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

UNLABELLED: 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 Ruminococcus, a genus heavily depleted in SLE. Conversely, upregulated catabolic enzymes and IMP dehydrogenase (IMPDH, the rate-limiting enzyme in de novo purine biosynthesis) were broadly distributed across multiple genera, buffering them against compositional shifts. A leakage-free random forest analysis integrating taxonomic and functional features showed moderate internal discrimination between SLE patients and healthy controls, with a mean area under the curve of 0.784, and identified IMPDH as the most frequently selected functional feature. Because arginine availability regulates T cell function through the GCN2 starvation-response pathway, this protein-abundance-based vulnerability of microbial arginine biosynthesis provides a candidate link between gut dysbiosis and SLE immune pathogenesis.

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 Ruminococcus-dependent arginine biosynthesis, are highly vulnerable to ecological disruption. Conversely, pathways distributed across diverse taxa-like nucleotide biosynthesis and arginine catabolism-remain robust despite taxonomic shifts. This asymmetric functional distribution shifts the perspective of SLE-associated dysbiosis from broad taxonomic profiling to the precise prediction of metabolic deficits. Crucially, identifying reduced microbial arginine-biosynthetic enzyme abundance provides a candidate microbe-derived link to the arginine-dependent T cell defects characteristic of SLE pathogenesis.