When the Gut Speaks, the Lungs Listen : Microbial Signals, Immunity and Cancer Risk

Over the past decade, scientists have uncovered an unexpected truth: the gut and the lungs are in constant communication, connected by immune pathways and microbial signals that influence inflammation, immunity and even cancer risk. This relationship, known as the lung-gut axis, is driven largely by metabolites and microbial products released in the gut that circulate through the bloodstream to shape lung health[1].

The most influential of these messengers include short-chain fatty acids (SCFAs) produced by gut bacteria, amino acid (tryptophan) metabolites, bile acids, polyamines and microbial components such as lipopolysaccharides[1]. Rather than staying confined to the digestive system, these signals influence lung inflammation, immune balance, tissue repair, and susceptibility to respiratory diseases.

As research expands, it is becoming clear that the lung-gut axis affects almost every aspect of pulmonary immunity, from how the lungs respond to infections, to how they react to allergens, and even how cancer may develop.

How Signals Travel From Gut to Lung

A central player in this connection is the diet. When gut bacteria digest fiber, they produce SCFAs, which act as continuous, low-level signals that keep the immune system calibrated and ready to respond. These SCFAs enter the bloodstream and bind to receptors such as FFAR2 and FFAR3 on immune cells and lung tissue, setting a “baseline immune tone” that influences how the lungs respond to stress or injury[2].

Studies comparing germ-free and conventionally raised mice show that mice lacking gut microbes have dramatically lower levels of SCFAs and lipopolysaccharides (LPSs), underscoring the microbiome’s role in generating these immune-modulating signals. Alveolar macrophages, the resident immune cells of the lungs, express receptors for these microbial metabolites and use them to calibrate their baseline activation state. In their absence, the macrophages become more pro-inflammatory, increasing lung inflammation and creating a less stable immune environment in the lungs. Reviews of SCFA biology further show that these metabolites regulate how immune cells behave in the lungs, including directing neutrophil movement, Regulatory T cell (Treg) expansion, T helper 17 (Th17) cell balance, and cytokine production in various lung diseases[2].

Together, these findings make it clear that gut microbes constantly influence the lungs’ readiness to respond to pathogens and injury.

How Dysbiosis Shapes Lung Inflammation

When the gut microbiome becomes imbalanced, this imbalance often extends to the lungs. Research in asthma and obesity shows that loss of microbial diversity and altered SCFA levels impair immune regulation in the airways, worsening airway hyperresponsiveness and promoting type 2 inflammation (a skewed immune response that promotes mucus production, eosinophilic inflammation, and airway remodeling). Because obesity already predisposes individuals to chronic inflammation, microbiome dysbiosis in this setting compounds immune dysfunction, and is linked to more severe asthma symptoms, including breathing difficulties and airway tightening.

Meta-omics studies integrating microbial and metabolic data show that disruptive changes in gut-derived metabolites alter lung immune signaling, intensifying airway inflammation and increasing airway sensitivity.

This connection also extends to metabolic disorders. Lower gut microbial richness is associated with obesity, insulin resistance and lipid abnormalities, all of which contribute to systemic inflammation that harms lung health. Reviews highlight that disruptions in the gut-adipose tissue axis also predict poorer metabolic and lung outcomes[1].

Microbial Metabolites and Lung Cancer

The lung-gut axis plays an increasingly recognised role in cancer biology. Research shows that gut-derived metabolites such as SCFAs, tryptophan derivatives and polyamines influence the immune microenvironment within the lungs, including how T cells, macrophages and natural killer cells behave.

When dysbiosis alters these metabolites, it promotes chronic inflammation, weakens immune surveillance and creates a tissue environment that favors tumor growth. In parallel, certain microbial metabolites can directly influence lung tissue structure, driving fibrotic remodeling that is a common precursor to lung malignancy.

This emerging evidence is significant for immuno-oncology. Improving microbial balance may make it possible to strengthen antigen presentation, enhance T cell responses and improve the effectiveness of immune checkpoint inhibitors in lung cancer[3].

The Overlap of Gut Health, Obesity and Lung Immunity

Obesity is one of the strongest modifiers of the lung-gut axis. It disrupts the microbiome in ways that increase systemic inflammation, alter SCFA production, and exacerbate lung disease, particularly asthma. Conversely, studies in overweight and obese adults show that specific gut microbial profiles are associated with better metabolic health and lower inflammation, which may also support greater resilience in the lungs[4].

Together, these findings highlight how metabolic health, gut microbial composition, and respiratory immunity are tightly interconnected, forming a shared network that shapes disease severity.

