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Abstract Christensenella minuta DSM 22607 has recently been suggested as a potential microbiome-based therapy for inflammatory bowel disease (IBD) because it displays strong anti-inflammatory effects both in vitro and in vivo. Here, we aimed to decipher the mechanism(s) underlying the DSM 22607-mediated beneficial effects on the host in a mouse model of chemically induced acute colitis. We observed that C. minuta plays a key role in the preservation of the epithelial barrier and the management of DNBS-induced inflammation by inhibiting interleukin (IL)-33 and Tumor necrosis factor receptor superfamily member 8 (Tnfrsf8) gene expression. We also showed that DSM 22607 abundance was positively correlated with Akkermansia sp. and Dubosiella sp. and modulated microbial metabolites in the cecum. These results offer new insights into the biological and molecular mechanisms underlying the beneficial effects of C. minuta DSM 22607 by protecting the intestinal barrier integrity and regulating inflammation.

Abstract Crohn’s disease (CD) is characterised by chronic inflammation. We aimed to identify a relationship between plasma inflammatory metabolomic signature and genomic data in CD using blood plasma metabolic profiles. Proton NMR spectroscopy were achieved for 228 paediatric CD patients. Regression (OPLS) modelling and machine learning (ML) approaches were independently applied to establish the metabolic inflammatory signature, which was correlated against gene-level pathogenicity scores generated for all patients and functional enrichment was analysed. OPLS modelling of metabolomic spectra from unfasted patients revealed distinctive shifts in plasma metabolites corresponding to regions of the spectrum assigned to N-acetyl glycoprotein, glycerol and phenylalanine that were highly correlated (R2 = 0.62) with C-reactive protein levels. The same metabolomic signature was independently identified using ML to predict patient inflammation status. Correlation of the individual peaks comprising this metabolomic signature of inflammation with pathogenic burden across 15,854 unselected genes identified significant enrichment for genes functioning within ‘intrinsic component of membrane’ (p = 0.003) and ‘inflammatory bowel disease (IBD)’ (p = 0.003). The seven genes contributing IBD enrichment are critical regulators of pro-inflammatory signaling. Overall, a metabolomic signature of inflammation can be detected from blood plasma in CD. This signal is correlated with pathogenic mutation in pro-inflammatory immune response genes.

Abstract Microbiome-based therapies for inflammatory bowel diseases offer a novel and promising therapeutic approach. The human commensal bacteria of the species Christensenella minuta (C. minuta) have been reported consistently missing in patients affected by Crohn’s disease (CD) and have been documented to induce anti-inflammatory effects in human epithelial cells, supporting their potential as a novel biotherapy. This work aimed at selecting the most promising strain of C. minuta for future development as a clinical candidate for CD therapy. Here, we describe a complete screening process combining in vitro and in vivo assays to conduct a rational selection of a live strain of C. minuta with strong immunomodulatory properties. Starting from a collection of 32 strains, a panel of in vitro screening assays was used to narrow it down to five preclinical candidates that were further screened in vivo in an acute TNBS-induced rat colitis model. The most promising candidate was validated in vivo in two mouse models of colitis. The validated clinical candidate strain, C. minuta DSM 33715, was then fully characterized. Hence, applying a rationally designed screening algorithm, a novel strain of C. minuta was successfully identified as the most promising clinical candidate for CD.