The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy

Abstract

The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer.

Keywords: biomarker; gut microbiota; gut-lung axis; immunotherapy; lung cancer.

Figure 1

Major routes of communications within the gut–lung axis. (1) Ruminococcus gnavus stimulates secretion of IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) by colon tissues, those cytokines activate DCs and ILC2 to produce cytokines IL-4, IL-5, and IL-13 and travel through the bloodstream to the lungs and lead to infiltration of the lung parenchyma by eosinophils and mast cells. (2) SCFAs transform macrophage and DC progenitors (MDPs) and their commitment into Ly6C− monocytes in the bone marrow, which can differentiate into alternatively activated macrophages (AAMs) in the lungs, thus control the immunopathology caused by infiltrating neutrophils.

Figure 2

Gut dysbiosis regulates lung inflammation and immunity. (1) Gut dysbiosis causes damage to the intestinal mucosal barrier, invading gut bacteria and metabolites affect the host’s inflammation and immunity locally and systematically which in turn leads to the carcinogensis of lung cancer. Bile acid (BA) stimulates inflammatory markers such as IL-1β、IL-6 and IL-8 in the lung. (2) 12,13-diHOME decreases the number of regulatory T (Treg) cells in the lungs resulting in a reduced anti-inflammatory effect. (3) Bacteria-derived antigens activates TLR4 in the intestine immune cells, which increases the level of IL-1β in peripheral circulation that activates NF-κB pathway, leading to pulmonary inflammation. (4) SFB-induced gut Th17 cells are preferentially recruited to lung due to robust expression in the lung of CCL20. (5) Gut dysbiosis leads to a decrease in the expression of ICAM-1, which decreases the number of activated and effective CD8+ T cells in tumors.