Tryptophan Metabolism ‘Hub’ Gene Expression Associates with Increased Inflammation and Severe Disease Outcomes in COVID-19 Infection and Inflammatory Bowel Disease

Abstract

The epithelial barrier’s primary role is to protect against entry of foreign and pathogenic elements. Both COVID-19 and Inflammatory Bowel Disease (IBD) show commonalities in symptoms and treatment with sensitization of the epithelial barrier inviting an immune response. In this study we use a multi-omics strategy to identify a common signature of immune disease that may be able to predict for more severe patient outcomes. Global proteomic approaches were applied to transcriptome and proteome. Further semi- and relative- quantitative targeted mass spectrometry methods were developed to substantiate the proteomic and metabolomics changes in nasal swabs from healthy, COVID-19 (24 h and 3 weeks post infection); serums from Crohn’s disease patients (scored for epithelial leak), terminal ileum tissue biopsies (patient matched inflamed and non-inflamed regions, and controls). We found that the tryptophan/kynurenine metabolism pathway is a ‘hub’ regulator of canonical and non-canonical transcription, macrophage release of cytokines and significant changes in the immune and metabolic status with increasing severity and disease course. Significantly modified pathways include stress response regulator EIF2 signaling (p = 1 × 10−3); energy metabolism, KYNU (p = 4 × 10−4), WARS (p = 1 × 10−7); inflammation, and IDO activity (p = 1 × 10−6). Heightened levels of PARP1, WARS and KYNU are predictive at the acute stage of infection for resilience, while in contrast, levels remained high and are predictive of persistent and more severe outcomes in COVID disease. Generation of a targeted marker profile showed these changes in immune disease underlay resolution of epithelial barrier function and have the potential to define disease trajectory and more severe patient outcomes.

Dysregulation of CD4+and CD8+resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis

“…These same metabolic genes are also significantly upregulated in enteric neural cells from CPI colitis versus HC ( figure 4C ). While these pathways have been implicated in UC pathogenesis, 12 13 they also distinctly characterize stromal cells in CPI colitis. Most DE genes between CPI colitis versus HC are distinct from genes from UC comparisons to healthy ( figure 4D,E , left), and in direct comparisons between UC and CPI colitis, NAD + catabolism, tryptophan metabolism, and metallothionein genes are again uniquely upregulated in CPI colitis stroma ( figure 4E , right).…”

Discovering KYNU as a feature gene in hidradenitis suppurativa

“…KYNU is widely expressed in nearly all organs of the body, with particularly elevated levels observed in the liver, urinary bladder, and appendix. 50 KYNU is involved in various inflammatory skin diseases, [51][52][53][54][55] cardiovascular diseases, 56 inflammatory bowel disease, 57,58 and several types of cancers, [59][60][61][62][63] exerting its effects through diverse pathways. While previous studies have indicated abnormalities in tryptophan metabolism within HS lesions, 18 there is currently a scarcity of research confirming the distinctive expression pattern of KYNU specifically in HS.…”

Stability Studies of Kynurenine Pathway Metabolites in Blood Components Define Optimal Blood Processing Conditions

“…MSD parameters and MRM transitions used for individual metabolites and labelled metabolites were set as previously described. 27…”

“…LC-MS/MS analysis of TRP, KYN, 3HK, 3HAA, 5-hydroxytryptophan (5HTP), xanthurenic acid (XA), 5-hydroxyindoleacetic acid (5HIAA), serotonin, KYNA and AA was carried out using a TSQ Vantage mass spectrometer (Thermofisher, USA) connected to a Vanquish solvent delivery/autosampler system (Thermo-Dionex, USA), according to a protocol previously described. 27 Briefly, chromatographic separation was achieved by injecting standards and samples (20 μL) onto a Luna ® PFP(2)100 Å reversed phase column (2 × 150 mm, 3 μm; Phenomenex) with the temperature of the column compartment set at room temperature by reverse phase gradient elution at 25°C. A binary solvent gradient was used which consisted of aqueous 0.1% formic acid (A) and methanol (B) at a flow rate of 300 μL/minute.…”

“…MSD parameters and MRM transitions used for individual metabolites and labelled metabolites were set as previously described. 27 Calibration curves of individual metabolites were constructed using the peak area ratios (peak area of the metabolite divided by peak area of the selected IS) of each calibrating solution versus its concentration. These calibration curves were used to calculate the concentrations of the endogenous metabolites in the samples.…”