The microbiota includes different microorganisms consisting of bacteria, fungi, viruses, and protozoa distributed over many human body surfaces including the skin, vagina, gut, and airways, with the highest density found in the intestine. The gut microbiota strongly influences our metabolic, endocrine, and immune systems, as well as both the peripheral and central nervous systems. Recently, a dialogue between the gut and lung microbiota has been discovered, suggesting that changes in one compartment could impact the other compartment, whether in relation to microbial composition or function. Further, this bidirectional axis is evidenced in an, either beneficial or malignant, altered immune response in one compartment following changes in the other compartment. Stimulation of the immune system arises from the microbial cells themselves, but also from their metabolites. It can be either direct or mediated by stimulated immune cells in one site impacting the other site. Additionally, this interaction may lead to immunological boost, assisting the innate immune system in its antitumour response. Thus, this review offers an insight into the composition of these sites, the gut and the lung, their role in shaping the immune system, and, finally, their role in the response to lung cancer.
The microbiota is a consortium of different microorganisms that includes bacteria (microbiota), fungi (mycobiota), viruses, and protozoa [
In this review, we give an overview of the composition of both the gut and the lung and describe the interaction between the immune system and microbiota using the intestinal tract as an example. In the case of the lungs, we are still only able to speculate about any similarity. We also examine immune stimulation of the gut to observe the effects on lung immunity, inflammation, and lung cancer, and finally, we discuss how these two sites might “cooperate” to achieve a productive immune and anticancer response.
The evolution of an individual’s microbiota begins at birth, with its composition becoming relatively stable after the age of two and remaining so throughout life. The GI tract is populated by more than 1,000 bacterial species. At the level of the phylum, the composition of the microbiota is similar in most healthy people. Over 90% of bacterial cells are Firmicutes and Bacteroidetes, followed by Actinobacteria, Proteobacteria, and Verrucomicrobia, together constituting 99% of the overall commensal microbiota [
Most frequently detected bacteria in GI tract and respiratory system of healthy volunteers or from healthy tissue samples. Results from different studies are presented by the taxa level in which they were originally detected, in order of decreasing abundance where possible. If the sampling, analysis method, or result was specific for a certain study, the reference was added adjacent to the corresponding information.
Sample source |
Phylum | Order or family | Genus or species | Reference | |
---|---|---|---|---|---|
GI tract | Faeces |
Firmicutes(79.4% of sequences), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%), and Verrucomicrobia (0.1%) |
|
Tap et al. [ | |
|
|||||
Oral cavity | Saliva |
Firmicutes, Proteobacteria, Actinobacteria, Fusobacteria, TM7, and Spirochaetes | Pasteurellaceae (5.8%), Enterococcaceae (2.6%), Veillonellaceae (2.0%), Burkholderiales (1.2%), and Lactobacillales (1.1%) |
|
Lazarevic et al. [ |
|
|||||
Nose | Swab |
Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes, and Fusobacteria | Staphylococcaceae |
Charlson et al. [ | |
|
|||||
Oropharynx | Swab |
Dominated by Firmicutes, Proteobacteria, and Bacteroidetes, and Fusobacteria, Actinobacteria, TM7, and SR1 follow (oropharynx was richer and less variable than the nostril microbiota) | Streptococcaceae, Lachnospiraceae, unclassified group of Clostridia [ |
Charlson et al. [ | |
|
|||||
Esophagus | Biopsy |
Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and TM7 |
|
Pei et al. [ | |
|
|||||
Lung | BAL |
Actinobacteria, Firmicutes, and Proteobacteria |
Streptococcaceae, Veillonellaceae, Prevotellaceae, Micrococcaceae, Neisseriaceae, Porphyromonadaceae, Lachnospiraceae, Actinomycetaceae, and Fusobacteriaceae |
|
Charlson et al. [ |
BAL: bronchoalveolar lavage.
