DNA-sensing AIM2 inflammasome promotes the overgrowth of ileal mucosal Lachnospiraceae to potentiate antitumor immunity

The spatial organization of gut microbiome is essential for their interactions with the host. Recently, microbiota alteration in ileum is getting the increasing recognition due to the close interplay with inflammatory diseases and the tumor immunosurveillance. However, how ileal microbiome is spatially regulated remains unclear. Here, we show that DNA-damaging chemotherapy specifically remodels microbiota in ileal mucosa, resulting in the overgrowth of local family Lachnospiraceae that promotes antitumor immunity and synergizes with immune checkpoint blockage. Mechanistically, the prominent proliferative state of transit amplifying cells (TACs) in the ileal crypt presents a vulnerability to chemotherapy-caused genomic stress, resulting in the accumulation of cytosolic dsDNA that subsequently activates AIM2 inflammasome. AIM2-dependent production of IL18 boosts Th1 immunity in ileal lamina propria, which further impairs the antimicrobial host defense of proximal Paneth cells via activating IFN-γ-JAK-STAT signaling. Our findings demonstrate that AIM2 inflammasome shapes ileal microbiome via governing the compartmentalized cellular interplay in ileal crypt, providing mechanistic insights into the regulation of gut biogeography and implicating therapeutic strategies of spatial microbiome intervention using chemotherapy.