Longitudinal flux balance analyses of a patient with Crohn's disease highlight microbiome metabolic alterations

Inflammatory bowel diseases (IBD) are characterised by episodic inflammation of the gastrointestinal tract. Gut microbial dysbiosis characterises the pathoetiology, but its role remains understudied. We report the first use of constraint-based microbial community modelling on a single individual with IBD, covering seven dates over 16 months, enabling us to identify a number of time-correlated microbial species and metabolites. We find that the individuals dynamical microbial ecology in the disease state drives time-varying in silico overproduction, compared to healthy controls, of more than 24 biologically important metabolites, including oxygen, methane, thiamine, formaldehyde, trimethylamine N-oxide, folic acid, serotonin, histamine, and tryptamine. A number of these metabolites may yield new biomarkers of disease progression. The microbe-metabolite contribution analysis revealed that some genus Dialister species changed metabolic pathways according to the disease phases. At the first time point, characterised by the highest levels of blood and faecal inflammation biomarkers, they produced L-serine or formate. The production of the compounds, through a cascade effect, was mediated by the interaction with pathogenic Escherichia coli strains and Desulfovibrio piger. We integrated the microbial community metabolic models of each time point with a male whole-body, organ-resolved model of human metabolism to track the metabolic consequences of dysbiosis at different body sites. The presence of D. piger in the gut microbiome influenced the sulphur metabolism with a domino effect affecting the liver. These results underline the importance of tracking an individuals gut microbiome along a time course, creating a new analysis framework for self-quantified medicine. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/520975v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@136ef4forg.highwire.dtl.DTLVardef@1993042org.highwire.dtl.DTLVardef@2f795forg.highwire.dtl.DTLVardef@c95a6d_HPS_FORMAT_FIGEXP M_FIG C_FIG