The Effects of Antibiotics on the Development and Treatment of Non-Small Cell Lung Cancer

Lung cancer, with its high incidence, prevalence, and mortality rates, is a significant health concern in the European Union (EU). According to the European Cancer Information System (ECIS), lung cancer was the leading cause of cancer-related deaths in men and the second leading cause of death in women in the EU in 2020, with only breast cancer having higher mortality than lung cancer. The age-standardized incidence rate (ASIR) and the prevalence were higher in men than women in the EU in the same year. The ASIR for lung cancer in men varied widely across the EU member states, ranging from 34.2 per 100,000 in Malta to 126.3 per 100,000 in Hungary. Similarly, the ASIR for lung cancer in women ranged from 6.9 per 100,000 in Cyprus to 37.7 per 100,000 in Denmark. The mortality rate due to lung cancer was also higher in men (57.3 per 100,000) than in women (14.4 per 100,000) in the EU in 2020. The high burden of lung cancer in the EU highlights the need for effective prevention, early detection, and treatment strategies (ECIS 2023).

Lung cancer is tightly connected with smoking. The role of smoking as a causing factor of cancerogenic processes in the lungs has been confirmed in both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) (Brawley et al. 2014; CDC 2023). These types of lung cancer are primarily caused by smoking tobacco, which exposes the lungs to numerous carcinogens, leading to cellular changes that can result in cancerous growth. According to the American Cancer Society and confirmed by more studies (Schabath et al. 2019), smoking accounts for about 80–85% of all lung cancer cases. Other common causes of lung cancer include exposure to secondhand smoke, radon, asbestos, air pollution, and specific occupational hazards, such as exposure to diesel exhaust or certain chemicals. In rare cases, lung cancer can be caused by genetic mutations, such as mutations in genes for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma virus family (KRAS), and others. This is most frequently found in adenocarcinomas (Weinberger et al. 2019; American Cancer Society 2023).

Because of the ability of SCLC to set metastasis very early, there is a difference in the staging and treatment approach compared to NSCLC. Also, the prognosis in SCLC is worse (Weinberger et al. 2019). Based on these facts, SCLC is often discussed separately. In our manuscript, we focused only on NSCLC.

Recently, the role of the microbiome has been diligently studied by which we understand the combined genetic material of microorganisms that constitute a community (Gopalakrishnan et al. 2018) on the whole human organism. Myriads of microorganisms live in the human body and cause no harm; this relationship is based on symbiosis (Lozupone 2012; Zitvogel 2016). For example, the intestinal microbiota refers to the actual collection of microorganisms themselves (Gopalakrishnan et al. 2018) and represents a complex ecosystem essential for maintaining gut homeostasis and preventing systemic inflammation (Lozupone et al. 2012; Zitvogel et al. 2016; Santacroce et al. 2020). Also, the role of bacteria in the respiratory system has been identified recently. The significant fact is that bacteria are commonly modified by antibiotics (ATB).

ATBs are a class of drugs that kill bacteria or inhibit their growth, allowing the body’s immune system to fight off the infection more effectively. ATBs have been widely used since the 1940s and have saved countless lives. However, their overuse and misuse have led to the emergence of ATB-resistant bacteria, which is a major public health concern (Derosa et al. 2018; Mayo Clinic 2023; WHO 2023).

Although we cannot imagine medicine without ATB, across the many studies we have reviewed, we have found differences between the microbiome in otherwise healthy patients and the microbiome of lung cancer patients, possibly in connection with ATB use. As a result of this review, we hope to understand how ATB changes the microbiome and how this change is related to lung cancer risk and treatment.

Numerous epidemiological investigations have sparked apprehension regarding a potential link between ATB use and increased susceptibility to cancer, specifically breast (Didham et al. 2005), hematologic (Chang et al. 2005), pancreatic, and genitourinary. On the other hand, subsequent studies have failed to substantiate these connections. Another study exploring the relationship between ATB use and breast cancer has generally shown that the initial connection reported by Velicer et al. (2004) showing that ATB is linked to a higher risk of incident breast cancer, can probably be attributed to unaddressed confounding factors, such as weakened immune system in patients with cancer (Zhang et al. 2008; Petrelli et al. 2019).

