Novel gut pathobionts confound results in a widely used model of human inflammatory disease

Forster et al. (BioRxiv) DOI: 10.1101/2021.02.09.430393

 

Keywords

  • DSS

  • Microbiome

  • Phenotypic heterogeneity

 

Main Findings

Forster et al show that disease outcome following DSS treatment is highly variable and predicted by the differential presence of disease- and health-associated taxa in the steady state microbiome. The authors further characterise four (2 health- and 2 disease-associated) species through monocolonization experiments, showing that disease-associated Duncaniella muricolitica and Alistipes okayasuensis exacerbate weight loss, mortality and monocyte/macrophage colonic infiltrate following DSS treatment. These 2 species are found to be common, but not ubiquitous, in 31 animal facilities providing a rationale for the potential inclusion of these bacteria in monitoring regimes. The authors also document a lack of correlation between weight loss and histopathology, raising the importance of viewing these as independent parameters that do not serve as substitutes for one another in the DSS model. 

Limitations

  • 3 other disease-associated species identified by linear discriminant analysis of pre- and post-DSS microbiomes not characterised further or included in intra-institutional variation analysis.

  • Open question: unexplored mechanism by which D. muricolitica and A. okayasuensis influence disease severity. 

  • Open question: factor driving weight loss not identified or discussed further.

  • Both open questions tie into the unexplored observation that mice monocolonized with disease-associated, in comparison to those with health-associated, species demonstrate exacerbated weight loss and mortality but not colon or caecum histopathology following DSS treatment. 

Significance/Novelty

Forster et al identify two novel bacterial species which exacerbate disease parameters in DSS colitis. This work highlights the importance of microbiome reporting/monitoring in the DSS model with implications on results obtained and data interpretation. As the DSS model is used in pre-clinical trials, these implications extend to the development of IBD therapeutics. The finding that weight loss is not a readout for intestinal pathology is an important consideration for DSS study design.

Credit 

Reviewed by Rebecca Jeffery as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow Rebecca on Twitter.