What disease areas can benefit from breath analysis?

This article covers three major case studies (cancer, liver disease, and microbiome) where breath biomarker analysis has been used, and where breath has considerable potential to transform biomarker analysis.

This discussion includes what disease areas, breath sampling, and analysis can be utilized for and offers some scope to the extent of potential applications of this method.

Cancer

The World Health Organization reports that all cancers were collectively responsible for an estimated 10 million deaths in 2020, making it a leading cause of death.¹

Owlstone has set itself the task of identifying new and improved ways to detect cancer earlier, which, in turn, significantly increases the chances of success in treating the disease.

A wide range of chemicals found in exhaled breath comes from deeper within the body, several of which may signal the presence of cancer long before any symptoms begin to show.

Lung cancer is among the leading causes of cancer-related death globally, due in part to the level of complexity in making an early diagnosis. Developing widespread screening programs for lung cancer, particularly those targeting at-risk populations, presents a significant opportunity to improve early detection and lung cancer survival.

Consequently, Owlstone Medical is conducting one of the most extensive breath lung cancer clinical trials called Evolution. The Evolution study is looking at whether it is possible to administer an EVOC probe to specifically target β-glucuronidase, an enzyme that is generally contained within the cells.

Due to the often leaky tissues of the tumor microenvironment, β-glucuronidase activity may be detected outside the cells near the tumor. The EVOC approach introduces a hydrophilic non-cell permeable substrate probe D5-ethyl-βD-glucuronide (D5-EtGlu) that releases D5-ethanol if metabolized by β-glucuronidase. Therefore, it is proposed that this unique volatile reporter can be measured in exhaled breath when interacting with extracellular β-glucuronidase enzyme surrounding a tumor.

Image Credit: Owlstone Medical Ltd

Dr. Mariana Leal, a Lead Translational Scientist at Owlstone, discussed their work on lung cancer with News Medical, highlighting the progress and future trajectories of the work.

Liver disease

While 90% of liver disease is preventable, liver disease does not tend to display any significant symptoms at the early stages. As a result, most cases are diagnosed at advanced to late stages. This is a cause for concern, as the later the diagnosis, the more likely it is that permanent damage has occurred, with reports of up to 75% of patients receiving a diagnosis of cirrhosis (scarring) of the liver only when liver failure has started.²

Detecting early stages of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), marks a significant clinical challenge. As it stands, invasive tissue biopsy remains the gold standard for diagnosis and monitoring. However, developing a breath test would facilitate non-invasive early liver disease detection.

Image Credit: Owlstone Medical Ltd

Limonene can effectively assess liver function through its metabolism by the CYP450 enzymes. This offers a clear alternative to liver biopsies for the diagnosis of cirrhosis and the detection of earlier stages of liver disease.^3,4

Further analysis has revealed that 29 volatile compounds varied significantly in those with cirrhosis vs control groups; the top four performing compounds for differentiating these groups were identified as 2-pentanone, eucalyptol, limonene, and dimethyl selenide.⁴

Interestingly, these compounds can be connected to blood metrics of liver function, and bringing them together in a classification model offered a better classification performance than any singular compound.

A subsequent liver disease trial revealed that the breath test was extremely accurate, even going as far as detecting the presence of liver damage in someone who had liver disease but was misallocated to a place in the healthy control cohort.

Therefore, breath testing for liver disease is one of the most promising areas where breath analysis can carve out a clear path toward creating a powerful diagnostic and monitoring tool with exceptional clinical benefits.

The microbiome

The human body is colonized by microbial species of bacteria, fungi, and archaea – collectively known as the microbiota or the microbiome – reshaping our perception of the processes behind health and disease. The microbiome is a growing field of interest across biomedical sciences, as it has been associated with the pathophysiology of several diseases, particularly gastrointestinal diseases, as the microbial community in the gut is one of the most richly diverse on the planet.⁵

Gastrointestinal diseases such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) trigger levels of discomfort that impact the quality of life, and diagnosing these conditions tends to be a slow, prolonged process.

An analysis of patients diagnosed with IBD between 1998-2016 showed that surprisingly, 10% of patients had reported symptoms to their doctor five years before receiving a diagnosis, and less than half of those suffering from persistent symptoms saw a specialist within 18 months.⁶

As many gastrointestinal diseases display significant symptom overlap, they are difficult to distinguish accurately without using more invasive tests, which can be time-consuming and difficult to tolerate. Furthermore, the right balance must be found, as treatment delays can have a detrimental effect on the prognosis of more severe diseases such as colorectal cancer (CRC).

Short-chain fatty acids (SCFAs) are a category of volatile chemical compounds that are produced by gut microbiota and are strongly associated with the development of several gastrointestinal diseases, including IBS, IBD, and CRC.^7–9

Several SCFAs, such as acetic acid, butyric acid, propionic acid, isobutyric acid, 2-methylbutanoic acid, and isovaleric acid, are contained in Owlstone’s Breath Biopsy VOC Atlas, a catalog of VOCs that can be detected in exhaled breath and reliably distinguished from background signal.

