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Objectives In systemic lupus erythematosus (SLE) higher gut permeability, favouring the translocation of bacterial products from the intestinal lumen into circulation, may contribute to the chronic activation of the immune system. Supporting this assumption, antibiotics and a vaccine against a gut pathobiont prevented autoimmunity and death in a lupus mouse model. In addition, patients with lupus nephritis (LN) exhibit an increased abundance of Ruminococcus gnavus correlating with disease activity. Our group also shown that women with SLE have higher endotoxemia. We therefore hypothesize that SLE involves gut microbial dysbiosis and increased intestinal permeability contributing to disease pathogenesis.Our aim is to study diet, physical activity, body composition, gut microbiota, gut permeability, and endotoxemia in patients with SLE and healthy controls.Methods Diet was assessed with three 24h-dietary recalls, adherence to the Mediterranean diet (MD) and physical activity with the PREDIMED/KIDMED and IPAQ questionnaires. Body composition was analysed by air displacement plethysmography. Gut microbiota was identified by 16S rRNA. Gut permeability was assessed with the lactulose/mannitol test, quantified by mass spectrometry. Zonulin, sCD14, and lipopolysaccharide binding protein (LBP) were quantified with ELISA assays. Lipopolysaccharide biological activity was assessed by TLR4 stimulation in a reporter cell line.Results Forty-five SLE patients meeting the 2019 ACR/EULAR criteria (11 children, 34 adults; 64% with LN) and 16 healthy controls were recruited. SLE patients, compared to controls had lower adherence to the MD (p<0.05), lower intake of n-3 polyunsaturated fatty acids (PUFA) (p<0.05), alpha-linolenic acid (p<0.0001), fibre (p<0.0001), manganese (p<0.001) and higher n-6/n-3 PUFA dietary ratio (p<0.005). SLE patients also exhibited higher body fat mass (p<0.05) and lower physical activity (p<0.05). They demonstrated reduced gut microbiota alpha-diversity, and bacteria from the Rikenellaceae family were increased in patients with LN. Gut permeability was higher in SLE patients (p<0.05), particularly in those with LN. There was an overexpression of zonulin (p<0.01). sCD14 (p<0.005), and LBP (p<0.05) were also overexpressed. Finally, serum from SLE patients induced a significantly greater TLR4 response (p<0.05).Conclusions SLE patients exhibit dysbiosis, increased gut permeability, and endotoxemia. Interventions focused on gut microbiota and maintenance of gut barrier integrity may be promising therapeutic targets in this disease.