Petrelli et al. (2019) provided a considerable metaanalysis dealing with the connection between using ATB and a higher risk of cancer. They studied 7,947,270 individuals from 25 observational studies, and they concluded that the use of ATB has been related to an 18% higher risk of cancer. According to their findings, with more prolonged use and higher doses of ATB, the risk of cancer increases. (Petrelli et al. 2019).

Zhang et al. (2008) conducted their populationbased study about the association between lung cancer and ATB use. For their final analysis, they used data from 4336 persons with lung cancer and established an index date as a date exactly one year before a diagnosis of lung cancer was made. The most often prescribed ATB groups were penicillins, macrolides, sulfonamides-trimethoprim, cephalosporins, tetracyclines, and quinolones. They found that the increased likelihood of developing lung cancer among individuals who use ATB might be attributed to shared factors such as smoking, respiratory infections, or compromised immune functions. Additionally, there could be an elevated risk of infections in individuals who already have subclinical cancer. At present, the available epidemiological evidence cannot establish a definitive conclusion regarding the potential carcinogenic impact of ATB on lung cancer (Zhang et al. 2008).

As mentioned, the microbiome encompasses microorganisms’ collective genetic material that constitutes a community, while the term “microbiota” describes an actual group of microorganisms. Inside the human body, an astonishing number of microbes, comparable to human cells, reside and engage in constant inter-actions with the host. These interactions occur at various sites throughout development, e.g., the skin and mucosal surfaces such as the gastrointestinal tract (Gopalakrishnan et al. 2018).

Colonization resistance, a defense mechanism provided by the natural microbiota, prevents the overgrowth of opportunistic microbes and the colonization of possibly dangerous microorganisms. The delicate equilibrium between the host and the natural microbiota is disturbed by applying antimicrobial drugs, though. The characteristics of the antimicrobial drugs, how they are absorbed, their route of excretion, and any potential enzymatic inactivation or binding to fecal matter are some variables that can cause disruptions in the microbiota. The most prevalent clinical effects of intestinal microflora abnormalities are diarrhea and fungus infections, which usually disappear following ATB therapy. A healthy microbiome is essential for preventing the emergence of bacteria strains that are resistant to treatment. We can reduce the danger of resistant strains developing and spreading among patients and the dispersal of resistance factors among other microorganisms by employing antimicrobial drugs that do not interfere with colonization resistance (Sullivan et al. 2001).

Even short-term ATB use can result in long-term alterations in the patients’ commensal microbiota, which can be seen two years after treatment. It can even cause the choice and maintenance of resistant strains and resistance genes, which declares the more significant meaning of studying the importance of the intestinal microbiota as a repository for transmitting resistance (Löfmark et al. 2006).

As Ramírez-Labrada et al. (2020) suggest in their article, although numerous studies have been devoted to the gut microbiota, lung microbiota, which displays many differences, needs to be studied as well. They confess that even if the microbiota consists of bacteria, archaea, protists, fungi, and viruses, most trials have been aimed at bacteria and focused on them. They attempt to highlight that lung microbiota interact with the lungs’ host defense mechanism, enabling identifying communities of microbes in the lower respiratory system. This, unlike the gut microbiota, can help understand the lung carcinogenesis mechanisms and anticipate the impact of various therapies. Sometimes, the same microorganism can be beneficial for human health, but sometimes, after a change of circumstances (e.g., immunodeficiency), it can cause disease (Ramírez-Labrada et al. 2020). According to various studies, healthy people have a different lung microbiota than people suffering from lung cancer (Lee et al. 2016; Liu et al. 2018). This finding might serve as a screening method in the future. Smoke from tobacco products, pollutants, and lifestyle affect lung microbiota composition. In this aspect, uncovering the role of lung microbiota in the host’s immune system can help to develop innovative immunotherapy strategies and find fresh therapeutic targets for the medical management of lung cancer (Ramírez-Labrada et al. 2020).

