Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy

doi:10.1016/j.semcancer.2021.07.005

Seminars in Cancer Biology

Volume 86, Part 3, November 2022, Pages 732-742

https://doi.org/10.1016/j.semcancer.2021.07.005 Get rights and content

Abstract

The lung microbiome plays an essential role in maintaining healthy lung function, including host immune homeostasis. Lung microbial dysbiosis or disruption of the gut-lung axis can contribute to lung carcinogenesis by causing DNA damage, inducing genomic instability, or altering the host's susceptibility to carcinogenic insults. Thus far, most studies have reported the association of microbial composition in lung cancer. Mechanistic studies describing host-microbe interactions in promoting lung carcinogenesis are limited. Considering cancer as a multifaceted disease where epigenetic dysregulation plays a critical role, epigenetic modifying potentials of microbial metabolites and toxins and their roles in lung tumorigenesis are not well studied. The current review explains microbial dysbiosis and epigenetic aberrations in lung cancer and potential therapeutic opportunities.

Introduction

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths, with over 1·7 million deaths worldwide reported alone in 2018 [1]. The histological subtypes of lung cancers are classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Globally, NSCLC accounts for about 85 % of all lung cancers, including adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma, while SCLC accounts for the remaining 15 % [2]. Even though the five-year survival for lung cancer has significantly increased due to various advancements from diagnosis to novel drug development, lung cancer remains a fatal disease. Thus, a broader understanding of the pathophysiology of lung cancer is needed. Understanding the lung microbiota and associated epigenetic modulations may lead to new opportunities to improve its clinical management.

As an integral part of the human body, the microbiota exists at various spatial and temporal levels and plays a vital role in human physiology [3]. About 1–3 % of our body mass is made up of the microbiome. Interestingly, various microorganisms can modulate or disrupt a wide array of human genes [4,5]. The human microbiome encodes a lot more proteins than the human genome itself. A recent study by Sberro et al. reported thousands of small proteins encoded by microorganisms [6]. In the case of healthy lungs, though initially believed to be sterile, diverse types of microorganisms were detected by advanced sequencing-based methods that habitat in the lungs of healthy never-smoking individuals [7,8]. The lung microbiota consists of bacteria, fungi, viruses, and bacteriophages that live in symbiotic harmony with the host, and their dysbiosis is involved in many severe lung diseases [[9], [10], [11], [12]]. Considering the relatively fewer microbiota present in the lung than other organs such as the gut, understanding the lung microbiome in normal subjects is essential. Even though, the lung microbial biomass is smaller than the gut, crucial cross-talk between their respective microbiota is evident and the role of gut–lung axis in health and diseases are widely reported [[13], [14], [15], [16]]. This bidirectional axis connects the gut and lung niches via bloodstream and allowing microbial metabolites, endotoxins, hormones, and cytokines to flow. Thus, gut-lung axis appears as an extended lung microbiome and in-depth understanding of this axis will provide new insights into the pathophysiology of lung diseases, including cancer.

Most of the microbiome studies are based on association analyses. Understanding whether dysbiosis is causing and facilitating the disease or dysbiosis is only a result of the disease process is often tricky. This review highlights the recent studies that address the causal link between the microbiome and lung cancer. Furthermore, we discuss the epigenetic changes underlying lung cancer and its microbial roots and ways to improve therapeutic interventions.

Section snippets

Establishment of lung microbiome

The presence of microbes in the placenta, fetal membranes, umbilical cord blood, and amniotic fluid reveals that the colonization and establishment of the newborn microbiota likely begin prior to birth [17,18]. The exact mechanisms of microbiota transfer from the mother to the fetus are not well understood. However, the initial colonization process of the newborn microbiome affected by several factors, including birth routes, nursing procedures, antibiotic use, clearly indicates that the

Microbial dysbiosis in lung cancer

Carcinogenesis is a highly complex event that involves multiple physiological processes. Various pathologic microbes are epidemiologically associated with cancer development [39]; however, dysbiosis of commensal microorganisms can significantly contribute to this process by altering the host susceptibility to carcinogenic events, including increased pathogenic microbial load. Bacterial metabolites and toxins can cause DNA damage and induce genomic instability in the host that can initiate tumor

Epigenetic contribution in transcriptional homeostasis

Epigenetic regulation of gene expression is categorized into three levels, DNA methylation, chromatin modification, and non-coding RNAs. DNA methylation plays a significant role in gene silencing and can alter chromatin architecture [63,64]. Transcription start sites are enriched with the CG-rich sequences called CpG islands which are usually unmethylated in normal cells. The methylation of CpG islands, which is often found in cancer cells, leads to silencing of the corresponding gene. DNA is

