From Microbiome to Malignancy: Unveiling the Gut Microbiome Dynamics in Pancreatic Carcinogenesis

Abstract

Pancreatic cancer is a major cause of cancer-associated mortality globally, characterized by a poor prognosis and limited therapeutic response. The current approach for treating pancreatic cancer involves locoregional control with surgical resection and systemic therapy in the form of cytotoxic chemotherapy. However, despite standard-of-care treatment, the outcomes remain dismal. Emerging evidence suggests that the gut microbiota plays a significant role in pancreatic carcinogenesis through dysbiosis, chronic inflammation and immune modulation. Dysbiosis-driven alterations in the gut microbiota composition can disrupt intestinal homeostasis, promote systemic inflammation and create a tumor-permissive microenvironment in the pancreas. Moreover, the gut microbiota modulates the efficacy of systemic therapies, including chemotherapy and immunotherapy, by impacting drug metabolism and shaping the tumor immune landscape. This review is mainly focused on exploring the intricate interplay between the gut microbiota and pancreatic cancer, and also highlighting its dual role in carcinogenesis and the therapeutic response.

Keywords: bile acids; gut microbiota; metabolites; oncobiome; pancreatic cancer.

Figure 1

The impact of microorganisms on pancreatic cancer progression remotely and locally. Gut microbiota and oral microbiota can inhibit the antitumor immunity of host, aiding in the progression of PDAC. Similarly, intrapancreatic microorganisms (local) also contribute to pancreatic carcinogenesis.

Figure 2

The microbiota shapes the immune microenvironment of the tumor: Within the TME (tumor microenvironment), the microbiota triggers the immune system and attracts immune cells. Under the influence of the microbiota, these immune cells undergo differentiation into distinct immune cell subtypes that secrete specific factors which exert either anti- or pro-neoplastic effects. For example, the presence of microbiota could lead to a decrease in immune cells known for their antitumor effects, such as CD8+ T cells, M1 macrophages (releasing IL-β/IL6/TNF) and Th1 cells (from CD4+ T cells and secreting IFN-γ). Conversely, microbiota could elevate immune cells with pro-tumorigenic effects, which include B cells, M2 macrophages (secreting IL10/TGF/CCL18), MDSCs, and Th2 (CD4+ cells; secreting IL6/TGF), Th17 (secreting IL17) and Treg (secreting IL-10) cells.

Figure 3

Factors affecting bacterial bile acid metabolism.