Toll-like receptor ( TLR) s ignals are key to maintaining hostmicrobial
i nteractions. T he T oll-interacting-protein (Tollip) is a
ubiquitously-expressed inhibitor of inflammasome a nd TLR
signaling. W e hypothesized that T ollip might control g ut
homeostasis. G enetic ablation of T ollip d id not lead to
spontaneous colitis b ut h ad d ramatic c onsequences on t he
intestinal expression of the α-defensin cryptidin 4 and the C-type
lectin R EGIIIβ. These c hanges were associated with intestinal
dysbiosis a nd e nhanced colonization b y segmented filamentous
bacteria - a k ey p ro-inflammatory component of the microbiota.
Tollip deficiency increased susceptibility to dextran sulfate sodium
(DSS) colitis and aggravated chronic Th17-driven colitis in IL-10-/-
mice. Flora d epletion w ith a ntibiotics in T ollip-/- mice w as not
sufficient to restore DSS colitis susceptibility and deletion of Tollip
in n on-hematopoietic c ells using bone-marrow chimeras w as
sufficient to increase s usceptibility t o DSS colitis. After D SS
administration, we o bserved several e pithelial defects i n Tollip-/-
mice including early tight junctions disruption, increased epithelial
apoptosis, and increased intestinal permeability. Overall, our data
show that T ollip significantly impacts intestinal h omeostasis by
controlling b acterial ecology and intestinal r esponse to chemical
and immunological stresses.