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BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are among the most common neoplasms of the small bowel; however, the molecular mechanisms underlying their pathogenesis are largely unknown. The multifocal nature of SI-NETs, their putative distinct genomic origins, and their enrichment in the distal ileum led us to hypothesize that environmental factors, such as pathogenic organisms, might play a role in the development of these lesions.MATERIALS AND METHODS: To study the tumor-associated microbiome of multifocal SI-NETs and its potential role in pathogenesis, we used matched whole genome and transcriptome sequencing data from a cohort of 10 multifocal SI-NET patients, including 70 primary ileal NETs and their matched normal ileal mucosa and/or whole blood specimens.RESULTS: Microbial communities in the ileal tissue samples were primarily composed of bacteria. The most abundant genera included well-known gastrointestinal, oral, and mucosal bacteria. Ileal tissue samples from individual patients contained distinct patient-specific microbial communities. Although the microbiota composition did not show significant differences between ileal NET and normal ileal tissues, genus was found to be enriched in the normal tissue specimens.CONCLUSIONS: This study comprehensively characterizes the tissue-resident ileal microbiome of multifocal SI-NET patients. We provide clear evidence that the microbial communities in the ileum are largely patient specific, whereas our genus-level analyses suggest that SI-NET pathogenesis is unlikely driven by individual microorganisms present in the tumors at the time of surgical resection.