Lipids, and Nucleotides in Psoriatic Arthritis Revealed by Unbiased Profiling of Serum Metabolites

Abstract

Objective The transition from psoriasis to psoriatic arthritis (PsA) occurs in 20–30% of patients; however, the mechanisms underlying the emergence of musculoskeletal disease are not well understood. Metabolic disease is prevalent in psoriasis patients, but whether metabolic factors, other than obesity, increase arthritis risk in psoriasis patients is not known. This study was undertaken to investigate the link between metabolic changes and disease progression in psoriasis patients. Methods To characterize the metabolic alterations during the progression of arthritis in psoriasis patients, we analyzed cross‐sectional healthy controls and PsA samples and longitudinal psoriasis serum samples, before and after PsA onset. Nontargeted metabolomic profiling was performed using liquid chromatography mass spectrometry. Results We identified several serum metabolites that differed between PsA patients, psoriasis patients, and healthy controls. Differentially abundant bile acids, purines, pyrimidines, glutathione, lipids, and amino acid metabolites were noted in these 3 groups. We also noted differences between psoriasis patients who progressed and those who did not progress to PsA. Bile acid and butyrate levels were depressed in those who progressed to PsA compared to those who did not, and the level of inflammatory lipid mediators increased following PsA diagnosis. In particular, the combination of leukotriene B4 and glycoursodeoxycholic acid sulfate were sensitive and specific predictors of PsA progression. Conclusion We observed notable differences in bile acid, purine, lipid, and amino acid–derived metabolites, among the healthy controls, psoriasis patients, and PsA patients and identified changes during the transition from psoriasis to PsA. The decreased bile acid and butyrate levels and elevated guanine levels in psoriasis patients at risk for PsA were particularly striking and may reflect gut microbial dysbiosis and dysregulated hepatic metabolism, leading to altered proliferation of immune cells and enhanced cytokine expression.

The Emerging Potential of Bile Acids as a Modulator of Psoriatic Inflammation

“…19 Here, a pre-progression metabolic analyses of serum from psoriasis patients who would eventually develop psoriatic arthritis demonstrated significant metabolic shifts, including a greater than 50% reduction in secondary bile acids deoxycholate, glycoursodeoxycholic acid sulfate, and deoxycholic acid 12-sulfate, compared to non-progressors. 19 Conversely, increases in BA serum levels correlated with decreased odds of psoriatic arthritis progression with a 1-unit increase in glycoursodeoxycholic acid sulfate correlating to a decreased odds of progression by 95%. 19…”

Bacterial Metabolites: A Link between Gut Microbiota and Dermatological Diseases

“…However, it is worth mentioning bile salts, the group of secondary bile acids modified in the gut by microbiota. These compounds are recognized as anti-inflammatory factors, and their positive effects can potentially decrease the severity of psoriasis and atopic dermatitis [ 140 , 141 , 142 , 143 ].…”

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

“…Changes in the levels of circulating glucuronic acid and α-ketoglutaric acid were detected among psoriasis patients with or without PsA [ 83 ] and a correlation was made between serum levels of the choline metabolite trimethylamine N -oxide (TMAO) and inflammation in PsA patients [ 84 ]. A more recent study used untargeted metabolomics to characterize the metabolic changes in the transition from psoriasis to PsA, revealing differences in the abundance of bile acids (particularly glycoursodeoxycholic acid sulfate) and butyrate to differentiate between psoriasis patients who did or did not progress to PsA [ 85 ].…”

“…The close link between lipid profiles and IMIDs was recently demonstrated in PsA patients, where oxylipins [ 102 , 103 , 105 , 106 ], endocannabinoids [ 103 , 107 ], fatty acids [ 105 , 106 , 107 ] and phospholipids [ 106 ] were found to be potentially pathophysiologically relevant. A recent study also found that the level of inflammatory lipid mediators in psoriasis patients increased following a PsA diagnosis, particularly leukotriene B4 [ 85 ]. However, a comprehensive study is required to compare the lipid profiles of patients with psoriasis and PsA, and this will be the first step toward the identification of lipid biomarkers that improve the diagnosis and treatment of PsA.…”

“…Considering that such panels of RA markers have been assembled based solely on proteomics data, it is clear that the combination of proteomics with orthogonal omics datasets plus more diverse data can increase the power of this approach exponentially, both for diagnosis/prognosis [ 129 ] and the monitoring of drug responses [ 130 ]. In one recent study, metabolomics and lipidomics analysis revealed that a combination of the bile acid conjugate glycoursodeoxycholic acid sulfate and lipid mediator leukotriene B4 provided a sensitive and specific predictor of progression from psoriasis to PsA [ 85 ]. However, adding new features will also require the careful evaluation of added value, both for discovery in basic research and translation to the clinic.…”