Emerging evidence indicates that the immune system can influence microbiome composition. Chen et al. now report that patients with active ulcerative colitis have low expression of NLRP12, which is best known for its role in immune responses. The authors further show that the function of NLRP12 in immune regulation contributes to the maintenance of the intestinal microbiome. Mice that were deficient in NLRP12 had a consistent predominance of the Erysipelotrichaceae family of bacteria, which correlates with greater colon inflammation in both humans and mice. Replenishing the colons of mice with specific “good” bacteria reduced inflammation and resulted in overall better colon function. In addition, neutralizing the inflammatory cytokines interleukin-6 and tumor necrosis factor with blocking antibodies also restored protective bacteria.