WP6: Novel treatments involving microbiome modulation

Two bacteria that can live inside the human gut, Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF), have been found to be related to the development of colorectal cancer (CRC). Fn can invade and live within human intestinal cells, while ETBF produces a toxin called BFT, that can also enter intestinal cells. Cells with Fn invasion or BFT toxin entry are compromised by these factors such that they are at risk to become cancerous. Both bacteria are primary examples of ‘oncomicrobes’.

However, these at-risk cells contain bacterial proteins, which should mark them for attack by immune system responses. It is currently unknown why Fn or BFT harboring cells are not sufficiently recognized and/or killed by immune cells in CRC, and whether there are differences in these immune responses between people that develop CRC and those who do not. To address this knowledge gap, we aim to firstly identify bacterial proteins our immune system can respond to, and then assess which of these most frequently leads to a sufficient immune response for elimination. Additionally, we will assess differences in immune responses to these bacteria between CRC patients and healthy controls. The results of this work will ultimately provide information that can be used to induce protective immune responses to these CRC-associated bacteria by vaccination.

Additionally, predatory bacteria, including a unique species called Bdellovibrio-and-Like Organisms (BALOs), have unique lifecycles that involve them targeting and killing their prey – other bacterial species. BALOs do not prey upon all bacterial cells, but only those with a particular type of membrane termed by microbiologists as ‘Gram negative”. Fn, ETBF and another oncomicrobe, pks+ Escherichia coli, are all Gram negative, and thus potentially vulnerable to attack by BALOs; meanwhile, most harmless microbes, as well as human cells, are left alone. Could we use BALOs as a type of therapy to selectively remove oncomicrobes from a person’s gut? Testing how BALOs target and destroy oncomicrobes, such as Fn, is crucial in our understanding of this dynamic and complex process. We will isolate BALOs from the environment, and ‘train’ them to improve their predatory behavior towards oncomicrobes in the human gut. The hope is to find BALO strains that can be developed into effective therapies to reduce numbers of oncomicrobes in patients with, or at risk of developing, CRC. 

Can we create microbiome therapies that will displace oncomicrobes from people’s guts and therefore reduce the chance of CRC development in people at risk of this disease? This is the third challenge for our team in this work package. Here we plan a randomized, placebo-controlled trial called METRIC (Microbial Ecosystem Therapeutics in Patients with Resectable Stage I-III Colon Cancer). This pilot trial will test an encapsulated defined microbial community (NB-5) developed by Allen-Vercoe and colleagues to be given orally, like a probiotic. METRIC is designed to address the safety and tolerability, the recommended dosage, and the effect on the gut microbiome of CRC patients who receive NB-5 in this pilot clinical trial.

Work Package Leaders