Faecal microbiome and metabolic signatures in rectal neuroendocrine tumors

Abstract

Background: The prevalence of rectal neuroendocrine tumors (RNET) has increased substantially over the past decades. Little is known on mechanistic alteration in the pathogenesis of such disease. We postulate that perturbations of human gut microbiome-metabolome interface influentially affect the development of RNET. The study aims to characterize the composition and function of faecal microbiome and metabolites in RNET individuals. Methods: We performed deep shotgun metagenomic sequencing and untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomic profiling of faecal samples from the discovery cohort (18 RNET patients, 40 controls), and validated the microbiome and metabolite-based classifiers in an independent cohort (15 RNET participants, 19 controls). Results: We uncovered a dysbiotic gut ecological microenvironment in RNET patients, characterized by aberrant depletion and attenuated connection of microbial species, and abnormally aggregated lipids and lipid-like molecules. Functional characterization based on our in-house and Human Project Unified Metabolic Analysis Network 2 (HUMAnN2) pipelines further indicated a nutrient deficient gut microenvironment in RNET individuals, evidenced by diminished activities such as energy metabolism, vitamin biosynthesis and transportation. By integrating these data, we revealed 291 robust associations between representative differentially abundant taxonomic species and metabolites, indicating a tight interaction of gut microbiome with metabolites in RNET pathogenesis. Finally, we identified a cluster of gut microbiome and metabolite-based signatures, and replicated them in an independent cohort, showing accurate prediction of such neoplasm from healthy people. Conclusions: Our current study is the first to comprehensively characterize the perturbed interface of gut microbiome and metabolites in RNET patients, which may provide promising targets for microbiome-based diagnostics and therapies for this disorder.

PitNETs and the gut microbiota: potential connections, future directions

“…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. Finally, they suggest that this disordered ecological structure may contribute to the diseasecausing process of this tumor (110). In gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the researchers found a significant decrease in bacterial species and an increase in fungi in the patients' gut microbes.…”

Multiomics analysis reveals gut profiles in patients with different brain tumors

“…After extracting the DNA of all samples, the total DNA was immediately stored in dry ice, and metagenomic sequencing was performed as soon as possible. All samples were sequenced using the Illumina platform (insert size 300 bp, read length 125 bp) at Novogene Bioinformatics Technology Co., Ltd. [17] A paired-end library was constructed using NEXTFLEX Rapid DNA-Seq (Bioo Scienti c, Austin, TX, USA). Adapters containing the full complement of sequencing primer hybridization sites were ligated to the blunt end of the fragments.…”

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

“…This shows the prevalence of microbial invasion in NENs. Hu et al profiled fecal samples for rectal NETs [ 99 ]. The results of that study are consistent with the general trend of the significant depletion of microbial species diversity in NETs.…”

“…The results of that study are consistent with the general trend of the significant depletion of microbial species diversity in NETs. Bacteria, including Haemophilus parainfluenzae , Veillonella unclassified, and Streptococcus salivarius, were significantly enriched in the healthy group, while species such as Erysipelotrichaceae bacterium_6_1_45 , Varibaculum cambriense , and Methanobrevibacter smithii were abundant in the rectal NET group [ 99 ]. For the functional characterization of the microbiome, glycerophospholipid metabolism as a key tumor-specific pathway is distinctively aberrant in rectal NET patients and is positively correlated with Methanobrevibacter smithii , which is mainly due to changes in the proportion of microbial species [ 99 ].…”

“…Bacteria, including Haemophilus parainfluenzae , Veillonella unclassified, and Streptococcus salivarius, were significantly enriched in the healthy group, while species such as Erysipelotrichaceae bacterium_6_1_45 , Varibaculum cambriense , and Methanobrevibacter smithii were abundant in the rectal NET group [ 99 ]. For the functional characterization of the microbiome, glycerophospholipid metabolism as a key tumor-specific pathway is distinctively aberrant in rectal NET patients and is positively correlated with Methanobrevibacter smithii , which is mainly due to changes in the proportion of microbial species [ 99 ]. The study implies that metagenome-based physiological dysfunction in the intestinal microenvironment drives the disease-progression state of individuals with rectal NETs.…”