The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs)

Abstract

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. 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. Ho, Stanford, California). 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. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. 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. 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). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. 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). 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. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. 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.

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

“…Eggerthella is part of the normal human intestinal microbiome and has been most commonly associated with infections spreading from the gastrointestinal tract 60 , but it has also been found interacting with food intake while influencing metabolism of drugs 61 . This genus has also been shown to be more abundant in individuals with psychiatric diseases 62 and higher grade neoplasms 63 . E. lenta from the same genus correlates with taurodeoxycholic acid, a bile acid metabolite, in the colon of smoke-exposed mice 64 and has increased abundance in the presence of blood in stool, which is a marker for CRC 65 .…”

PitNETs and the gut microbiota: potential connections, future directions

“…Neuroendocrine tumor (NET) is a heterogeneous group of tumors originating from different neuroendocrine organs or cells (108). In addition to PitNETs, the NETs in other organs have also been linked to gut microbes (109). By studying stool samples from 18 patients with rectal neuroendocrine tumor (RNET) and 40 controls, Hu et al found that patients with RNET had aberrant depletion and attenuated connection.…”

Impact of Erythromycin as a Prokinetic on the Gut Microbiome in Children with Feeding Intolerance—A Pilot Study

“…To reduce batch effect, all samples were stored at −20 • C, then processed and analyzed concurrently for microbial composition. The methodology, including DNA extraction, PCR amplification, library preparation, and sequencing, is detailed in Appendix A and was previously reported by our lab [79,80]. Library sequencing was completed on an Ion Torrent S5 sequencer (ThermoFisher Scientific,.…”