Dickson and Huffnagle (2015) published an article concerning lung microbiome in which they claim that human lungs are not sterile, and more than 30 studies confirmed this idea. The article examines the lung microbiome’s purpose in respiratory health and illnesses. Similarly, Ramírez-Labrada et al. (2020) define the lung microbiome as a collection of microorganisms that reside in the lungs, including bacteria, viruses, fungi, and other microbes. The article suggests that understanding the lung microbiome might lead to new strategies for diagnosing and treating respiratory diseases. The authors point out that traditional bacteriological methods, which rely on culturing microorganisms, have limitations in identifying the diverse microbiota in the lungs. Thus, new methods, such as next-generation sequencing, have been developed to more comprehensively analyze the microbial communities in lungs. The authors also highlight the role of the lung microbiome in respiratory health. They suggest that the microbiota in the lungs play an important function in keeping immunological homeostasis in balance and preventing pathogen invasion. Moreover, disruptions in the lung microbiome might assist in the growth and progression of respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD) and chronic lung diseases, including lung cancer. Respiratory pathogen colonization is crucial for controlling immunological tolerance in the lung microenvironment. However, this delicate balance could be disrupted by ATB use or chronic infection, and this could raise the possibility of developing lung cancer (Dickson and Huffnagle 2015).

However, other factors besides ATB can also affect the structure of the gut microbiota. Rizzo et al. (2022) made a systematic review and meta-analysis about using proton pump inhibitors (PPI) and histamine- 2-receptor antagonists (HH2RA) and their influence on immune checkpoint inhibitors (ICI) treatment effects. They claimed that one of the mechanisms of this effect could be a change in a gut microbiome. The authors analyzed six studies concerning the concomitant use of PPI and/or HH2RA and ICI, which revealed that there was a decreased progression-free survival (PFS) and overall survival (OS) in all trials in NSCLC patients receiving ICI and using concomitantly PPI or HH2RA (Rizzo et al. 2022).

According to Gonugunta et al. (2023), compared to patients with melanoma, those with lung cancer have more significant comorbidities, and as such, they are more often indicated for ATB treatment than patients with melanoma. The most often prescribed ATB groups are quinolones, beta-lactams, macrolides, tetracyclines, sulfonamides, lincosamides, nitroimidazoles, a group of others, and peptides. The most often prescribed ATB groups are quinolones, beta-lactams, macrolides, tetracyclines, sulfonamides, lincosamides, nitroimidazoles, a group of others and peptides. Topical, ophthalmic, and other locally administered drugs are not mentioned because it is expected they have minor systemic effects, mainly those on the gut microbiome (Gonugunta et al. 2023). Weinberger et al. (2019) mention the most common bacteria causing pneumonias are Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus aureus, a variety of Gram-negative organisms as Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. (Weinberger et al. 2019).

While Löffling et al. (2021) agree that ATB can also act as a contributory factor due to their impact on immune system function or host-microbiota constitution, they refuse to perceive ATB as a modifying risk factor. Their population-based study examined patterns of pre-diagnostic ATB use as a potential early sign of lung cancer. It demonstrated a potential connection between a lung cancer diagnosis and a history of prior use of ATB, utilizing typically gathered data. There were 27,017 patients with lung cancer in their final cohort for the research and 129,355 controls. It revealed that the percentage of lung cancer patients with no less than one prescription began to increase approximately three to four months before the diagnosis, independent of a history of COPD, but it stayed stable for those without lung cancer. They add that when comparing people with and without a history of COPD, those with COPD filled their ATB prescriptions more frequently in both cases and controls. Löffling et al. (2021) found out that between two and three times as many participants with lung cancer as controls had recently filled four or more prescription drugs in the three years before diagnosis. Moreover, they argue that pulmonary infections in the area of lung tumors are not uncommon, and the infection can be the first sign of malignancy, therefore their finding about ATB use before diagnosing lung cancer was not surprising (Löfling et al. 2021).

Kilkkinen et al. (2008) in their study state that ATB can affect inflammation and immunological responses, as well as the composition and operation of the gut microbiota. This, in turn, can affect the growth of different cancer types. They provided a nationwide cohort study between 1995 and 2004 which included 3,112,624 individuals and collected data about ATB use from 1995 until 1997. Then during the seven-year follow-up, there were 1,340,070 cancer cases identified. Due to the results, the authors associate using ATB with a higher risk of lung cancer; while they found an association in both groups, men and women. They conclude that their substantial cohort study showed that ATB use did predict the increased risk of cancer and claim that the study was mainly limited by the fact that little is known about the risk factors of cancer; still, it is difficult to state whether the lack of information considerably discomposes their finding’s as only limited data is available on factors that affect ATB use. For instance, smoking is a possible major confounder because it is linked to both the risk of developing certain malignancies and the usage of ATB. The authors acknowledge that smoking can explain the link between lung cancer and ATB use, but they also point out that additional factors may have had an impact on their findings. This all leads them to the conclusion that due to the relatively weak association between ATB use and cancer, it can be suggested that ATB use may serve as a predictor rather than a cause of cancer (Kilkkinen et al. 2008).

