Gut metaproteomics reveals activated arginine catabolism and impaired arginine biosynthesis in systemic lupus erythematosus.

The resilience of microbial metabolic functions during gut microbiome dysbiosis depends on functional redundancy across taxa. However, this ecological principle remains largely unexplored in human autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we utilized quantitative metaproteomics to analyze fecal samples from 103 SLE patients and 62 healthy controls. Analysis of 30,124 protein groups revealed a protein-abundance-based shift in microbial arginine pathway capacity. Specifically, argininosuccinate synthase (ArgG), the committed enzyme for arginine biosynthesis, was significantly downregulated in SLE. In contrast, carbamate kinase and ornithine carbamoyltransferase-key enzymes of the arginine deiminase catabolic pathway-were upregulated. Taxonomic attribution demonstrated that ArgG expression was driven almost exclusively by IMPORTANCE: By applying quantitative metaproteomics to a large clinical cohort, we demonstrate that the metabolic consequences of gut dysbiosis in systemic lupus erythematosus (SLE) are largely dictated by the degree of functional redundancy within the microbiota. We show that functions restricted to a single bacterial lineage, such as