Strongly correlating to long-term diet [
The microbiota is now considered key to the proper development, maturation, and reactivity of the immune system [
Interaction of the microbiota and intestinal mucosa. (a) Microorganisms in the intestine provide pathogen-associated molecular patterns (PAMPs) that serve as ligands for different Toll-like receptors (TLRs) on the luminal or basolateral surface of the intestinal epithelial cells (IECs). (b) TLRs stimulation activates a signalling cascade resulting in transcription factor activation and gene transcription, enhancing the cell barrier and further stimulating the immunological cells in the lamina propria. This cascade can be inhibited by toll-interacting protein (TOLLIP).
Commensal microorganisms can enter intestinal lamina propria in several ways: through an opening in the barrier as a result of injury or through active sampling by DCs or M cells. In any case, microorganisms in the lamina propria are either phagocytosed and eliminated by macrophages [
Specific populations of commensal bacteria, for example,
To understand more precisely which commensal microbiota has this immunostimulatory effect, the well-known
Likewise, introducing probiotic strains such as
Immunity and inflammation are not necessarily affected by bacterial cells but may be influenced by bacterial products. Bacterial products that have a significant effect on overall host status surely included short-chain fatty acids (SCFAs), by-products of the microbial fermentation of dietary fibre. Among others,
As mentioned previously, changes to the gut microbiota are related to, for example, changes in diet, antibiotic administration, chemotherapy, and a person’s general immune status. Whether with a transient or permanent effect, these changes often lead to dysbiosis, with an altered ratio of beneficial bacterial species (
Apart from the direct pathological effect, an absence of the appropriate microbial composition in the immune system’s early development has more far-reaching effects. This is evident from studies on mice reared in germ-free (GF) conditions. These animals have impaired GI-driven immune development, characterized by smaller Peyer’s patches, fewer CD8
The human respiratory tract is the primary and continuous entry portal for numerous microorganisms and particles, such as viruses, bacteria, or fungi. These are primarily airborne but can also be transferred through saliva. Below the vocal cords, the human airways harbour bacteria and other microbes in rich surroundings [
In 2014 Dickson et al. [
Starting with the upper respiratory airways, the nostril is dominated by Firmicutes and Actinobacteria; Firmicutes, Proteobacteria, and Bacteroidetes are prevalent in the oropharynx [
The ecological determinants of the lung microbiota (immigration, elimination, and regional growth conditions) change during acute and chronic lung disease, as seen in chronic obstructive pulmonary disease (COPD) (often a precancerous inflammatory state) and lung cancer (Table
Most frequently detected bacteria in the lung of patients suffering from their respective diseases. Results from different studies were presented by the taxa level in which they were originally detected, in order of decreasing abundance where possible. If the sampling, analysis method, or result was specific for a certain study, the reference was added adjacent to the corresponding information.
Disease | Sample source | Phylum | Order or family | Genus or species | Reference | |
---|---|---|---|---|---|---|
Analysis method | ||||||
Lung | COPD | BAL |
Proteobacteria (44%) and Firmicutes (16%) followed by Actinobacteria (13%), with Bacteroidetes,Fusobacteria, Tenericutes,SR1 incertae, TM7, and Synergistetes identified in lower proportions (<3%) |
|
Erb-Downward et al. [ | |
Lung cancer | Sputum |
Flavobacteriales, Burkholderiales, Campylobacterales, Spirochaetales(more abundant), and Bacteroidales(less abundant) |
|
Rybojad et al. [ |
COPD: chronic obstructive pulmonary disease; BAL: bronchoalveolar lavage; DGGE: PCR-denaturing gradient gel electrophoresis; SCC: small cell carcinoma; AC: adenocarcinoma.
