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Colorectal cancer: guided by the gut?

Recent evidence suggests a role of the microbiome in cancer pathogenesis and as a potential therapeutic target, but it is still early days

The gut microbiome continues to bask in the preclinical limelight and rightly so. An increasing body of research aims at elucidating its implication in intestinal health and major diseases including cancer in general, and colorectal cancer in particular. Over recent years, several studies have demonstrated that disruption to microbiota composition can significantly elevate the risk of disease. Achieving deeper insights into its role in the modulation of inflammation, tumor growth and metastasis, as well as the mediation of response to anti-cancer medicines, is at the heart of these endeavors.

Advances in microbial detection technologies have led to the discovery of several previously overlooked microorganisms that assume important functions in human disease. One such pathogen is Fusobacterium nucleatum – the most prevalent and highly enriched bacterial species in colorectal cancer (CRC). Elevated levels of F. nucleatum in tumors correlate with less T-cell infiltration, advanced disease, poorer overall survival, and clinical characteristics including right side anatomical localization, mutations of the BRAF gene and microsatellite instability.

In an elegant report (Science. 2017 Dec 15;358(6369):1443-1448), research showed that the colonisation of human CRC with Fusobacterium and its associated microbiome is found in primary tumors and persists in liver metastases. In this same study, results evidenced that the antibiotic treatment of mice bearing F. nucleatum-positive PDXs significantly decreased tumor growth, supporting the causal role for the bacterium in tumorigenesis in CRC.

In advanced rectal cancer, a subsequent study (Ann Oncol. 2020 Oct;31(10):1366-1375), showed that persistency of this bacterium after neoadjuvant chemoradiotherapy associated with higher relapse in patients with locally advanced rectal cancer. When F. nucleatum persists after treatment, an immunosuppressive microenvironment is created to prevent immune cells effectively attacking the tumor, and where F. nucleatum was not detected, CD8T+ cells sharply increased and inflammatory response was stronger. Suppression of this gut bacterium creates an antitumoral microenvironment which could potentially open a future avenue exploring new targeted treatments to reduce the risk of tumor immune evasion.

These observations, as well as those of many other groups, have undoubtedly provided a strong rationale to pursue targeted approaches directed against this bacterium and other key components of the cancer microbiome. But we have only really scratched the surface in unraveling the intricate mechanisms involved in microbiota dysbiosis and its interplay in human health and the pathogenesis of disease.

Microbial markers in young onset CRC

Alarmingly, colorectal cancer rates continue to rise in younger individuals - a trend sadly witnessed by many of us in our own clinics over the past few years. According to a recent article (CA Cancer J Clin. 2021 May;71(3):209-249), early-onset colorectal cancer (age at diagnosis <50 years) is increasing in many countries, including the United States, Canada, Australia, and 6 other high-income countries, with incidence rising by 1% to 4% per year.

Hypothesizing that patients’ diets and gut bacteria might be contributing factors, colleagues at the University of Cincinnati Cancer Center and University of Cincinnati College of Medicine, investigated the association between bacteria in the microbiome and rates of CRC in younger populations.

Recently presented on the ground at this year’s 2022 ASCO Annual Meeting (J Clin Oncol 40, 2022 (suppl 16; abstr 3532), data from their metagenomic analysis of fecal microbiome in patients with CRC versus healthy controls as a function of age, point to causal mechanisms of enriched species of bacteria observed in young onset CRC patients.

While species of bacteria most closely associated with driving colorectal cancer, colibactin, fadA and increased F. nucleatum, were observed in older patients, they were not detected in higher levels among young patients. Five other bacteria were found in elevated levels in these individuals versus older patients, including B. wadsworthia that is associated with a sulfur microbial diet; which has been linked to a higher increase risk of CRC in younger people.

Based on their findings, the authors suggest that interactions between diet and the microbiome may potentially mediate the development of CRC cancer cells and increased risk in younger patient populations. These findings warrant further research into bacteria species found in higher levels in these patients, and how they might influence the development of cancer as well as response to treatment.

In the science of gut and microbiota in cancer myriad questions remain, including how the microbiome modulates response to currently available treatments, immune-based therapies in particular. Moving forward, mounting preclinical evidence will certainly spur efforts aimed at manipulating gut microbiota cross-talk toward more effectively treating and even preventing disease, but we still have a long road to travel.

Continued investigations exploring the mechanisms of distinct bacteria in host physiology and therapy promise to cement the necessary foundations for building potential strategies based on gut microbial makeup and function.

Microbiota medicine in oncology? Not yet - but it’s more than a gut feeling.

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