Microbial and metabolic features associating outcome of infliximab therapy in pediatric Crohn's disease
Abstract Background: Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn's disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Methods: Fecal samples were collected from 20 healthy children, and 29 CD children pre- and post-IFX treatment. 16S rRNA/ITS2 gene sequencing, and targeted metabolomics analysis were applied to profile the gut bacterial microbiota, mycobiota, and metabolome, respectively.  Results: Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including Blautia, Faecalibacterium, and Roseburia, which were coupled well with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were remarkably in concordance with decerased relative abundances of Bifidobacterium and Clostridium clusters IV and XIVb. IFX treatment enhanced the abundances of SCFAs-producing bacteria and those expressing 7a-dehydroxylase in CD subjects, which effectively explained the increases of SCFAs, conjugated BAs pool and the unconjugated/conjugated BAs ratio, respectively. Amino acids L-Proline, L-Valine, and organic acids arachidonic acid, DHA, doscosapentaenoic acid 22n 6, L-Lactic acid, methylamlonic acid, and threnoci acid were found decreased in CD patients after IFX treatment. Notable higher abundances of Sphingomonas, Staphylococcus, Lactobacillus, Methylobacterium, Clostridium XlVb, and Streptococcus were identified in patients with sustained remission (SR) at baseline. Moreover, the SR subjects had higher fecal concentrations of multiple amino acids including, L-Alanine, L-Asparagine, L-Aspartic acid, L-Arginine, L-Glutamine, Glycine, L-Histidine, L-Lysine, L-Lactic acid, L-Leucine, L-Serine, and L-Tyrosine before IFX therapy. Conclusions: The severity of CD is strongly correlated with gut microbiota dysbiosis and metabolic alterations. The effects of IFX in treating pediatric CD were partially attributed by enriching Firmicutes taxa that producing SCFAs and bile salt hydrolases (BSH) thereby inhibiting inflammation and restoring the BAs pool composition. The fecal levels of amino acids have a potential to become prognostic biomarkers of IFX therapy for pediatric CD.