Gut dysbiosis has been associated with intestinal and extra-intestinal malignancies but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. Rapid onset of tumorigenesis induced a burst of Reg3y release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long lasting dysbiosis dominated by Gram positive Clostridium species. Pharmacological blockade of B-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin or co-housing of tumor bearers with tumor free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Cancer patients harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extra-intestinal malignancies requiring specific therapies.