Various studies have demonstrated that ATB is able to change the constitution of the intestinal microbiota over time. ATB dysbiosis influences taxonomic richness and is linked to a decline in microbial diversity. Jernberg et al. (2007) studied effects of 7 days treatment of clindamycin on the gut microbiota.

According to Gopalakrishnan et al. (2018), the relationship between the immune system and the intestinal microbiota plays a crucial role. It not only helps the immune system recognize and respond to opportunistic bacteria, which prevents infections but also helps the body tolerate commensal bacteria and dietary antigens. This microbiota also influences innate and adaptive immunity. It is conceivable that the microbiota of the gut exert a substantial influence on the response and side effects of various cancer treatments. While initial investigations predominantly relied on murine models to study these interactions, an expanding body of evidence from studies of humans has supported the notion that the intestinal microbiota is a key player in determining the effectiveness as well as potential toxicity of these therapeutic approaches (Gopalakrishnan et al. 2018).

In their study, Gopalakrishnan et al. (2018) discovered a substantially greater diversity of gut microbiota in patients who reacted to anti-programmed cell death protein 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) therapy, as well as a comparatively greater quantity of Clostridiales, Faecalibacterium and Ruminococcaceae. The role of Akkermansia muciniphila has been intensively studied in association with its favorable effect on cancer patients’ response to ICI therapy (Routy et al. 2018a).

Derosa et al. (2018) conducted a trial with the hypothesis that anti-PD-1 monoclonal antibodies and ATB-induced gut microbiota alterations may contribute to ICI resistance (mAb) and anti-PD-L1 mAb. The 2017 trial, which assessed the effects of ATB to cause resistance to anti-PD-(L)1 therapy, included patients with renal-cell cancer (RCC) and NSCLC treated with ICI and ATB within the beginning of the ICI therapy. They studied 239 patients suffering from NSCLC and 121 patients with RCC, who were treated by anti- PD-(L)1 mAb alone or together with anti-T lymphocyte-associated antigen 4 (anti-CTLA-4) mAb. They reviewed patients’ records to assess their oral or intravenous ATB use within the 30 and 60 days of the anti- PDL-(L)1 therapy and they assessed the PFS and OS between ATB users and nonusers. 20% of patients with NSCLC received ATB within 30 days of ICI treatment. The most administered ATB were beta-lactams ± inhibitors in both groups of patients, in NSCLC group other frequently used ATB were quinolones and sulfonamides. While recent ATB use did not increase the rate of primary disease progression (PD) in NSCLC patients (in contrast to RCC patients), it was associated with significantly shorter PFS and OS compared to those who did not receive ATB, which applied to the RCC group as well. The results for the ATB use within 60 days of the ICI therapy are similar; in the RCC cohort, the ATB group had an increased risk for PD, worse PFS, and OS; in the NSCLC cohort ATB group did not show any significant association with worse objective response and PFS but remained significantly associated with poorer OS compared to no ATB group. Therefore, ATB use appeared to be an independent predictor of poor prognosis about immunotherapy, regardless of traditional prognostic markers (Derosa et al. 2018). But the authors come to the conclusion that more study is required to create innovative diagnostic tools using the gut microbiota in cancer patients, estimate response/resistance to ICI, and identify the crucial microbiota characteristics for each tumor location. Although it has been proved that the most immunogenic bacteria necessary to activate the immune system unlocked by PD-(L)1 inhibition are likely eliminated by ATB-related dysbiosis, there is still disagreement about whether ATB therapy is causally related to ICI resistance or simply reflects a general prognostic correlation (Derosa et al. 2018).

Tomita et al. (2020) reported on the beneficial effect of Clostridium butyricum MIYA-BM, therapy on ATB-related gut dysbiosis. ATB can cause gut dysbiosis, leading to a compromised response to ICI in cancer treatment (Tomita et al. 2020). These findings highlighted the crucial role of healthy gut microbiota in improving the efficacy of ICI and provided a promising target for cancer treatment (Derosa et al. 2018; Tomita et al. 2020).