Shaping Future Treatments Through the Lung–Gut Axis

Because gut microbes influence lung immunity so deeply, researchers are exploring new therapeutic strategies using this connection.

1. Immune priming with SCFAs
High-fibre diets and SCFA-producing probiotics can increase beneficial metabolites in the lungs, helping immune cells respond more appropriately to infection and inflammation[5].

2. Microbiota-directed therapies
Emerging therapies such as probiotics, prebiotics, synbiotics and fecal microbiota transplantation show promise in lung diseases including asthma, COPD, and respiratory infections[5].

3. Enhancing immunotherapy in cancer
By restoring healthy metabolite profiles, microbiome-based strategies may improve outcomes of immunotherapies such as PD-1 and PD-L1 inhibitors in lung cancer[6].

These therapeutic directions show tremendous potential, offering ways to influence lung immunity by acting through the gut, a concept once considered impossible.

A New Horizon for Immune and Cancer Therapy

The lung-gut axis is emerging as a powerful framework for understanding how microbial signals shape inflammation, immune regulation, and cancer risk in the lungs. By revealing the crosstalk between distant organs, mediated by metabolites and immune pathways, this field is redefining how respiratory disease and cancer are understood, and how they may be treated. As this knowledge advances, it will inform a new generation of therapies designed to intervene earlier, more precisely, and with greater biological insight.

At Helix BioPharma, we are committed to advancing science that translates these insights into action. By harnessing immune and metabolic pathways, we aim to develop more targeted and effective therapies that reflect the true complexity of cancer.

References:

1. Deepika, Alsharari ZD, Ahmad MF, et al. Gut-lung axis, probiotics, and prebiotics: insights on dysbiosis, mechanism, and prevention of lung cancer. Front Nutr. 2025;12:1624803. Published 2025 Jul 30. doi:10.3389/fnut.2025.1624803

2. Liu, Q., Tian, X., Maruyama, D., Arjomandi, M., & Prakash, A. (2021). Lung immune tone via gut-lung axis: Gut-derived LPS and short-chain fatty acids’ immunometabolic regulation of lung IL-1β, FFAR2, and FFAR3 expression. American Journal of Physiology – Lung Cellular and Molecular Physiology, 321 (1), L65–L78. doi:10.1152/AJPLUNG.00421.202

3. Li X, Shang S, Wu M, Song Q, Chen D. Gut microbial metabolites in lung cancer development and immunotherapy: Novel insights into gut-lung axis. Cancer Lett. 2024;598:217096. doi:10.1016/j.canlet.2024.217096

4. Tashiro H, Kuwahara Y, Takahashi K. Gut-lung axis in asthma and obesity: role of the gut microbiome. Front Allergy. 2025 Jun 16;6:1618466. doi: 10.3389/falgy.2025.1618466. PMID: 40589493; PMCID: PMC12206879.

5. Ney LM, Wipplinger M, Grossmann M, Engert N, Wegner VD, Mosig AS. Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections. Open Biol. 2023;13(3):230014. doi:10.1098/rsob.230014

6. Shi M, Wang LF, Hu WT, Liang ZG. The gut microbiome in lung cancer: from pathogenesis to precision therapy. Front Microbiol. 2025 Aug 20;16:1606684. doi: 10.3389/fmicb.2025.1606684. PMID: 40909921; PMCID: PMC12405165.

Jacek Antas

Chief Executive Officer

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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James B. Murphy

Chief Financial Officer

Mr. Murphy is a certified public accountant with over thirty years of experience in finance and operations management. He is currently a consultant with Danforth Advisors LLC (“Danforth”), a leading provider of outsourced strategic and operational specialists across functions in the life sciences industry. While at Danforth, Mr. Murphy has served over fifteen private and publicly held life sciences companies as CFO and CFO Advisor, helping them secure over USD 0.5 billion in financing and successfully execute pivotal asset transactions. Mr. Murphy functions as a consultant to Helix pursuant to a consulting agreement between the Company and Danforth.

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Thomas Mehrling

Medical Adviser

Thomas Mehrling (PhD in Pharmacology and MD) has over 20 years’ experience in multinational Pharma companies developing novel oncology compounds from preclinical research through to registration. Prior to entering the industry, he spent 13 years as an MD at the University Hospital in Frankfurt, working on preclinical and translational projects. He served as Director of European Oncology at Mundipharma International (2003–2013), building the company’s first European oncology business from the ground up out of Cambridge, UK, and completing the clinical development, registration and launch of two major products in Europe, DepoCyte® and Levact® (Ribomustin® and Treanda®). In 2013, he led the establishment of the Mundipharma Group’s start-up, Mundipharma EDO, developing anti-cancer therapeutics for solid tumours out of Basel, Switzerland.