The time between when a volatile compound is produced in the gut and its detection in the breath is only five minutes or less based on gut microbial-produced hydrogen gas measurements.10 Therefore, detecting endogenously produced compounds in the breath can offer a real-time view into the ongoings of microbial metabolism in the gastrointestinal tract, a critical perspective for studying gastrointestinal diseases.

Image Credit: Owlstone Medical Ltd

As SCFAs are produced through the fermentation of dietary compounds, the evidence indicates that in several cases, it may be possible to reverse the negative effects of unbalanced levels of SCFAs by making simple dietary changes.^9,11

Continuous monitoring of non-invasive breath samples could evaluate how effective dietary intervention is. If successful, this method could potentially improve the quality of life for a great number of people by reducing the risk of developing gastrointestinal diseases and limiting the severity of such conditions, resulting in symptom alleviation.

Conclusion

Owlstone Medical focuses on improving and saving 100,000 lives and $1.5B in healthcare costs while establishing itself as the global leader in Breath Biopsy for clinical use.

Although Owlstone’s first mission was the fight against cancer, the company has determined that breath biomarkers could potentially improve diagnostic tests and lead to the creation of better monitoring technology for clinical trials across a range of diseases, as well as offering the ability to investigate the impact that the microbiome has on human health.

Ultimately, Owlstone believes that the promise of breath analysis could revolutionize diagnostic and disease monitoring techniques, as well as improve drug development. Therefore, Owlstone aims to bring about a wider adoption of breath analysis technology for clinical applications.

References and further reading

1. Cancer [Internet]. [cited 2023 Apr 19]. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer
2. Labenz C, Arslanow A, Nguyen-Tat M, Nagel M, Wörns MA, Reichert MC, et al. Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL. J Hepatol. 2022 Sep;77(3):695–701. DOI: 10.1016/j.jhep.2022.04.009
3. Ferrandino G, Orf I, Smith R, Calcagno M, Thind AK, Debiram-Beecham I, et al. Breath Biopsy Assessment of Liver Disease Using an Exogenous Volatile Organic Compound—Toward Improved Detection of Liver Impairment. Clinical and Translational Gastroenterology. 2020 Sep;11(9):e00239. DOI: 10.14309/ctg.0000000000000239
4. Ferrandino G, De Palo G, Murgia A, Birch O, Tawfike A, Smith R, et al. Breath Biopsy^® to Identify Exhaled Volatile Organic Compounds Biomarkers for Liver Cirrhosis Detection. Journal of Clinical and Translational Hepatology. 2023 Jun 28;11(3):638–48. DOI: 10.14218/JCTH.2022.00309
5. Cronin P, Joyce SA, O’Toole PW, O’Connor EM. Dietary Fibre Modulates the Gut Microbiota. Nutrients. 2021 May 13;13(5):1655. DOI: 10.3390/nu13051655
6. Blackwell J, Saxena S, Jayasooriya N, Bottle A, Petersen I, Hotopf M, et al. Prevalence and Duration of Gastrointestinal Symptoms Before Diagnosis of Inflammatory Bowel Disease and Predictors of Timely Specialist Review: A Population-Based Study. Journal of Crohn’s and Colitis. 2021 Feb 1;15(2):203–11. DOI: 10.1093/ecco-jcc/jjaa146
7. Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de los Reyes-Gavilán CG, Salazar N. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol. 2016 Feb 17;7:185. DOI: 10.3389/fmicb.2016.00185
8. Mirzaei R, Afaghi A, Babakhani S, Sohrabi MR, Hosseini-Fard SR, Babolhavaeji K, et al. Role of microbiota-derived short-chain fatty acids in cancer development and prevention. Biomedicine & Pharmacotherapy. 2021 Jul 1;139:111619. DOI: 10.1016/j.biopha.2021.111619
9. Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJ, Faber KN, Hermoso MA. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Frontiers in immunology. 2019:277. DOI: 10.3389/fimmu.2019.00277
10. Read NW, Al-Janabi MN, Bates TE, Holgate AM, Cann PA, Kinsman RI, et al. Interpretation of the breath hydrogen profile obtained after ingesting a solid meal containing unabsorbable carbohydrate. Gut. 1985 Aug;26(8):834–42. DOI: 10.1136/gut.26.8.834
11. Lee JH, Zhu J. Analyses of short-chain fatty acids and exhaled breath volatiles in dietary intervention trials for metabolic diseases. Experimental Biology and Medicine. 2021 Apr;246(7):778-89. DOI: 10.1177/1535370220979952 

About Owlstone Medical Ltd

Owlstone Medical is developing a breathalyzer with a focus on non-invasive diagnostics for cancer, inflammatory disease and infectious disease, the company aims to save 100,000 lives and $1.5B in healthcare costs.

The company’s Breath Biopsy^® platform has introduced a new diagnostic modality making it possible to discover novel non-invasive biomarkers in breath using a platform with the potential to transition to point-of-care. The award winning ReCIVA Breath Sampler ensures reliable collection of breath samples.

Breath Biopsy is supporting research into early detection and precision medicine with applications in cancer and a wide range of other medical conditions. Highly sensitive and selective, these tests allow for early diagnosis when treatments are more effective and more lives can be saved.

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