Mapping the Colitis-Body Axis Uncovers an Interorgan Mechanism Protecting Against Liver Injury

Colon diseases often manifest alongside extraintestinal disorders, yet the mechanisms that link colon pathology and distant organ dysfunction remain largely unknown. A major barrier is the lack of knowledge about the systemic effects of colon diseases across the body. Here, we systematically map the organism-wide changes in gene expression induced by colitis triggered by a chemical, dextran sodium sulfate, or bacterial infection with Citrobacter rodentium or Clostridioides difficile. We find that all three colitis models lead to changes in gene expression beyond the colon, including pathways that are shared or specific across tissue and disease types. Using germ-free mice and blocking antibodies against eight cytokines, we discover that gene expression in the bone marrow, colon, and liver is most strongly impacted by the microbiota and that TNF, IL-12, IL-10, and IL-18 critically impact colitis severity and extraintestinal responses. Next, we reveal that colitis modulates disease phenotypes in extraintestinal tissues, such as exacerbation of skin psoriasis and protection against liver injury. Mechanistically, we show that three short chain fatty acids - acetate, propionate, and butyrate - combine to modify the metabolic state of the liver, thereby preventing acetaminophen toxicity. Lastly, we test the potential clinical relevance of our findings using explant cultures of human liver tissue. Our work thus provides a foundation to study the role of the colitis-body axis in extraintestinal diseases, to identify and target inter-organ pathways that modulate disease sensitivity, and to redefine the gut as a central hub for regulating organism-wide immunity.