Influence of gut and lung dysbiosis on lung cancer progression and their modulation as promising therapeutic targets: a comprehensive review

Abstract

Lung cancer (LC) continues to pose the highest mortality and exhibits a common prevalence among all types of cancer. The genetic interaction between human eukaryotes and microbial cells plays a vital role in orchestrating every physiological activity of the host. The dynamic crosstalk between gut and lung microbiomes and the gut-lung axis communication network has been widely accepted as promising factors influencing LC progression. The advent of the 16s rDNA sequencing technique has opened new horizons for elucidating the lung microbiome and its potential pathophysiological role in LC and other infectious lung diseases using a molecular approach. Numerous studies have reported the direct involvement of the host microbiome in lung tumorigenesis processes and their impact on current treatment strategies such as radiotherapy, chemotherapy, or immunotherapy. The genetic and metabolomic cross-interaction, microbiome-dependent host immune modulation, and the close association between microbiota composition and treatment outcomes strongly suggest that designing microbiome-based treatment strategies and investigating new molecules targeting the common holobiome could offer potential alternatives to develop effective therapeutic principles for LC treatment. This review aims to highlight the interaction between the host and microbiome in LC progression and the possibility of manipulating altered microbiome ecology as therapeutic targets.

Keywords: dysbiosis; gut microbiome; lung cancer; lung microbiome; probiotics.

FIGURE 1

Gut microbiome species and impact of gut dysbiosis on human health. Gut constitutes well controlled and highly regulated microbial strain on healthy condition. Gut microbiota, either by their direct involvement or via metabolic products, dynamically regulate various organs of host. Dysbiosis of gut has been reported for their direct impact on health and functionality of most of the vital organs of human body. The bidirectional network that promises gut microbiome interaction to distant organs of body are gut–brain axis, gut–brain endocrine axis, gut–heart axis, gut–pancreas axis, gut–lung axis, gut–liver axis, gut–bone axis, gut–muscle axis, gut–skin axis, gut–reproductive axis, gut–kidney axis, and gut–bladder axis. The figure was reproduced with permission and slight modification (in BioRender) from Afzaal et al.

FIGURE 2

Outline of GLA and its material basis. Under symbiotic conditions, gut and lung's epithelial system comprises intact physiological barrier and maintain site‐specific microbial composition. Alveolar macrophages safeguard the lung tissue, while Treg and intestinal macrophages protect lumen lamina propia, together regulate the GLA homeostasis. Dieting habit, antimicrobial agents, various diseased conditions, lifestyle, and numerous environmental factors may lead to gut microbiota dysbiosis. Dysbiotic gut provokes the inflammation causing epithelial cell death, disrupts the compact epithelial barrier, and enhances intestinal permeability. Loose epithelial barrier provides easy access for normal flora, secondary metabolites, inflammatory cytokines such as TNF‐α, TGF‐β, IL‐1β, IL‐5, IL‐6, IL‐13, IL‐17, IL‐18, 1L‐10, and 1L‐30, other chemokines to systemic circulation. Also, various proinflammatory immune cells such as neutrophils and T‐cells can be recruited and induce lymphoid aggregation at gut mucosa, which subsequently get into systemic circulation and infiltered into distant organs including lung parenchyma. Additionally, mesenteric lymphatic system serves as significant way to translocate gut‐derived proinflammatory mediator to respiratory channel and stimulate alveolar macrophages and establish inflamed alveolar milieu. This imbalance causes alveolar epithelial cells apoptosis and alters alveolar barrier. Further, microbiome‐derived metabolites when reached the circulatory system, they can alter lung epithelial functions along with innate/adoptive immune response. This way inflammatory pathogenesis can mediate via GLA and alter lung physiology. Image was reproduced with permission (License no 5857010930891, dated August 27, 2024) from Eladham et al.

