several statistically credible cell-type changes in healthy tissue compared to both non-inflamed and inflamed tissue in both epithelium and lamina propria at an FDR level of 0.2, using Immature Goblet cells and CD8 + intraepithelial lymphocytes (IELs) as automatically selected reference. Notably, we tested scCODA with different reference cell types (Supplementary Fig. 8), and did not detect credible changes for CD8 + IELs in the lamina propria with any reference cell type, backing up that CD8 + IELs are a good reference that does not change with respect to any other cell type. In the epithelium, both Dirichlet regression and scCODA identified significant and statistically credible changes, respectively, in the absorptive and secretory lineage, but scCODA also identified an increase in enteroendocrine cells. For comparison, ANCOM only identified significant changes in M cells (healthy vs inflamed) and enteroendocrine cells (healthy vs non-inflamed). M cells are lowly abundant and only 3 out of 16 inflamed samples had more than ten cells. When we compared the M-cell-positive subset of inflamed samples to healthy samples, though, M cells were indeed credibly increased. In the lamina propria, B-cell subpopulations showed several changes, e.g., a decrease of plasma B cells with disease (validated with stainings
