Systemic lupus erythematosus (SLE) is an autoimmune syndrome, for which expanding evidence suggests a role for the microbiome in its etiology and pathogenesis. Translocation of bacteria outside the gut, likely due to failures in gut barrier integrity, is a hallmark in SLE patients. Despite significant progress made in determining species-level interactions, there is a need for functional analyses of the gut microbiomes of SLE patients in order to identify specific pathways that drive specific immune phenotypes that specifically arise from breaches in the gut intestinal barrier. Yet, to date, there has not been a single metagenomics study on SLE patients. A key challenge in using metagenomics data to analyze the microbiome is linking these functions to mechanisms important in disease. We have developed a high-throughput method that can broadly assign host-relevant disease mechanisms to proteins produced by the gut microbiota. Leveraging known protein-protein interactions (PPIs), we first apply a homology modeling approach to identify potential microbiota-host interactions and then identify which of these interacting proteins is present in metagenomic datasets and is specifically associated with disease. Our novel method has uncovered a trove of diagnostic markers and therapeutic targets (in addition to possible therapeutics) for colorectal cancer, type 2 diabetes, obesity and IBD. Surprisingly, we find bacterial proteins targeting pathways associated with SLE in microbiomes associated with these disorders, revealing common underlying mechanisms relating autoimmunity. Through collaboration with the Kriegel Lab at Yale, our goal is to investigate the underlying mechanisms of SLE governed by bacterial-host PPIs. The Kriegel lab has extensive experience working with patients with SLE and uncovering several species-level microbiome-host interactions important to lupus pathophysiology. We hypothesize that these interactions may underlie the roles of different organisms previously found to modulate SLE severity. Together we aim to: (1) Identify proteins differentially associated with SLE using metagenomic sequencing and their associated human pathways using bacterial-host PPI mapping. (2) Examine bacterial proteins identified as targeting SLE-associated pathways through PPI mapping and novel human targets associated with SLE, specifically improving gut-barrier function. (3) Perform proteomics of blood plasma from patients to identify human-targeting bacterial proteins that enter the bloodstream. Our overarching goal is to identify therapeutic biomarkers within the gut microbiota that can be used to modulate known SLE human protein biomarkers.