Elevated levels of circulating microbial-associated uremic toxins are associated with metastatic duodenopancreatic neuroendocrine tumors in patients with Multiple Endocrine Neoplasia Type 1

Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Fusobacterium nucleatum, Faecalibacterium prausnitzii, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85-1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an Men1<sup>fl/fl</sup>Pdx1-Cre<sup>Tg</sup> mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.

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Journal
Cancer Letters
Published
2025-02-07
DOI
https://doi.org/10.1016/j.canlet.2025.217537
Primary Topic
Neuroendocrine Tumor Research Advances
Type
article
Field-Weighted Citation Impact
0.00

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article

Elevated levels of circulating microbial-associated uremic toxins are associated with metastatic duodenopancreatic neuroendocrine tumors in patients with Multiple Endocrine Neoplasia Type 1

Ranran Wu, Lee S. Weinstein, Jenny E. Blau, Naris Nilubol et al.
Cancer Letters
Neuroendocrine Tumor Research Advances
article

Elevated levels of circulating microbial-associated uremic toxins are associated with metastatic duodenopancreatic neuroendocrine tumors in patients with Multiple Endocrine Neoplasia Type 1

Ranran Wu, Lee S. Weinstein, Jenny E. Blau, Naris Nilubol, James Welch, Ehsan Irajizad, Ricardo A. León-Letelier, Gerlof D. Valk, Nancy D. Perrier, Sunita Agarwal, Yining Cai, Amanda R. Wasylishen, Samir Hanash, Steven Gerard Waguespack, Hiroyuki Katayama, Kim‐Anh Do, Courtney Olsen, Johannes Francois Fahrmann, Carolina R C Pieterman, Jennifer B. Dennison, Mary Walter, Rachel S. van Leeuwaarde, Mark J C van Treijen, Riccardo Ballarò, Smita Jha, Huiling Liu, Menno R. Vriens
article en

Abstract

Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Fusobacterium nucleatum, Faecalibacterium prausnitzii, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85-1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an Men1<sup>fl/fl</sup>Pdx1-Cre<sup>Tg</sup> mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.

Cancer LettersVol. 614
National Institutes of Health (US), The University of Texas MD Anderson Cancer Center (US), University Medical Center Utrecht (NL), National Institute of Diabetes and Digestive and Kidney Diseases (US), Office of the Director (US), Oncode Institute (NL), National Cancer Institute (US), University of Cincinnati Medical Center (US)
Cancer Prevention and Research Institute of Texas, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 96%
Neuroendocrine Tumor Research Advances
DOIOpen Access PDFOpenAlex
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