Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder influenced both intrinsically by immune cell alterations, genetic factors, and the microbiome, as well as extrinsically by environmental factors. Methods: In this pilot study, we investigated the role of various peripheral immune cells (CD3+, CD4+, CD8+, CD4+/CD8+, CD4-/CD8-, NK cells (CD16+CD56+), and CD19+) and the gut and salivary microbiota in patients with SLE, comparing these factors to healthy controls. Results and Discussion: Results showed significant alterations in the proportions of CD4+ and CD8+ T cells in SLE patients, with an inverse correlation between these subsets. Additionally, the CD4+ ratio was found to be elevated in SLE. CD4+ T cells were strongly correlated with double-negative T cells, while CD8+ T cells correlated with NK cells. Metagenomic shotgun sequencing of fecal and salivary samples revealed a disruption in the microbiome, particularly the taxa Pasteurellaceae and Veillonella, which were altered in both the gut and oral microbiomes of SLE patients. These changes suggest that there may be overlap in the composition and function of these microbial populations across different body sites. Dysbiosis was observed in both the gut and oral microbiomes of individuals with SLE, distinguishing them from healthy controls. Conclusion: Our findings highlight specific microbiome alterations in SLE patients and suggest that microbiome composition could serve as a potential exploratory tool for diagnosing and prognosticating the disease in larger, adequately powered cohorts.