Highlights from the Inaugural International Cancer Microbiome Consortium Meeting (ICMC), 5-6 September 2017, London, UK

Abstract

The International Cancer Microbiome Consortium (ICMC) is a recently launched collaborative between academics and academic-clinicians that aims to promote microbiome research within the field of oncology, establish expert consensus and deliver education for academics and clinicians. The inaugural two-day meeting was held at the Royal Society of Medicine (RSM), London, UK, 5-6 September 2017. Microbiome and cancer experts from around the world first delivered a series of talks during an educational day and then sat for a day of roundtable discussion to debate key topics in microbiome-cancer research. Talks delivered during the educational day covered a broad range of microbiome-related topics. The potential role of the microbiome in the pathogenesis of colorectal cancer was discussed and debated in detail with experts highlighting the latest data in animal models and humans and addressing the question of causation versus association. The impact of the microbiota on other cancers-such as lung and urogenital tract-was also discussed. The microbiome represents a novel target for therapeutic manipulation in cancer and a number of talks explored how this might be realised through diet, faecal microbiota transplant and chemotherapeutics. On the second day, experts debated pre-agreed topics with the aim of producing a consensus statement with a focus on the current state of our knowledge and key gaps for further development. The panel debated the notion of a 'healthy' microbiome and, in turn, the concept of dysbiosis in cancer. The mechanisms of microbiota-induced carcinogenesis were discussed in detail and our current conceptual models were assessed. Experts also considered co-factors in microbiome-induced carcinogenesis to conclude that the tripartite 'interactome' between genetically vulnerable host, environment and the microbiome is central to our current understanding. To conclude, the roundtable discussed how the microbiome may be exploited for therapeutic benefit in cancer and the safety implications of performing such research in oncology patients.

Keywords: cancer; consortium; gut; microbiome; microbiota.

Figure 1.. (a) Anatomy of the faecal cylinder. Hybridisation with Bac303 (Bacteroides) Cy3 (yellow fluorescence) probe. 10–100 μm bacteria-free mucus layer (white arrow) covers the faecal cylinder. This mucus limits direct contact between the bacteria and the colonic mucosa. Figure courtesy of Dr Alexander Swidsinski. (b) Colonoscopy in a mouse demonstrating colorectal tumour. Figure courtesy of Professor Daniel Rosenberg.

Figure 2.. The TIMER framework summarises the mechanisms by which chemotherapeutics can interact with the gut microbiome. Translocation: cyclophosphamide can damage the mucosal barrier, permitting translocation of commensal bacteria. Immunomodulation: intestinal microbiota facilitate a plethora of chemotherapy-induced immune and inflammatory responses. For example, Lactobacillus mediates the accumulation of T-helper cell responses and bifidobacteria increase T-cell numbers in the tumour microenvironment in patients treated with anti-PD-L1 immunomodulator. Metabolism and enzymatic degradation: the microbiota harbour a large suite of metabolic processes (such as reduction, hydrolysis, dehydroxylation and dealkylation) which can modify pharmaceuticals to potentiate desirable effects, abrogate efficacy or liberate toxic compounds. For example, bacterial β-glucuronidases cleave the glucuronide from the inactive metabolite of irinotecan (SN-38G), releasing the active metabolite (SN-38) into the gut and causing diarrhoea. Reduced diversity: chemotherapy can modify the diversity of the intestinal microbiota through altered biliary excretion and secondary metabolism or associated antibiotic use and dietary modifications. The resulting expansion of pathobionts can lead to deleterious effects such as diarrhoea and colitis. PRR, pattern-recognition receptor; TAMC, tumour-associated myeloid cell; TLR, toll-like receptor; T_reg cell, regulatory T cell. Reproduced from Alexander et al [12] 2017 with kind permission.

Figure 3.. Interaction between diet and the microbiota results in the production of co-metabolites which can modify colon cancer risk. Saccharolytic fermentation of carbohydrates in fibre generates short-chain fatty acids, such as butyrate, which has anti-inflammatory and anti-neoplastic properties as indicated. On the other hand, a high fat/high animal protein diet promotes the formation of secondary bile acids and toxic nitrogenous and sulphur metabolites, which are pro-neoplastic. Reproduced from O’Keefe et al [17] 2016 with kind permission.