C. butyricum is a type of spore-forming bacteria known for its ability to produce high levels of butyric acid and is typically found in soil. One particular strain of C. butyricum MIYAIRI 588 known as MIYA-BM, is commonly used as a probiotic therapy in Japan and China to alleviate symptoms related to gut dysbiosis, such as constipation and diarrhea (Seki et al. 2003). This strain has been found to increase the levels of beneficial bacteria, including lactobacilli and bifidobacteria, which are known to have anti-tumor and immune-boosting properties. Bifidobacterium, in particular, has been shown to enhance the effectiveness of ICI therapy in cancer treatment. However, the clinical significance of administering specific bacterial species to alter the gut microbiota in patients receiving ICI has not been fully understood yet. While further research is needed to fully understand the mechanisms behind the gut microbiota’s impact on cancer treatment, the use of C. butyricum MIYA-BM as a probiotic therapy may hold promise as a way to increase the effectiveness of cancer treatment (Sivan et al. 2015; Matson et al. 2018).

Tomita et al. (2020) found out that in patients with NSCLC treated with ICI, probiotic C. butyricum MIYA-BM therapy (CBT) significantly improved PFS and OS when compared to patients without probiotic CBT. Additionally, they state that these results promise that the probiotic manipulation of commensal microbiota can improve the reduced efficacy of ICI due to ATB treatment. They retrospectively evaluated 118 patients with advanced NSCLC treated with ICI (nivolumab, pembrolizumab, atezolizumab). They compared PFS and OS in patients with CBT treatment 6 months before or concurrently with ICI with those without CBT treatment. They confirm that using CBT 60 days before or concurrently with ICI is associated with longer PFS and OS (Tomita et al. 2020).

In contrast to other findings in the field (Derosa et al. 2018; Routy et al. 2018a), they also found that using ATB around the initiation of ICI therapy is not significantly associated with worse clinical outcomes of ICI therapy. In patients with no ATB therapy, probiotic CBT did not improve PFS but did improve OS. Tomita et al. (2020) believes that C. butyricum MIYA-BM can improve the efficacy of ICI through increasing commensal Bifidobacterium. But he also declares that they did not identify the mechanism of how C. butyricum MIYA-BM positively affected the clinical outcomes. They conclude that profiling the gut microbiome during ICI therapy should be done to shed light on the mechanism of effects of probiotic CBT (Tomita et al. 2020).

Lurienne et al. (2020) evaluated the relationship between the effectiveness of NSCLC immunotherapy and ATB usage in a systematic review and meta-analysis. They found significant negative effects of ATB use around ICI treatment on the PFS and OS. They concentrated on research examining the effect of ATB use on the survival of NSCLC patients receiving ICI and they finally analyzed 23 studies published between 2017 and 2019. They analyzed PFS and OS in patients with NSCLC in relation to ATB use in comparison to abstinence before, during, or after the initiation of ICI treatment. They found that pembrolizumab, atezolizumab, avelumab, durvalumab, tremelimumab, and ipilimumab (used along different lines), and their combinations or combinations with chemotherapy were used and claimed that 17 studies were analyzed for PFS. ATB use has a considerable negative impact on PFS when it occurs around ICI treatment. Moreover, they also analyzed 21 studies for OS, which demonstrate that ATB use around the start of ICI treatment has a considerable negative impact on patients’ OS as well. Lurienne et al. (2020) sum up that the negative effect of ATB use on the efficacy of ICI is most significant in the time window around ICI treatment initiation, later the detrimental effect of ATB vanishes. This meta-analysis was the first study on the impact of ATB use on the survival of NSCLC patients treated with ICI therapy. Due to the lack of relevant data, they can neither confirm with certainty that there is a causal link between ATB use and ICI efficacy nor can they describe the mechanism of this association and they speculate that microbiota could be the missing link (Lurienne et al. 2020).

Determining whether the use of ATB is an indicator of overall poor physical health, including compromised immune function, or whether it directly affects the gut microbiome is a complex task. It is challenging to establish a clear relationship between ATB use and its effects on the gut microbiome, as it may also serve as a surrogate marker for unfavorable outcomes. In this section, we discuss the existing data regarding the influence of ATB on the response to ICI in individuals with cancer and the clinical implications of these findings (Elkrief et al. 2019).

