Fecal microbiota transplantation attenuates hypertension in a female mouse model of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic multisystem autoimmune disorder that disproportionately affects women. SLE is characterized by a breach of immunological self-tolerance and the expansion of autoreactive T and B lymphocytes, leading to the production of autoantibodies. Autoantibody production leads to downstream chronic inflammation resulting in high rates of hypertension, renal injury, and cardiovascular disease. Alterations in the gut microbiota, or gut dysbiosis, is associated with many autoimmune diseases, including SLE. In the present study, we hypothesized that gut dysbiosis in SLE may play a role in the development of immune system dysfunction and hypertension in an experimental model of SLE, and that fecal microbiota transplantation (FMT) with microbes from control mice may improve these parameters. To test this hypothesis, we treated 26-week-old female control (NZW, n=19) and SLE (NZBWF1, n=19) mice with broad spectrum antibiotics (0.4 g/L ampicillin, 0.4 g/L neomycin sulfate, 0.4 g/L metronidazole, and 0.2 g/L vancomycin) in drinking water for one week to deplete the existing microbiota. Subsequently, mice were given 0.1 mL of fecal microbes via oral gavage two times per week for four weeks in the following groups (n=9-10 mice/group): Control-vehicle, Control-SLE microbes, SLE-vehicle, SLE-Control microbes. Changes in the gut microbiome before and after FMT were assessed by 16S rRNA analysis of the microbiome. Mean arterial pressure (MAP, mmHg), measured in conscious mice by carotid artery catheter was higher in SLE mice that received SLE microbes (Control: 112±3 vs. SLE: 140 ±2 mmHg, p<0.0001). SLE mice that received FMT with control microbes had lower blood pressure (SLE-Control microbes: 126±4 mmHg, p=0.03). Renal injury, as assessed by urinary albumin excretion at the conclusion of the study, was not significantly different among the groups (p=0.3523). Circulating autoantibodies and immunoglobulins were also measured at the conclusion of the study. Anti-dsDNA IgG was elevated in SLE mice compared to control (Control: 149±38 vs. SLE: 527±114 kU/mL, p=0.02), and were significantly lower in SLE mice treated with control microbes (SLE-Control microbes: 126±4 mmHg, p=0.03). Circulating IgM was also elevated in SLE mice (Control: 0.053±0.008 vs. SLE: 0.32±0.04 mg/mL, p<0.0001), and FMT lowered IgM in SLE mice that received FMT (0.19±0.03 mg/mL, p=0.0069). These data suggest that gut microbiota present in NZBWF1 mice contribute to both autoantibody production and the development of hypertension, and that interventions to alter the microbiora could have a beneficial impact on disease activity in SLE patients. NIH NIGMS P20GM104357 to UMMC Department of Physiology and Biophysics, NIH NHLBI R00HL146888 to Erin Taylor This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.