Xbp1 controls the reparative function of intestinal ILC2s during colitis

Ulcerative colitis (UC) is primarily characterized by inflammation-induced tissue damage, but impaired tissue repair also drives disease progression. This study demonstrates group 2 innate lymphoid cells (ILC2s), key players in tissue repair, are dysfunctional in UC and experimental colitis due to disrupted endoplasmic reticulum protein processing. We show that the pro-repair function of gut ILC2s depends on the IRE1α-Xbp1 branch of unfolded protein response (UPR), supported by IL-25 and suppressed by interferon-γ (IFN-γ). During colitis, loss of IL-25 and rise of IFN-γ hinder Xbp1 mRNA splicing, weakening ILC2s’ ability to mediate tissue repair. Mechanistically, spliced Xbp1 drives folate-dependent one-carbon (1C) metabolism by promoting dihydrofolate reductase expression. Translationally, the 1C metabolite adenosine 5′-monophosphate alleviated colitis in both ILC2-specific Xbp1 knockout and wild-type mice. Our findings highlight the UPR’s role in sensing gut environment to regulate ILC2 function and suggest folate-mediated 1C metabolism as a potential target for UC therapy.