Recent data suggest a strong association between the gut microbiome and the development of colorectal cancer (CRC), one of the world’s most widely identified malignancies. A significant shift in composition was reported when comparing the gut microbiome of CRC patients with healthy individuals, a phenomenon commonly referred to as dysbiosis. Particularly, the presence of certain types of bacteria such as Bacteroides fragilis and Escherichia coli have been associated with an increased risk for the development of CRC (Wu et al., 2009; Eaton and Yang, 2015), while Lachnospiraceae species seem to have an antitumor effect in the colon by producing metabolites such as short-chain fatty acid butyrate promoting apoptosis of colonic cancer cells (Hague et al., 1995; Ruemmele et al., 2003). Various observations suggest that microbial dysbiosis leads to loss of protective and the enrichment of cancer-promoting populations (Jobin, 2013; Zackular et al., 2013). Radiotherapy, via external beam or endocavity radiation, plays a vital adjunctive role in the management of CRC recurrence (that range from 20 to 30% after curative surgery). However, the usage of radiotherapy has been known to cause mucositis and radiation induced ulceration which expose the underlying tissues to bacteria, thereby changing the host–microbial interaction and as such driving substantial changes in the gut microbiome leading to intestinal dysbiosis (Meyers, Sasson and Sigurdson, 2003; Fuzun et al., 2004; Bowne et al., 2005). This dysbiosis is often characterised by symptoms such as diarrhoea, rectal bleeding and malabsorption which is accompanied by epithelial destruction and mucosal ulceration, that could also have prognostic values for tumour recurrence.
It is well known that radiotherapy (and surgical intervention) will cause disturbance for the gut flora CRC patients. However, what is lacking and of tremendous importance is whether this dysbiosis will be towards a cancer promoting or protective populations and it association to the CRC recurrence. We hypothesis these interventions will result in a disrupted microbiome (dysbiosis) harbouring cancer promoting microbial communities that plays a role in the recurrence of CRC. In addition, we also intend to investigate the application of the fecal microbiota transplantation (FMT) on the treatment of CRC patients. We hypothesis that FMT is able to resolve radiotherapy induced dysbiosis and protect against CRC recurrence. Longitudinal study involving mice models together with the clinical samples will be used and analysed using 16S metagenomics. The specific aims are:
• To identify temporal shift patterns in the gut microbiome of hospitalized and recurrent CRC patients undergoing radiotherapy and surgical interventions
• To validate the dysbiosis in the gut microbiome in irradiated CRC mouse model and investigate its relation to the recurrence of CRC
• To investigate ability of FMT to resolve radiation induced dysbiosis and protect against CRC recurrence in CRC mouse model