The microbial factors that may be responsible for lung cancer development are still not well known, unlike the many genetic predispositions and mutations that underlie the different types of lung cancer [
Inflammation of the lung is associated with a loss of epithelial integrity and results in the “leakage” of serum proteins into the airways [
Obstruction of the lumina with mucus introduces pockets of increased temperature and decreased oxygen tension, selectively favouring the growth of well-known disease-associated microbes [
Lung microbiota was also shown to vary according to clinical endpoints. In nonmalignant lung tissue from advanced stage cancer, alpha diversity had increased, while it had decreased in the tumour lung tissue. Also, the interaction between the upper and lower airways involving the microbial population present in lung cancer is clearly shown in the study carried out by Yan et al. [
As mentioned above, IL-6 and IL-8 are cytokines that become elevated during inflammatory stress. They are involved in tumorigenesis by acting directly on lung epithelial cells to stimulate the NF-
To summarize, the appearance of dysbiosis or malignancy is likely the product of a dynamic interaction between various immune, microbial, and environmental factors. At least one of these acts as an initiator but others often readily follow. This is why it remains difficult to reach any conclusions regarding the true aetiology of disease and what might be the best intervention and, more importantly, prevention approach.
Recently, we have reached a greater understanding of microbial influence on the complex and interconnected axis between gut and lung. This stems from the simple fact that ingested microorganisms can access both sites—from gastrointestinal tract microbiota that enters the lung through aspiration [
This interaction can be mediated in different ways—by the microbiota and its products or via immune cells (Figure
Proposed pathways of the gut-lung interaction. Microbiota and its products that enter intestinal mucosa (blue arrows) are phagocytosed and transferred to mesenteric lymph nodes (MLN) by antigen presenting cells (APC), where they stimulate priming of the T and B cells. Once activated, with the expression of proper homing receptors, these cells can migrate back to the original site (intestinal mucosa) (black dashed arrow) or to distal locations such as the lung epithelium and lung nodes through lymphatic and blood circulation. There, they can directly act on their target or continue to stimulate other immune cells. On the other hand, bacterial products from the intestinal mucosa or surviving bacteria can also reach the lung by blood or lymphatics to stimulate the immune system in the same way as they would have done in the intestinal tract. Depending on the tissue prestimulation, type of stimulus, and local and general immunological status, the result can be positive, as effective bacterial clearance or antitumour activity, or overinflammatory response, promoting further tissue damage, pathogen colonization, and tumour progression. The same schema is proposed in the other sense, beginning with the lung mucosa and finishing with distal effect on the gut. Although not known for the moment, there is also a possibility that bacterial products of the lung microbiota can exert their effect in the intestinal mucosa, being delivered in the same way as explained above. APC: antigen presenting cell; DC: dendritic cell; GALT: gut-associated lymphatic tissue; IEC: intestinal epithelial cell; LLN: lung lymph node; MLN: mesenteric lymph node; SCFA: short-chain fatty acid. Colour legend (borders/arrows): blue: influence of gut on lung; orange: influence of lung on gut; black: mutual influence.
Another way to influence the pulmonary region is through the migration of immunological cells. As previously mentioned, translocated microorganisms and their parts within the lamina propria are transferred to the mesenteric lymph nodes by antigen presenting cells (APCs) and used for priming naïve B and T cells. Activated B cells capable of producing antigen-specific immunoglobulins, that is, plasma cells, will not only produce immunoglobulins in situ, but will reach draining lymph nodes and other mucosal tissues, thereby spreading immunological “information.” The constitutive entry of antigen at steady state stimulates inflammasome conversion of pro-IL-1
Although this theory explains the unilateral interaction, it is reasonable to speculate that this axis works in precisely the same way when it originates in the lung mucosa and lung lymph nodes (Figure
The composition of “healthy,” or rather balanced, gut microbiota is shown to have a serious influence on the effectiveness of lung immunity. GF mice, devoid of their intestinal microbiota during the development of their immune system, show impaired pathogen clearance in the lung, which results in their growth and dissemination [
Interestingly, modified gut microbiota not necessarily characterized as dysbiotic may also influence immune response efficiency, as seen in obese mice. These mice had an impaired expression of cytokines in their lungs (IFN
Nutrition may also impact microbial development and the composition of our respiratory tract microbiota [
The above-mentioned findings clearly show how important the overall composition of the intestinal microbiota is for a productive immunological response in the lung. Lack of an appropriate stimulus during the developmental phase, as during infection, will disable a quick and effective immune reaction, resulting in pathogenic colonization, increased susceptibility to infection, damage, the possible development of cancer, and increased mortality. At the same time, just one single strain, bacterial part, or product can turn the tables and provide the boost needed to stimulate the correct immune response.
