Sarcoidosis resolvers and progressors demonstrate distinct systemic metabolomic profiles

Abstract

Sarcoidosis is an idiopathic syndrome with striking disparities in clinical outcome. We have previously identified immune distinctions between sarcoidosis clinical cohorts that either resolve or progress. A significantly higher percentage of Programmed Death 1 (PD-1)+Th17 cells was present in sarcoidosis and IPF subjects experiencing disease progression. Metabolites, or bioactive compounds, have been shown to interact with immune cells, such as Th17 cells by regulating cellular processes such as proliferation, signaling and differentiation. Metabolomic analysis was conducted on two subject cohorts: Sarcoidosis (n=19) and healthy controls (n=23). Sarcoidosis subjects were further subdivided by clinical outcome and prior to therapeutic initiation: disease progression or clinical resolution. Metabolites are considered significant if they had a fold change greater than two and a p-value is <0.05 in pairwise 2-sample t-tests. Multiple group comparison was performed using ANOVA and Tukeys honestly significance difference post hoc tests to identify statistically different pairwise differences. Progressors exhibit significantly elevated serum levels of trimethylamine N-oxide (TMAO) and taurine, with reduced glycerate, alanine, and proline concentrations (Figure 1A-C). TMAO is elevated in sarcoidosis progressors relative to resolvers. Taurine levels are also significantly elevated in progressors, comparing to resolvers. The significant reductions in glycerate, alanine, and proline in progressors compared to resolvers, along with elevated TMAO, point to disruptions in core metabolic pathways, including glycolysis, pyruvate metabolism, and collagen synthesis, that underlie bioenergetic dysfunction, altered amino acid utilization, and impaired tissue repair. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/642370v1_fig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@12b058corg.highwire.dtl.DTLVardef@1795b24org.highwire.dtl.DTLVardef@4e993dorg.highwire.dtl.DTLVardef@2e97da_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Comparison of metabolome clusters among sarcoidosis and healthy control cohorts. A) PLS-DA demonstrates clusters among sarcoidosis resolver, progressor, and controls, and B) only between resolver and progressor. Circles indicate 95% confidence region of each group. Distinct signatures exemplified using boxplots C). Metabolites with a fold change greater than two and a p-value is <0.05 in pairwise 2-sample t-tests are considered significant. Multiple group comparison were performed using ANOVA and Tukeys honestly significance difference post hoc tests to identify statistically different pairwise differences. *p<0.05, **p<0.01, ***p<0.001. C_FIG