A big retrospective study made by Gonugunta et al. (2023) in the USA studied 310,321 patients, of whom 280,068 patients (90%) had lung cancer and 30,253 (10%) had melanoma. They observed that patients with lung cancer had more comorbidities than patients with melanoma. During the time frame of 6 months before or after diagnosis of cancer, there were 117,748 patients with lung cancer (42%) and 7297 (24%) patients with melanoma prescribed ATB (Gonugunta et al. 2023). Generally, the most indications for ATB treatment in NCLSL patients are pneumonia, urinary tract infection, and prophylaxis before surgery (Galli et al. 2018; Geum et al. 2021; Nyein et al. 2022), also supported by Ruiz-Patiño et al. (2020) study.

The balance of the gut microbiota can be disrupted by ATB use. It can lead to the diminishing of the essential microbial species or even to the eradication of commensal organisms. This disturbance, referred to as intestinal dysbiosis, disrupts the natural balance within the gut, which can have local and systemic metabolism impacts and therefore affect the immune system (Routy et al. 2018b). Maintaining a diverse and balanced microbiota is crucial for establishing a harmonious and symbiotic relationship, while any disturbance in these factors may result in an undesired immune response. The composition of the microbiome can greatly impact the outcomes of immune ICI therapy, as the effectiveness of ICI relies on activating immune effectors to trigger anticancer responses (Ruiz-Patiño et al. 2020). When ATB causes dysbiosis, the composition of the gut microbiota may change for a few weeks which shows the study of gut microbiota composition after use of meropenem, gentamicin and vancomycin (Palleja et al. 2018). Furthermore, dysbiosis can persist as long as ATB are given during ICI treatment (Geum et al. 2021).

Several trials have assessed the effect of ATB on the efficacy of lung cancer treatment with ICI. A retrospective cohort study conducted in Latin America between 2013 and 2018. The study included 140 patients with NSCLC and Ruiz-Patiño et al. (2020) described a decreased OS in patients using ATB (mostly fluoroquinolones and beta-lactams) around the beginning of ICI treatment, but there was no significant decrease in PFS (Ruiz-Patiño et al. 2020). Conversely, Majeed et al. (2021) published the results of their trial about NSCLC patients treated by ICI and using ATB at the same time. They state there was no negative impact on PFS, and OS in NSCLC patients treated by ATB, but they found a 2,8-fold increased risk of development of immune-related adverse events (IrAEs) of ICI treatment. The most administered ATB were fluoroquinolones (36,2%) and beta-lactams (14,7%) (Majeed et al. 2021). According to a trial from Galli et al. (2018) based on 157 cases of lung cancer treated with ICI and using ATB as levofloxacin, amoxi-clavulanate or ceftriaxone within this therapy, the detrimental effects of ATB depend on the length of the therapy, rather than the simple use of ATB

The results of a Korean trial from Geum et al. (2021) are similar to the previous ones. The OS was significantly lower in patients using ATB compared to those without ATB therapy. The PFS, however, was not substantially different between the two groups. They also use the term “antibiotics days of therapy” (DOT), and they show DOT of piperacillin/tazobac- tam (PTZ) treatment was negatively linked with OS. Also, the DOT of third-generation cephalosporins was adversely related to OS, as was fluoroquinolone use (Geum et al. 2021). The administration of PTZ has a notable impact on the gut microbiota, as evidenced by several studies that confirmed a significant decrease in anaerobic commensal bacteria within four to eight days after its use. Specifically, PTZ has been found to diminish the population of Bifidobacterium, Eubacterium, and Lactobacillus strains, which are recognized as key components of the human gut microbiota. Interestingly, the study revealed a difference in the intestinal microbiome between responders and non-responders to ICI, underscoring the crucial connection between the composition of commensal microbes and the clinical response to ICI (Routy et al. 2018a; Pierrard and Seront 2019; Thomas 2020).

Also, Schett et al. (2020) conducted a retrospective observational study about using ATB before and within ICI treatment in 218 NSCLC patients. They intended to test the idea that ATB alters patients’ gut microbiotas, which in turn controls the adaptive immune system and lowers the effectiveness of ICI therapy. They discovered that the usage of ATB within two months prior to the administration of ICI therapy was substantially linked with a higher incidence of PD and a lower incidence of complete or partial responses (CR, PR) according to RECIST criteria 1.1. There was decreased PFS in patients who had been treated with ATB within two months before ICI treatment compared with those who had not. But, when the ATB were taken during or after ICI treatment, there was no significant negative impact on survival. Thus, Schett et al. (2020) state that the two-month period before starting ICI treatment is the most critical period for the negative impact on the gut microbiota caused by ATB use. Similarly, Alkan et al. (2022) claims based on the trial of 90 patients with NSCLC, that ICI treatment effectiveness (OS, PFS) is most notably affected by ATB use within the first 12 weeks of ICI treatment.

