Introduction/Background: When compared to other cancers, the prevalence of midgut neuroendocrine tumors (NETs) has disproportionally increased over the past decades. To date, very little progress has been made in the discovery of (epi)genetic drivers and treatment options of these tumors. Recent microbiome research has provided novel treatment targets among various cancer types. However, its role in midgut NETs and the Carcinoid Syndrome (CS), a frequently present syndrome of hormonal hypersecretion, have not been studied.

Aim: To analyze the role of the gut microbiome in midgut NET patients.

Material and Methods: Fecal samples, collected from patients and controls, were analyzed with next generation 16S sequencing. Relevant variables were extracted from questionnaires and electronic health records. Microbial composition was compared between patients and controls as well as between patients with and without CS.

Results: 182 participants were included: 87 patients, of whom 53 with the CS, and 95 controls. Midgut NET patients had a less rich and diverse gut microbiome compared to controls. A total of 31 differentially abundant species were found, 6 of which were more abundant in patients. A gut microbial signature consisting of 17 species was identified that was predictive of the presence of a midgut NET with an area under the receiver operating characteristic curve of 0.865. When comparing CS with non-CS patients, no differences in microbial richness or distribution were found.

Conclusions: Midgut NET patients have an altered gut microbiome, independent of the presence of the CS, which could suggest a role in NEN development and provide novel targets for microbiome-based diagnostics and therapeutics.