Self-renewing cells acquire mutations and some of these provide survival advantages, leading to the emergence of somatic clones that contribute to tumorigenesis. Nanki et al. now report that such somatic evolution also occurs in the context of ulcerative colitis (UC). They show that the UC epithelium accumulates loss-of-function and gain-of-function somatic mutations in genes that provide resistance to IL-17A-mediated apoptosis.

Credit: S. Bradbrook/Springer Nature Limited

The authors established colorectal organoids from patients with UC and healthy controls, focusing on left-sided UC in order to establish uninflamed (UCuninf) and inflamed (UCinf) organoids from the same donor. Notably, unlike in healthy or UCuninf organoids, UCinf organoids acquired recurrent truncating mutations in genes related to the IL-17–NF-κB signalling pathway. In UCinf organoids, truncating mutations were identified in NFKBIZ and PIGR, which encode the NF-κB regulator IκBζ and the polymeric immunoglobulin receptor, respectively, as well as in TRAF3IP2, which encodes an adaptor that is essential for activation of NF-κB downstream of the IL-17 receptor. Further studies identified a ZC3H12AS438L mutation in several UCinf organoids; notably, this mutation led to gain of function in ZC3H12A, an RNA-binding protein that helps to dismantle the mRNAs of inflammatory genes, including NFKBIZ and IL17RA.

Using CRISPR-based knockout screening in colon organoids, the authors showed that the mutations identified in the UCinf organoids confer resistance to IL-17A-mediated cytotoxicity. This suggests that IL-17A is detrimental to the epithelial lining and that epithelial cells that acquire resistance to IL-17A have a selective advantage in tissue affected by UC. Exploration of the cytotoxic mechanism involved indicated that IL-17A induces pro-apoptotic signals that affect the superficial layer of the epithelium via the induction of inducible nitric oxide synthase and nitric oxide.

This study shows that in patients with ulcerative colitis, the epithelium can accrue mutations affecting the IL-17 signalling pathway that are irrelevant for tumorigenesis but that enable the selective expansion of mutant clones under inflammatory conditions. Notably, some of the genetic mutations identified in this study are linked to worse colitis in mouse models; therefore, the authors suggest that extensive expansion of mutant clones may exacerbate inflammatory bowel disease.