Emerging trends and potential clinical applications of microbial biomarkers in thoracic surgery

Introduction

In the era of precision medicine, recent technological advancements in next-generation sequencing and bioinformatics have empowered medical practitioners to tailor treatments based on individual patient characteristics (1,2). These innovations have not only revolutionized traditional medical practices but have also opened intriguing avenues for exploration, such as how microbes can be used in precision lung cancer surgery.

Despite tremendous advancements in cancer research, lung cancer continues to rank among the most prevalent causes of cancer-related death globally (3,4). This highlights the pressing need for alternative diagnostic, treatment, and follow-up approaches to enhance patient outcomes. This article seeks to highlight how the potential integration of microbial biomarkers into lung cancer surgery can improve patient outcomes.

Here, the predictive potential of microbial biomarkers in assessing tumor aggressiveness and preoperative treatment response is explored. Furthermore, their role in identifying intraoperative and postoperative complications is discussed. Challenges and future directions in the field are also discussed, providing insight into the opportunities and challenges associated with the clinical adoption of microbial biomarkers in lung cancer surgery.

The objective of this editorial commentary is to summarize recent progress and trends in the use of microbial biomarkers, with a focus on their potential clinical applications in Thoracic surgery. The review does not aim to address specific questions such as which microbial biomarkers should be used or how they should be tested, as there is no clinical consensus or sufficient evidence for such detailed conclusions at this stage. The review has the potential to inform discussions relevant to the advancement of precision thoracic surgery, including future research endeavors.

How microbial biomarkers can be used in precision lung cancer surgery

As defined by the National Cancer Institute, biomarkers are biological molecules found in tissues, blood, or other bodily fluids that provide valuable information about the physiological state of an individual. Among the diverse array of biomarkers employed in thoracic surgery, microbial biomarkers are emerging as a promising frontier in precision medicine, including in preoperative assessments and postoperative follow ups (5).

Traditionally, microbes were primarily associated with infectious diseases. However, recent research is unveiling their potential utility in precision lung cancer surgery (6-13). The enhanced analysis and understanding of microbial signatures can empower surgeons to make informed decisions regarding patient care and personalised surgical interventions. Advancing research on microbial biomarkers and their eventual inclusion throughout preoperative, intraoperative, and postoperative surgical phases could improve patient outcomes (14).

Preoperative assessments

In contrast to currently used assessment techniques, which heavily rely on biopsies, microbial biomarkers offer deeper insights into the intricate interplay between tumor, immune, and stromal cells in the surrounding tumor microenvironment (12). By providing valuable insights into the tumor microenvironment and its influence on tumor behavior, microbial biomarkers hold the potential to predict tumor aggressiveness earlier than traditional biopsies. They achieve this by unveiling unique microbial diversity associated with specific tumor types or stages (8,12). A handful of studies have demonstrated the potential of different microbial signatures to predict early-stage lung cancer (8). For example, research by Yan and colleagues identified significant alterations in salivary levels of Capnocytophaga, Selenomonas, Veillonella, and Neisseria in lung cancer patients, including those with squamous cell carcinoma (SCC) and adenocarcinoma (AC), compared to control subjects, suggesting that microbial biomarkers may be useful for both disease detection and classification (8,15).

In addition to cancer staging, microbial biomarkers hold the potential to provide early indications of treatment response, including responses to chemotherapy and radiotherapy, before imaging or clinical changes become apparent (8). For example, Liu and colleagues demonstrated how biomarkers, such as specific bacteria and their metabolites, play roles in immune modulation, influencing tumor development and response to therapies. Unique microbial signatures associated with enhanced expression of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α have been observed following radiotherapy (8). This suggests that biomarkers could serve as predictive targets, offering insights into treatment outcomes (16).

Although advances are being made in understanding lung cancer-associated microbial biomarkers, ethical and logistical challenges in obtaining lung tissue for research remain significant. As a result, researchers commonly use nasal secretions, saliva, sputum, and bronchoalveolar lavage (BAL) fluid as accepted approaches for the indirect study of the lung microbiome (17). The ability to detect relevant microbial biomarkers from samples such as sputum can improve the feasibility of less invasive pre-surgical evaluations (8,15). This capability for real-time monitoring through less invasive sampling can facilitate the early detection of not only therapy resistance, but metastasis as well.

Microbial biomarkers can also serve as valuable indicators of chronic inflammation or immunosuppression within the tumor microenvironment, offering early insights into immune dysregulation processes that frequently precede observable clinical manifestations (8,11). Microbial biomarkers can offer real-time insights into immune-modulating factors beyond specific aspects of immune function captured by conventional methods such as immune cell profiling or cytokine analysis (8,11,12). They can enable the early identification of underlying inflammatory and immunosuppressive processes within the tumor microenvironment, which can predispose patients to intraoperative and postoperative complications such as bleeding, impaired wound healing, surgical site infections, and sepsis.

Overall, whether in conjunction with other tests or independently, microbial biomarkers have the potential of enhancing the timeliness, accuracy, and comprehensiveness of pre-surgical assessments, surpassing conventional assessment techniques. The incorporation of microbial biomarkers into pre-surgical assessments holds the potential to guide personalized surgical planning, potentially improving patient outcomes. For example, the lymph node dissection extent or resection margins could be informed by tumor-associated microbial profiles. Alternatively, by considering the inflammatory or immune-compromised state of the tumor microenvironment, surgeons can proactively mitigate risks through personalised surgical techniques and perioperative care. This may involve using preventive techniques to reduce tissue trauma and minimize wound size, as well as offering perioperative anti-inflammatory or immunomodulatory therapy.

