Background and aims: Faecalibacterium prausnitzii , a highly abundant bacterium in the human gut microbiota, has been linked to overall health and is decreased in several pathological conditions, such as Inflammatory Bowel Disease (IBD). F. prausnitzii has shown anti-inflammatory properties in human and mouse models, notably through the induction of IL-10 signaling. Here, we investigated which cell types from human blood and intestinal tissue are responsible for producing IL-10 induced by F. prausnitzii , and providing the first mechanistic insights. Methods: Immune cells isolated from human blood and intestinal lamina propria of patients with IBD and non-inflamed controls, were stimulated with either F. prausnitzii EXL01 strain or Escherichia coli lipopolysaccharide (LPS) and analysed by Legendplex, ELISA, flow cytometry, RNA-sequencing (RNAseq), and Seahorse technology. Results: F. prausnitzii EXL01 strain induced the direct and dose-dependent production of IL-10 in CD14 ⁺ monocytes from the systemic circulation and intestinal tissue of IBD patients and non-inflamed controls, without inducing a pro-inflammatory response as compared to LPS stimulation. RNAseq analysis corroborated these results and revealed that F. prausnitzii EXL01 strain differentially affects cell energy metabolism compared to LPS. The anti-inflammatory response induced by F. prausnitzii in monocytes was dependent on mitochondrial respiration. Conclusion: F. prausnitzii induces an anti-inflammatory response and rewires energy metabolism in human monocytes, which might explain its beneficial impact on intestinal inflammation and human health in general. These results provide new insight into the mechanisms underlying the anti-inflammatory effects of F. prausnitzii and are crucial for a better understanding of its potential use in the treatment of IBD.

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