Treatment with male gut microbiota or metabolite downregulates gene expression associated with inflammation in kidneys of lupus-prone mice 2260396

Abstract

Abstract Introduction Lupus nephritis (LN) is a serious complication of lupus. We have found that male gut microbiota transplants (M-F) suppress LN and improve survival in lupus-prone female NZBxNZWF1 (BWF1) mice, and have identified a microbial metabolite, phytanic acid (PA) as a major player in protection. Previously, we found that these treatments increase peripheral Treg induction and macrophage efferocytosis, but did not evaluate the effects of these treatments directly on kidneys. Here, we examined gene expression in kidneys of female BWF1 mice that received either M-F or PA vs their respective controls. Methods Kidneys were collected from control female BWF1 mice when proteinuria scores indicated severe LN (4; scale of 0-5; 5=death) and age-matched treated BWF1 female mice (scores ≤1). For treatments, female BWF1 were fed with either M-F shortly after weaning then monthly through the end of the experiment, or PA in PBS 3x per week beginning at 12 weeks of age through the end of the experiment. Kidneys were processed for bulk RNAseq and data analyzed using DESeq2 and Ingenuity Pathway Analysis. Results In kidneys of M-F vs control mice, 585 genes were downregulated and 13 genes upregulated. In kidneys of PA-treated vs control mice, 191 genes were downregulated and 21 genes were upregulated. 76% of the genes that were downregulated in PA-treated mice were also downregulated in M-F treated mice; >73 of those genes were immune/inflammation-associated including many genes associated with immune cell trafficking pathways (e.g., chemokines/chemokine receptors, integrins) but also IL-1B, STING, TNFSF1B as well as genes associated with other immune/inflammation-associated pathways. Conclusion These data suggest that male microbiota and PA have similar effects and may downregulate kidney responses to the immune assaults that propagate pathogenesis in LN. Funding Source DOD Topic Categories Therapeutic Approaches to Autoimmunity (THER)