Intraoperative management

Recent research suggests that the majority of intratumoral bacteria are localized within poorly vascularized and highly immunosuppressive micro-niches situated at tumor margins (6). Exploring these types of key microbial biomarkers may offer an avenue to improve the accurate delineation of tumor margins intraoperatively. Although point-of-care microbial biomarker tests for assessing resection margins intraoperatively are currently unavailable, similar non-microbial biomarker tests are currently being used. For example, in fluorescence-guided glioma surgery with 5-aminolevulinic acid, protoporphyrin IX is detected (18). Ongoing rapid advancements in technology and research may pave the way for similar microbial biomarker tests in the near future.

Current techniques used for intra-operative evaluation of tumor margins, such as frozen section analysis, have limited accuracy and resolution. However, by integrating microbial biomarkers alongside existing techniques or as standalone techniques, comparable or superior accuracy and resolution could be achieved. Moreover, quantifying microbial communities in tumor margins by means such as quantitative polymerase chain reaction, could provide an objective and quantitative method for assessing resection margins, reducing the subjectivity of solely relying on visual interpretation of histopathological slides.

Postoperative assessment

Monitoring for residual disease or disease recurrence via serial imaging, with its associated costs and cumulative radiation exposure, presents challenges. However, microbial biomarkers offer a promising avenue for overcoming these obstacles (10,13).

Microbial biomarkers can enable early intervention by uncovering cellular changes that may be missed by conventional histopathology techniques (19). Additionally, they offer the potential for real-time, non-invasive, and cost effective monitoring, enabling timely intervention, even before definitive imaging confirmation.

By leveraging microbial biomarkers, surgeons could tailor interventions based on real-time monitoring of residual disease after surgery, consequently optimizing patient outcomes. For instance, in patients undergoing adjuvant therapy, timely detection of minimal residual disease can inform treatment modification before clinical or imaging progression becomes apparent.

Challenges, future research directions, and ethical considerations

Challenges associated with the adoption of biomarkers

While there is a growing body of promising evidence suggesting the utility of microbial biomarkers in lung cancer surgery (6-8,10-13). numerous challenges hinder their adoption in clinical practice.

A critical barrier lies in the validation and standardization of microbial biomarker assays, sequencing protocols, and sample processing methods. These factors introduce variability, potentially yielding misleading diagnostic outcomes (7,9).

Characterizing the low-biomass of lung microbiome using next-generation sequencing technologies remains challenging, despite advancements in the field (13,20,21). Furthermore, the relatively lower abundance of non-bacterial microorganisms and the lack of well-characterized reference genomes for fungi and viruses limit the exploration of microbial agents beyond bacteria (8,9).

The translational potential of many studies conducted in laboratory mice is constrained by inherent differences in microbiome structure between humans and mice (8). Additionally, the identification of potential biomarkers in most studies has been limited to the genus level or higher, hindering the development of precise diagnostic tools (9).

Potential future directions for research and ethical considerations

To advance the adoption of microbial biomarkers in lung cancer surgery, several potential future directions for research and technological advancements can be pursued in order to address current challenges.

Efforts to standardize experimental protocols and optimize sample collection, processing, and storage methods are crucial. This will ensure the reproducibility of results and minimize variability, enhancing the reliability of microbial biomarker assays and sequencing protocols (7,9).

Advancements in metagenomic sequencing technologies, particularly deep metagenomic sequencing and third-generation sequencing technologies, holds tremendous potential for advancing our understanding of the lung microbiome dynamics at a species level (9).

Exploring the role of non-bacterial microorganisms, such as fungi and viruses, in lung cancer pathogenesis could uncover possible diagnostic biomarkers that are not currently researched. Additionally, the development of innovative preclinical models that accurately replicate human lung microbiome dynamics is essential for effectively translating research findings into clinical practice (8,9,22).

Leveraging technological advancements, including artificial intelligence and machine learning, can revolutionize microbial biomarker research. These technologies can facilitate the seamless integration of genomic data to transcriptomic and metabolomic data, providing a comprehensive understanding of the tumor microenvironment and allowing potentially specific and sensitive microbial biomarkers to be efficiently identified.

Collaborative efforts between interdisciplinary teams, including clinicians, microbiologists, bioinformaticians, and ethicists, are pivotal in driving future research. More real-world studies or clinical trials investigating microbial changes and the efficacy of identified biomarkers across various stages of lung cancer progression are warranted at this time (7). These studies should consider stratifying participants based on intrinsic and extrinsic factors, including geography, diet, medication, cancer history, smoking habits, as well as radiological and histological characteristics of nodules. As microbial biomarker research potentially advances towards clinical adoption, ethical considerations regarding patient privacy, consent, and data management will become vital. The potential for sensitive health information leaks, such as disease prognosis, highlights the need for stringent measures to safeguard patient confidentiality and ensure informed consent during trials or real-world studies.

Conclusions

In conclusion, the integration of microbial biomarkers into precision cancer surgery presents a ground breaking approach with transformative potential for early diagnosis and treatment of lung cancer. Given their potential to enhance preoperative and postoperative assessments, as well as intraoperative management, microbial biomarkers could pave the way for personalized surgical planning, execution, and post-surgery follow-up, ultimately improving patient outcomes. Despite existing challenges, such as assay standardization and technological limitations, collaborative efforts and advancements in metagenomic sequencing hold promise for overcoming these barriers. As progress is made towards potential clinical adoption, ethical considerations surrounding patient privacy and consent must remain paramount.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-17/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-17/coif). E.E.A. serves as a consultant for IPACmavens. His role with IPACmavens is entirely independent of the work and content presented in this manuscript, and there is no overlap or relationship between the two. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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