Unlike the local and systemic influence of intestinal microbiota, the influence of lung microbiota and its products and their circulation is yet to be properly assessed. One study reported that nonabsorbable tracer deposited into the nasal cavity of mice can be found in the GI tract a short time later [
Due to a number of genetic alterations resulting in the loss of normal cellular regulatory processes, cancer cells express neoantigens that are tumour-specific and distinguish tumour cells from healthy cells. The importance of the gut microbiota in anticancer response has been described by Chen and Mellman [
To create a higher response to neoantigens, the immune system’s peripheral tolerance must be reduced. It is already known that the commensal microbiota induces the generation of CD4+ T cells against their own antigens [
Observing these effects, it is interesting to speculate that at least a transient disruption of intestinal barrier functions and microbiota translocation is a primary factor in shaping the relationship between the gut microbiome, the immune system, and cancer.
Probiotics, best known in nutritional therapy, are defined as “live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host” [
Although the first evidence of probiotic influence on lung cancer was seen in 1985 [
In a lung adenocarcinoma viral model, when vancomycin was used to eradicate Gram-positive bacteria it compromised the efficacy of cyclophosphamide- (CTX-) based chemotherapy and correlated with a reduced intratumoural CD8+ T effector/FoxP3+ regulatory T cell ratio [
On the other hand, feeding mice orally with
Recently, there was considerable interest in evaluating the role of gut microbiota in lung cancer therapy using immune checkpoint inhibitors. One of the first studies of this principle was done using a mouse melanoma model but is readily applicable to other cancer types, as shown in the study. Here, oral administration of a
Vétizou et al. [
To summarize, as scientists delve deeper, the beneficial effects of probiotics on the immune system continue to emerge. As seen, certain strains have the power and ability to stimulate antitumour response or to simply stimulate the immune system to show lower tolerance, thus promoting higher reactivity and tumour eradication. The future objective is to find the optimum probiotic cocktail that may one day completely substitute conventional therapies, thereby obtaining equal or better success and lowering toxicity, one of the biggest problems in cancer treatment.
The importance of the gut microbiota and its composition has long been recognized, for digestion as well as for overall wellbeing. Recently, the presence of the lung microbiota and the role it plays, in health and in disease, have been receiving attention. The lung and gut microbiota, both continually reseeded through interaction with the environment, modulate our local and systemic immunity. More than simply two distinct microbiota, they are now seen as functioning in dialogue, altering previous ideas of airway sterility and the existence of a “barrier” between the two compartments, due to their perceived distance or functional differences. By providing stimulating signals through its epitopes or products (such as SCFA butyrate), the gut microbiota directly enhances the intestinal barrier. Likewise, it stimulates the priming and maturation of T and B cells, ensuring improved microbial clearance and mucosal protection through antibodies. This effect is not only retained in the intestinal system but is spread along other mucosal surfaces by means of lymphatic and blood circulation, influencing distal site immune response. So, even though the antigen was introduced in the gut, an immunological response can also be elicited in the lung, although there was no direct prior contact with the antigen, and vice versa. Bacteria and their products that go through the first immunological barrier also reach distal sites through the lymphatic system and blood and modulate the immune response at the remote site. The site where the first encounter between the immune system and microbial antigens took place is also important, since it influences reactivity and the influx of these cells into other tissues. Applying prebiotics to target a specific microbial group could be a good way to restore “healthy” microbial composition, which will consequently increase intestinal barrier function and stimulate the immune system. The relevance of natural microbial support in chemotherapy effectiveness or replacement has already been demonstrated. In future, further discoveries will surely be made in this new and exciting area of research, adding to the complexity of, but also clarifying the reasons behind, this axis; opening ideas to new or enhanced therapies based on the natural behaviour of the organism; increasing longevity; and decreasing therapeutic side-effects or the effects of disease itself.
The authors hereby declare that no conflicts of interest exist with respect to the publication of this article.