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Kim Gaspar

Director Quality Assurance

Kim is the Director of Quality Assurance at Helix BioPharma Corp. An experienced quality assurance professional with expertise in Canadian, US, and EU regulations, she has been involved in all aspects of Phase I/II biopharmaceutical product development over the years, including regulatory submissions, QC laboratory compliance, tech transfer and third-party oversight of CMC activities, clinical QA, and bioanalytical data analysis. Kim joined Helix in 2000, transitioning into QA in 2003. She holds a B.Sc in Biochemistry and a Ph.D in Veterinary Physiological Sciences, both from the University of Saskatchewan.

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Brenda Lee

Director Clinical Operations

Brenda is the Clinical Operations Director at Helix Biopharma Corp. A clinical research operations professional with 25 years of experience managing clinical trials, ranging from early Phase I to late Phase IIIb/IV studies, she brings experience in clinical study protocol writing and development, trial start-up and vendor management, and a proven track record in planning and managing clinical trials to quality standards, timelines and budget. Brenda joined Helix Biopharma Corp. in 2018, working to advance the clinical program of L-DOS47. She holds B.Sc and M.Sc. degrees from the University of Toronto, specializing in Nutritional Sciences and Human Biology.

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Jerzy Leszczynski

Director

Jerzy Leszczynski is a shareholder of the Company, has spent more than 35 years developing businesses and has served in the capacity of board member of various real estate development companies. Mr. Leszczynski obtained his Master of Science in Chemistry from the Warsaw Institute of Technology.

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Janusz Grabski

Director, Chair of Audit Committee

Janusz (John) Grabski is a lawyer specialized in corporate and real estate law with over twenty years of experience.

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Malgorzata Laube

Director

Malgorzata Laube has over 19 years of experience in nuclear medicine. In her last role with Alberta Health Services, she was the Department Supervisor, Nuclear Medicine at Royal Alexandra Hospital. Ms. Laube obtained a MSc degree in Environmental Engineering from the Warsaw University of Technology and is based in Edmonton, Alberta, Canada.

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Jacek Antas

Chairman of the Board

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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Jonathan Davis

Advisor, ADC Discovery

Jonathan Davis received his Ph.D. from University of California, San Francisco, where he studied protein structure and function using NMR. After a post-doc at Harvard Medical School exploring RNA selection and structure in the labs of Jack Szostak and Gerhard Wagner, he went to work at EMD Serono, where his work involved improving antibody-based therapeutics, inventing a platform technology for generating heterodimeric Fcs as a basis for multifunctional molecules, and developing a novel scaffold based on an artificially-designed protein from David Baker’s lab. In 2008 he took a job at Bristol-Myers Squibb in Waltham/Cambridge MA, working on antibody discovery and platform development in a wide range of therapeutic areas, with a particular focus on multispecific therapeutics. He moved to Madison, WI in 2019 to take on the role of VP of Innovation and Strategy at Invenra, a biotech focused on bispecific antibodies, and where he is currently head of the Scientific Advisory Board. In early 2024 he left the corporate world to found Creative Antibodies, a consulting firm that helps guide companies to successful antibody discovery and development projects, from mAbs to multispecifics, ADCs, and other formats. Outside of science, Jonathan is a conservatory trained cellist, plays numerous other instruments, and founded the UCSF Orchestra (now Symphony Parnassus) in San Francisco, where he was Music Director for six years.

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Davide Guggi

Advisor, CMC

Davide graduated as a pharmacist and received his PhD in Pharmaceutical Technology and Biotechnology from the University of Vienna. He has over 20 years of experience in the pharmaceutical industry, principally in the field of oncology. At the beginning of his career, Davide led oncology business units and commercial departments at Mundipharma and Gilead across Austria and Eastern Europe. Since over 10 years he has been working as a CMC expert, covering operational and regulatory CMC functions on behalf of over 20 different small- and medium-sized biotech companies across the world. He has served as CMC Director and CSO/CTO for several years, developing both small molecules and biologics (mABs, Fab, ADCs and Radio-immuno-conjugates) from early discovery to NDA/BLA in the US, EU and Canada, with a focus on First-in-Human and Phase I/II studies in oncology indications.

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