FIGURE 3

Composition of lung microbiome in health and diseased condition. Eubiotic lung comprises the higher abundance of Proteobacteria, Firmicutes, Fusobacteria, Bacteroidetes, and Actinobacteria family. They polarize naïve T cells, stimulate the maturation and differentiation of alveolar macrophages and Treg, sustain Th1/Th2 balance, and promote the local immune system homeostasis. However, when lung suffers with infectious disease, there is remarkable disruption on microbiome homeostasis; pathogenic and harmful microorganism oversite the lung tissue and cause lung dysbiosis. Then, translocation of immune cells to infected tissue promotes the secretion of pro‐inflammatory cytokines, activates inflammasome and DC, and induces inflammatory immune response. Altered cytokines mileu can promote lung tissue modeling and apoptosis.

FIGURE 4

Ageing, population, or gene susceptibility are associated with tumorigenesis. As extrinsic factors, the microbiota produced the cytotoxicity‐related components, inducing the DNA damage of host cells. The microbiota and its metabolites (e.g., short‐chain fatty acids [SCFAs]) trigger downstream immune and metabolic signaling pathways, which further promote or suppress the malignant behaviors of host cells. Environmental factors (ultraviolet rays, cigarettes, and particles) can cause altered community of microbiota and gene mutations to promote the occurrence of lung cancer.

FIGURE 5

Impact of the gut microbiota on antitumor immunity. Crosstalk between host microbiome and immune cells may regulate cancer either in positive or negative way. Under properly maintained good gut microbiota and high fiber‐rich dietary condition, SCFAs obtained from beneficial flora translocate to systemic circulation and subsequently regulate T‐cell mediated response. SCFAs specifically facilitate the CD4+, ICOS+, CD8+ T cells accumulation, promote granzyme B, IFN‐γ, and TNF‐α expression, and strengthen the response toward immunotherapies like anti‐PD1/PD‐L1, anti‐CTLA4 antibodies, and CAR T cell therapy. SCFAs further stimulate IFN‐γ producing T‐cells on TME, collectively generate antitumor immunity. In contrast, gut dysbiosis enriched with harmful microbiome potentially upregulates BA production, which when enters to blood, triggers COX2 activation, enhances PGE2 synthesis, suppresses hepatic CXCL16, and diminishes NKT cells recruitments. These all contribute to tumor progression. Inhibition of CD103+ DC, accumulation of IFN‐γ, TNF‐α, and higher Treg presentation at TME help cancer cells tumor evasion. Overexpression of CD8+ T cells and severe chronic inflammation by dysbiotic flora cause T‐cells exhaustion and neutrophils recruitments that subsequently block antitumor immunity. This way, dysbiosis contributes to the cancer development. Image reproduced with permission from Mohseni et al.

FIGURE 6

The mechanisms of microbiota impacting efficacy of cancer treatment. (A) Specifically, administration of Enterococcus and Barnesiella can restore the antitumor efficacy of cyclophosphamide‐based chemotherapy through stimulating tumor‐specific T cells and producing IFN‐γ, and butyrate, a product of dietary fiber fermented by gut microbes, can increase the anticancer effects of oxaliplatin‐based chemotherapy by regulating the function of CD8 + T cells in the TME through IL‐12 signaling. (B) Lactobacillus rhamnosus was illustrated to stimulate the antitumor activity of PD‐1 immunotherapy through cGAS–STING signal pathway, activating IFN‐α, β signaling, and activating cytotoxic CD8 + T cells; SCFAs limit the antitumor effects of CTLA‐4 blockade via alleviating Treg cells, and higher concentration of butyrate could decrease the anticancer activity of ipilimumab by inhibiting the accumulation of related CD4 + T cells. (C) Probiotics can protect gut mucosa from radiation injury through a TLR‐2/COX‐2‐dependent manner, stimulating mesenchymal stem cells to the crypt. FMT, fecal microbiota transplantation; SCFAs, short‐chain fatty acids; IL, interleukin; IFN‐ γ, interferon γ; CTLA‐4, cytotoxic T lymphocyte‐associated antigen 4; Treg, cell regulatory T‐cell; TLR, Toll‐like receptor; COX‐2, cyclo‐oxygenase‐2. Figure reproduced with permission and with slight modification from Ref. .