Microbiome and lung cancer treatments

The local microbiota, directly or indirectly, affects the host-targeted cancer therapy by either facilitating drug efficiency, abolishing and compromising anticancer effects, or mediating toxicity [170]. Dysbiosis reduces microbial efficiency to metabolize the xenobiotics and drugs, modify the host immune responses that may play a role in carcinogenesis, and interfere with anticancer therapy [171]. Likewise, it has also been reported that both cancer and anticancer treatments influence the

Conclusion and future direction

Increasing evidence from sequencing-based methods suggests that the lungs shelter a complicated and diverse variety of microbes that could be affected by both host and environmental conditions. However, the lung microbiome has relatively low microbes compared to the gastrointestinal tract yet exhibits significant diversity. The microbiota in the lungs and gut can cross-talk and plays a crucial role in preserving normal respiratory physiology and immunity. The change in population dynamics of

Funding source

No funding source to declare.

Transparency document

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

We thank Dr. Shafiul Haque (Jazan University) and Tanvir-Ul Hasan Dar (Baba Ghulam Shah Badshah University) for critical discussion.

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The datasets used and/or analyzed during the current study are available from the The corresponding author on reasonable request.
Special issue Microbes in Cancer Research in 'Seminar in Cancer Biology' 2021
2022, Seminars in Cancer Biology

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Microbiome dysbiosis and epigenetic modulations in lung cancer: From pathogenesis to therapy

Abstract

Introduction

Section snippets

Establishment of lung microbiome

Microbial dysbiosis in lung cancer

Epigenetic contribution in transcriptional homeostasis

Microbiome and lung cancer treatments

Conclusion and future direction

Funding source

Transparency document

Declaration of Competing Interest

Acknowledgements

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

CA Cancer J. Clin.

Lung cancer: understanding its molecular pathology and the 2015 WHO classification

Front. Oncol.

Defining the human microbiome

Nutr. Rev.

Molecular paths linking metabolic diseases, gut microbiota dysbiosis and enterobacteria infections

J. Mol. Biol.

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

Genome Med.

Large-scale analyses of human microbiomes reveal thousands of small, novel genes

Cell

Topographical continuity of bacterial populations in the healthy human respiratory tract

Am. J. Respir. Crit. Care Med.

Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals

mBio

The microbiome of the lung

Transl. Res.

Functional effects of the microbiota in chronic respiratory disease

Lancet Respir. Med.

The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda

Lancet Respir. Med.

Microbiome dysbiosis in lung cancer: from composition to therapy

NPJ Precis. Oncol.

Microbes, metabolites, and the gut–lung axis

Mucosal Immunol.

The gut-lung axis in health and respiratory diseases: a place for inter-organ and inter-kingdom crosstalks

Front. Cell. Infect. Microbiol.

The cross-talk between gut microbiota and lungs in common lung diseases

Front. Microbiol.

Role of lung and gut microbiota on lung cancer pathogenesis

J. Cancer Res. Clin. Oncol.

Detection of ureaplasmas by the polymerase chain reaction in the amniotic fluid of patients with cervical insufficiency

J. Perinat. Med.

The placenta harbors a unique microbiome

Sci. Transl. Med.

The maternal infant microbiome: considerations for labor and birth

MCN Am. J. Matern. Child Nurs.

Development of upper respiratory tract microbiota in infancy is affected by mode of delivery

EBioMedicine

The airway microbiome at birth

Sci. Rep.

Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery

Nat. Med.

The impact of breastfeeding on nasopharyngeal microbial communities in infants

Am. J. Respir. Crit. Care Med.

Microbiota and chronic lung disease in preterm infants. Where is the truth?

J. Perinatol.

Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children

Am. J. Respir. Crit. Care Med.

The development of lower respiratory tract microbiome in mice

Microbiome

The lung microbiome: new principles for respiratory bacteriology in health and disease

PLoS Pathog.

The microbiota of the respiratory tract: gatekeeper to respiratory health

Nat. Rev. Microbiol.

Respiratory microbiome and epithelial interactions shape immunity in the lungs

Immunology

Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture

PLoS One

The germfree animal in nutritional studies

Annu. Rev. Nutr.

Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells

Immunity

Paradigms of lung microbiota functions in health and disease, particularly, in asthma

Front. Physiol.

Bacterial topography of the healthy human lower respiratory tract