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

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^fl/flPdx1-Cre^Tg 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.