Human microbiota colonization and pancreatic ductal carcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate and a poor prognosis. The human microbiota has been confirmed to participate in oncogenesis and may influence the treatment response to both chemotherapy and immunotherapy. Evidence for the association of the microbiota with PDAC risk, tumorigenesis, treatment response, and survival period is rapidly emerging. The oral microbiota and gut microbiota have the potential to be used in early diagnosis and risk stratification. Intratumor microbiota-targeted intervention strategies may be used as adjuvants to current treatments to improve therapeutic efficacy and overall survival. Here, we summarize the effect and association of the oral, gut and intratumor microbiota on the oncogenesis, progression and treatment of PDAC, as well as the potential of the microbiota to serve as a biomarker for the diagnosis and prognosis of PDAC, as well as a therapeutic target.

Keywords:

• Microbiota
• pancreatic microbiome
• pancreatic ductal adenocarcinoma

Disclosure statement

The authors report there are no competing interests to declare.

Figure 2. Colonization of the PDAC intratumor microbiota. Oral pathogens were found to be enriched in pancreatic cystic precursors; experiments demonstrated that microbiota within pancreatic tissues arise from retrograde migration from the duodenum via the pancreatic duct which opens in the duodenal papilla, but this translocation may not be a physiological process; translocation of duodenal microbiota cannot explain the origin of approximately 70% microbiota in PDAC.

Figure 1. Mechanisms of microbiota affecting the occurrence and treatment of PDAC. The figure shows mechanisms by which human commensal microbiota affects the oncogenesis, progression, and therapeutic effect of PDAC. Oral pathogen P. gingivalis induces protumorigenic genes TP53 and KRAS mutations by secreting peptidyl-arginine deaminase. F. nucleatum facilitates tumorigenesis and metastasis in a variety of ways: F. nucleatum binds to host cells via FadA adhesin proteins, thereby enabling cellular internalization and thus activating (NF) -κB and IL-6 pathways, resulting in pro-inflammatory cascades; F. nucleatum may also bind to D-galactose-b(1–3)-N-acetyl-D-galactosamine (Gal-GalNAc) on the surface of tumour cell via Fap2, therefore promoting epithelial mesenchymal transformation (EMT). Intact gut microbiota was found to induct immune suppression via up-expression of hosts pattern recognition receptors (PRRs) which upregulate TLR signalling. However, not all gut microbiota contributes to tumorigenesis, butyrate-producing bacteria such as Ruminococcaceae family enhance CTLs function via SCFAs secretion, SCFAs activate mTOR to regulate cell metabolism and inhibit HDAC enzymes to regulate the epigenetic state of immune cells. Intratumor microbiota was reported mainly contributed to tumour metastasis but not tumorigenesis, while expression of CDD_L in Gammaproteobacteria was confirmed to metabolize gemcitabine which lead to chemotherapy resistance in patients with PDAC.

Table 1. Summary of studies on the microbiota and PDAC.

Additional information

Funding

This work was supported by the CAMS Innovation Fund for Medical Sciences（CIFMS）2021-I2M-1-002.