Based on Ochis’ et al. (2021) trial, PD-L1 expression also plays a role in how ATB can influence ICI effectiveness. The impact of ATB on ICI efficacy depends on PD-L1 expression. In this trial, ATB had no impact on the efficacy of ICI in patients with PD-L1 < 50% NSCLC but was associated with lower efficacy of ICI in PD-L1 ≥ 50% NSCLC (Ochi et al. 2021). Additional studies conducted on mice have further supported the idea that gut microbiota affects the efficiency of ICI (Matson et al. 2018; Routy et al. 2018b).

There might be other potential agents influencing the gut microbiota besides ATB. One of the largest studies (1,512 patients) by Chalabi et al. (2020) examined the influence of many ATB classes (penicillines, cephalosporines and fluoroquinolones) and/or PPI on the efficacy of ICI (atezolizumab) and chemotherapy (docetaxel). Their data showed that in individuals receiving atezolizumab, the use of PPI was linked to an increased likelihood of PD or death. Furthermore, the use of ATB was related to a higher risk of mortality. In the group of patients treated with docetaxel, the authors noticed that the use of ATB or PPI was connected to a decrease in OS, although the extent of this disparity was minimal and did not reach statistical significance (Chalabi et al. 2020).

More studies have concerned the relationship between the efficacy of treatment of NSCLC and comedication Fang et al. (2019) studied the association between using gefitinib in first-line therapy of NSCLC and PPI. The studied population involved 1,278 patients who received first-line gefitinib and dealt with the impact of concurrent PPI. They conclude that exposure to PPI during first-line gefitinib treatment significantly negatively impacted the OS of patients with EGFR- mutant NSCLC (Fang et al. 2019).

Also, prior use of chemotherapy influences the effectiveness of ICI. Nyein et al. (2022) provided a retrospective trial, and they brought an interesting result: a poor ICI response, stable disease (SD) or PD, was substantially related to past chemotherapy exposure. However, they also discovered that prior ATB usage was not substantially linked to worse ICI results, but there was a trend suggesting that in ATB users, there might be an increased risk of poorer outcomes. Lastly, they confessed that the use of PPI did not affect treatment response examined at six and twelve months after therapy began (Nyein et al. 2022).

Several studies show that ATB use can also have a beneficial effect on cancer treatment. Bedaquiline is a relatively new agent for the treatment of multidrugresistant tuberculosis (MDR-TB) (Ritter et al. 2020). Wu et al. (2018) conducted a trial where they verified the effect of bedaquiline on the development, survival, and angiogenesis of lung cancer cells. They confirmed that bedaquiline inhibited lung cancer and angiogenesis in vitro and in vivo and proved effective against lung cancer despite genetic and cellular heterogeneity (Wu et al. 2018). Also, Lamb et al. (2015) came up with the idea to repurpose some FDA (Food and Drug Administration) approved ATB for cancer treatment. They described the ability of some drugs to eliminate cancer stem cells in various tumor types. They claim five classes of ATB can affect cancer stem cell metabolism by targeting mitochondrial metabolism; the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug pyrvinium pamoate, and chloramphenicol have this ability (Lamb et al. 2015).

The study by Bullman et al. (2017) demonstrated the efficacy of metronidazole in treating colon cancer xenografts in mice. The findings revealed that metronidazole treatment reduced the abundance of Fusobacterium, suppressed cancer cell proliferation, and decreased tumor growth overall (Bullman et al. 2017).

The positive effect of ATB in cancer treatment was confirmed by Le Noci et al. (2018) who studied the effect of inhaled aerosolized ATB vancomycin and neomycin or probiotics on the metastasis mass of melanoma in the lungs and suggested that lung microbiota function to prevent the colonization of respiratory infections and also play an essential part in the immunological tolerance of the lung microenvironment; this hypothesis was backed up by solid evidence. They concluded that aerosolized Lactobacillus rhamnosus significantly enhances immunity against B16 lung metastases and added that probiotics or ATB increase the effectiveness of chemotherapy against advanced B16 metastases. This way, they could define lung microbiota’s role in metastasis and indicate the therapy capable of preventing metastases and strengthening reactions to chemotherapy, which might be targeted through aerosolization (Le Noci et al. 2018).

