ABSTRACTThe aim of the present study was to examine whether the immune‐modulatory bacteria Lactobacillus fermentum CECT5716 (LC40) ameliorates disease activity and cardiovascular complications in a female mouse model of lupus. Eighteen‐week‐old NZBWF1 systemic lupus erythematosus (SLE) and NZW/LacJ (control) mice were treated with vehicle or LC40 (5 × 108 colony‐forming units/d) for 15 wk. LC40 treatment reduced lupus disease activity, blood pressure, cardiac and renal hypertrophy, and splenomegaly in SLE mice. LC40 reduced the elevated T, B, regulatory T cells (Treg), and T helper (Th)‐1 cells in mesenteric lymph nodes of lupus mice. LC40 lowered the higher plasma concentration of proinflammatory cytokines observed in lupus mice. Aortas from SLE mice showed reduced endothelium‐dependent vasodilator responses to acetylcholine. Endothelial dysfunction found in SLE is related to an increase of both NADPH oxidase‐driven superoxide production and eNOS phosphorylation at the inhibitory Thr495. These activities returned to normal values after a treatment with LC40. Probiotic administration to SLE mice reduced plasma LPS levels, which might be related to an improvement of the gut barrier integrity. LC40 treatment increases the Bifidobacterium count in gut microbiota of SLE mice. In conclusion, our findings identify the gut microbiota manipulation with LC40 as an alternative approach to the prevention of SLE and its associated vascular damage.—Toral, M., Robles‐Vera, I., Romero, M., de la Visitación, N., Sánchez, M., O'Valle, F., Rodriguez‐Nogales, A., Gálvez, J., Duarte, J., Jiménez, R. Lactobacillus fermentum CECT5716: a novel alternative for the prevention of vascular disorders in a mouse model of systemic lupus erythematosus. FASEB J. 33, 10005–10018 (2019). www.fasebj.org