Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification

Abstract

Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.

Intestinal inflammation modulates the expression of ACE2 and TMPRSS2 and potentially overlaps with the pathogenesis of SARS-CoV-2 related disease

“…We also compared the intersections between COVID-19 associated genes and those associated with three different murine models of intestinal injury or inflammation. We observed a significant overlap between genes up-regulated with COVID-19 response in the NHBE lung model with genes upregulated in either a 1) Dextran Sodium Sulfate (DSS) induced intestinal injury model 35 ; 2) TNBS-intestinal injury model 36 , especially two days post TNBS administration or 3) adoptive T cell transfer colitis model 37 following a 6-week time period (ie W0<W2<W4<W6). Some examples of genes found commonly up-13 regulated amongst the 3 IBD-mouse models and NHBE-COVID-19 response included C3, IFITM3, IL1B, S100A9, TGM2 (transglutaminase 2) and PLAUR (plasminogen activator, urokinase receptor) (Table S22).…”

Transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis

“…[30][31][32][33][34] Several other SDE genes in colon and blood from our study including Lipg, Gm5483, B230303A05Rik, Ambp and Trem3 have not been shown previously in this model. The largest overlap of 1,566 SDE genes was with a recent study by Czarnewski et al, where deep RNA sequencing 35 was performed to stratify different subtypes of human UC using the common genes in human and mouse UC. Although they used a very similar approach, neither non-coding RNAs nor blood transcriptome were considered in their study.…”

“…In the Czarnewski et al study, 650 SDE genes common between human and mouse UC colon were identified, but no non-coding RNA and blood profiling was performed. 35 Apart from these studies, to the best of our knowledge, there are no human-mouse UC comparative studies considering both colon and blood as well as coding and non-coding RNAs to the scale of our study.…”

“…To date, few studies using colon have compared the transcriptional changes in UC mouse models and human UC. [33][34][35] Holgersen et al identified 92 SDE genes in both human CD and UC, 33 which were used for comparison to their three mouse models. In the DSS model, since colon samples were pooled, no statistical significance of differences could be calculated between disease and healthy mice.…”

The Atlas of Inflammation-Resolution (AIR)

“…Other phenotypes (monocyte extravasation; M1 phenotype and behavior; acting cytoskeleton reorganization) were upregulated, suggesting that RvD1 brought the whole systems quickly towards the inflammation resolution phase in comparison to the exposure with zymosan alone. Right: In another example, we highlight the influence of MIM components on various processes associated with the acute inflammation onset and resolution after mapping of time-series transcriptomics profile from mouse colitis model 49 . The graph indicates normalized phenotype levels (a.u.)…”