Ifnlr1-signaling in Lgr5⁺ ISCs provides nonhematopoietic protection from GVHD. (A) Heat map displaying differentially abundant operational taxonomic units consistently increased or decreased in separately housed or cohoused B6 WT and/or Ifnlr1^–/– mice. Cohousing was performed for 4 weeks before transplantation (n = 10 per strain and housing condition, combined from 2 experiments). (B) Principal component analysis of fecal microbial composition for mice as in panel A. (C) Survival of recipients in panel A transplanted with BALB/c BM + T cells. (D) Representative images. (E-F) Numbers (E) and size (F) of GI organoids grown from colonic crypt isolates and enumerated at day 5 (n = 6-7, combined from 3 experiments). (G-H) Representative images (G) and semiquantitative GVHD histopathology scores (H) at day 7 after BMT from tamoxifen-treated Cre-positive or Cre-negative Lgr5^Cre.Ifnlr1^fl.fl recipient mice (n = 10, combined from 2 experiments). (I) Numbers of GI organoids grown from colonic crypt isolates and enumerated at day 5 from mice as in panels D-E (n = 6, combined from 2 experiments). Data are presented as mean ± SEM. P values were calculated by using the 2-tailed Mann-Whitney t test. Survival calculated by using the log-rank Mantel-Cox test. *P <.05, **P < .01. PCI, first principal component; PC2, second principal component.