Telomerase deficiency induces early senescence and defects in proliferating cell populations, but in mice it has not been associated with inflammatory bowel disease. Genetically engineered mice lacking either telomerase reverse transcriptase (TERT) or telomerase RNA were examined for chronic diarrhea and wasting. Affected mice had pasty stools, thickened nondistensible colon walls, and contracted ceca. Histologically, the cecal mucosa was largely replaced by inflammatory infiltrate consisting of plasma cells, neutrophils, lymphocytes, and macrophages with marked widespread fibrosis and ulceration. Remaining epithelium was disorganized and hyperplastic, with multifocal dysplasia. Colonic mucosa was markedly hyperplastic with similar inflammation and epithelial dysplasia. Multifocal adenomatous hyperplasia, but no inflammation, was present in the small intestine. Microaerophilic spiral bacteria with 16S rRNA gene sequences identical to Helicobacter mastomyrinus were isolated from the colon and cecum. Severe granulomatous typhlocolitis without epithelial dysplasia developed in germ-free recombination-activating gene (RAG) knockout (KO) recipients of CD4+ T cells and inoculated with cecal contents from affected TERT KO mice and in specific pathogen-free recipient RAG KO mice and interleukin-10 KO mice inoculated with H mastomyrinus. Typhlocolitis in mice given H mastomyrinus was more severe than in mice given Helicobacter hepaticus. Telomerase-deficient mice are susceptible to helicobacter-associated typhlocolitis. H mastomyrinus causes severe disease in susceptible mouse strains.