In this study, we found that EcNΔlpp::A5‐aTN can neutralize TNF‐α and cooperatively ameliorate inflammation by inhibiting ROS/JNK/p38/Caspase‐8/Caspase‐3‐mediated apoptosis, upregulating tight junction proteins, and modulating the immune‐microbiome balance in mice with colitis. Here, MAPK8 is linked to colitis.