Similarly, ATB may also decrease the risk of certain cancers, such as gastric cancer, according to You et al. (2006), who studied the effects of treatment for Helicobacter pylori. They confirmed that the risk of developing precancerous gastric lesions was reduced by treating H. pylori with amoxicillin and omeprazole. This might contribute to reducing the incidence of gastric cancer (You et al. 2006).

Antibiotics have been found to have a complex role in the development and treatment of NSCLC. There are several perspectives that we introduced and that we need to observe when evaluating the potential links between ATB use and NSCLC. These include the direct carcinogenic effects of ATB, the impact of ATB use on NSCLC occurrence, the detrimental effects of ATB on the immune system, ATB and its role during ICI cancer treatment, and last but not least, ATB and its potentially positive effects in lung cancer treatment.

First, numerous epidemiological investigations have raised concern regarding a potential link between First, numerous epidemiological investigations have raised concern regarding a potential link between ATB use and increased susceptibility to cancer. The higher risk of cancer is described to rise with the dose and duration of ATB treatment (Petrelli et al. 2019). In contrast, Zhang et al. (2008) argue that the leading cause is smoking, respiratory infections, or compromised immune functions among ATB users, making ATB use rather less important. Additionally, there could be an elevated risk of infections in individuals who already have subclinical lung cancer, where it was found that most of the ATB therapy was indicated in a short time before the cancer diagnosis (Zhang et al. 2008).

Also, some studies dealt with the impact of ATB on the lung microbiota (Dickson and Huffnagle 2015; Lee et al. 2016; Liu et al. 2018; Ramírez-Labrada et al. 2020), but more trials studied ATB (and PPI) concerning the gut microbiota changes (Chalabi et al. 2020; Rizzo et al. 2022) and their further consequences. Patients’ commensal gut flora can undergo long-lasting changes after even brief use of ATB, which can be seen two years after medication (Löfmark et al. 2006). According to several studies, the lung microbiota in healthy persons is different than in persons with lung cancer, which might serve as a screening method in the future (Lee et al. 2016; Liu et al. 2018), and it can be a key factor in lung carcinogenesis and lung cancer treatment efficacy also (Ramírez-Labrada et al. 2020). Understanding how the host immune status in the lungs interacts with the lung bacteria could aid in the comprehension of the lung carcinogenesis process, predict the impact of various treatments, and develop new immunotherapy strategies for the treatment of lung cancer (Ramírez-Labrada et al. 2020). At this point, Dickson and Huffnagle (2015) highlighted the role of next-generation sequencing to analyze the microbial communities in lungs more comprehensively.

Moreover, we saw that ATB may function as an indicator of infection in the period shortly before the diagnosis of lung cancer. Therefore, they may act as a predictor of the onset of lung cancer. Lung cancer patients have more comorbid conditions than patients with other cancers, such as melanoma, and as such, they are more often indicated for ATB treatment (Gonugunta et al. 2023), therefore some authors suggested that ATB use may serve as a predictor rather than a cause of cancer (Kilkkinen et al. 2008).

Another finding we made was that prior use of ATB impacts the treatment of NSCLC with ICI. According to most of the studies dealing with this issue we have reviewed, the effects of ATB were mostly negative, such as decreased PFS and OS in patients treated with ICI (Derosa et al. 2018; Luriene et al. 2020). The PD-L1 expression in the tumor tissue (Ochi et al. 2021) and the timing of ATB treatment in ICI therapy also play their role (Schett et al. 2020; Alkan et al. 2022). Moreover, some trials also explored the positive impact of ATB on lung cancer treatment (Lamb et al. 2015; Wu et al. 2018).

In conclusion, ATB are a group of drugs that are commonly used in the world. In different relations, we found many trials concerning ATB, lung and gut microbiota, lung cancer, and ICI therapy. As there might be various perspectives of their potential meaning, more research needs to be done to uncover the most significant and relevant aspect; therefore, it is important to note that the research on the relationship between antibiotics, the microbiome, and lung cancer is evolving, and more studies with different designs are needed to establish definitive conclusions.