Microbiota regulate innate immune signaling and protective immunity against cancer

Microbiota play critical roles in regulating colitis and colorectal cancer (CRC). However, it is unclear how the microbiota generate protective immunity against these disease states. Here, we find that loss of the innate and adaptive immune signaling molecule, TAK1, in myeloid cells (Tak1ΔM/ΔM) yields complete resistance to chemical-induced colitis and CRC through microbiome alterations that drive protective immunity. Tak1ΔM/ΔM mice exhibit altered microbiota that are critical for resistance, with antibiotic-mediated disruption ablating protection and Tak1ΔM/ΔM microbiota transfer conferring protection against colitis or CRC. The altered microbiota of Tak1ΔM/ΔM mice promote IL-1β and IL-6 signaling pathways, which are required for induction of protective intestinal Th17 cells and resistance. Specifically, Odoribacter splanchnicus is abundant in Tak1ΔM/ΔM mice and sufficient to induce intestinal Th17 cell development and confer resistance against colitis and CRC in wild-type mice. These findings identify specific microbiota strains and immune mechanisms that protect against colitis and CRC. [Display omitted] •Myeloid-specific Tak1-deficient mice are completely resistant to colitis and CRC•Specific microbiota in Tak1ΔM/ΔM mice play a key role in protective immunity•Innate immune pathways and gut Th17 cells are required for protective immunity•O. splanchnicus alone induces Th17 cells and confers resistance to colitis and CRC Xing et al. report that myeloid-specific Tak1-deficient mice are completely resistant to colitis and colon cancer and show that the microbiota of these mice have the ability to induce intestinal Th17 cells and confer protective immunity. Additionally, the work identifies Odoribacter splanchnicus as a single protective strain.