Tumor classification based on differentiation, referring to the extent to which neoplastic cells morphologically resemble endocrine cells of origin, divides GEP-NENs into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NENs are classified according to histological differentiation, grade, tumor burden, origin of the primary tumor, and extent of metastatic disease. A Surveillance, Epidemiology, and End Results (SEER) analysis showed seven-fold increase in the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) over the last decade in the United States. Neuroendocrine neoplasms (NENs) are a diverse group of neoplasms that arise from endocrine cells throughout the body a significant proportion originate in the gastrointestinal tract. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.
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This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were substantial differences associated with dietary habits and therapeutic responses. In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis ( p = 0.022), and Eggerthella lenta ( p = 0.00018) species compared to lower grade tumors. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs ( p = 0.048, 0.0022 and 0.034, respectively). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant.
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We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response.
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We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E.
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In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Gut microbiome balance plays a key role in human health and maintains gut barrier integrity.