Background/Purpose: Unclear mechanisms underlying diffuse NPSLE (anxiety, cognitive dysfunction) lead to the devastating impact of this disease on patients’ health-related quality-of-life. Dysbiosis of gut microbiota is observed in patients with, and mouse models of, SLE. Fecal microbiota transfer from SLE-prone B6.Sle1Sle2Sle3 (B6.TC) mice, as well as patients with SLE, induced production of anti-dsDNA antibodies as well as an inflammatory response in germ-free C57BL/6 (B6) mice, suggesting dysbiosis may be involved in SLE pathogenesis. We and others show that oral antibiotic treatment (OAT) have beneficial effects on systemic manifestations in SLE-prone mice. However, the impact of OAT on behavioral deficits in SLE is largely unexplored. OAT can induce anxiety and cognitive deficits in control mice, yet OAT has shown dramatically protective effects in Alzheimer’s disease and multiple sclerosis models, potentially through modulating the gut-microbiota-brain-axis and altering microglial activation. As we find microglial activation in NPSLE-prone mice, we will elucidate the impact of OAT on behavioral deficits in NPSLE.

Methods: Separate cohorts of 4-week-old female B6 and B6.TC (Jackson #007228) mice were given autoclaved water plus ampicillin, neomycin sulfate, metronidazole (1 g/L), and vancomycin (0.5 g/L), supplemented with 2% sucralose or 1% sucrose 2x/wk for 5 wks with no observable weight loss. Mice underwent behavioral tasks. Perfused brains from the sucralose cohort were extracted after intravenous CD45 labeling to exclude remaining circulating immune cells, dural meninges were removed, and cells were analyzed by flow cytometry. Brains from the sucrose cohort were similarly processed, individual preps were hashed, and live CD45+ cells were FACSorted (n=3/strain) for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq; 10X Genomics 5’ v2; analysis pending).

Results: OAT significantly reduced anxiety in B6.TC mice in the Zero maze task with no positive effect on known defects in coordination and motor learning in the Rotarod task. As expected, OAT induced mild anxiety in B6 mice in the Zeromaze task. Results were independent of the choice of sweetener. OAT did not impact systemic disease markers, including splenomegaly and lymphadenopathy. Analysis of sucralose-treated mice shows characteristic increases in total microglia, the disease-associated microglia (DAM) subset, macrophages, and extra-vascular CD4+ T cells in B6.TC mice compared to B6 mice. We did not observe the characteristic increase in extra-vascular CD8+ T cells, suggesting sucralose may impact this population in B6.TC mice. Strikingly, analysis of OAT mice shows further expansion of total microglia, DAM, and macrophages, as well as an increase in extra-vascular CD8+ T cells in B6.TC mice compared to B6 mice.

Conclusion: We find that OAT reduces anxiety in NPSLE-prone mice and further expands total microglia, DAM, and macrophage populations already elevated in disease. Future studies will identify changes in the activation status of these and other immune cell subsets in the brain by CITE-seq to interrogate potential mechanisms linking dysbiosis of gut microbiota to anxiety and other manifestations of NPSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/oral-antibiotic-treatment-reduces-anxiety-in-a-murine-model-of-neuropsychiatric-manifestations-of-systemic-lupus-erythematosus/