Recent studies have demonstrated the potential of a fecal microbiota transplantation (FMT) in modulating immunotherapeutic outcomes of colorectal cancer (CRC) subjects (Rosshart et al., 2017). Questions have arisen as to whether or not FMT should be standardized as a preventive measure for suspected tumor growth within the gut. These enquires are incentivized by recent findings indicating the presence of onco-epigenetic markers within the gut of gnotobiotic mice receiving CRC fecal samples (Sobhani et al. 2019). Put together, epigenetic screening and FMT transplantation of at-risk patients could become an effective strategy to undermine CRC development and the microbiome which supports it.
The study by Sobhani et al. focused on three key factors that define CRC etiology: altered intestinal structure, microbiome composition, and DNA methylation. Two main groups were tested, with mice receiving either healthy microbiota (N-µ) or CRC microbiota (CRC-µ) from human patients. The CRC-µ group showed an increased presence of aberrations in crypt foci (AFC) on histological staining of the murine colonic mucosa after 7 weeks. In contrast, the N-µ group display healthy intestinal architecture with no discernible AFC present. Moreover, they observed an increased presence of bacteria associated with precancerous lesion formation and a decrease in genera that promote anti-inflammatory effects within the microbiome community of CRC-µ. Additionally, CRC-µ mice displayed high levels of DNA methylation commonly associated with human tumor tissues (Guinney et al., 2015) and increased populations of Parvimonas micra and Bacteroides fragilis (Purcell et al., 2017).
Although results showed accurate replication of CRC etiology in mice, the podcast hosts highlighted key issues concerning the model, mechanism of CRC development, and application of DNA analysis into a medical setting. They were reasonably skeptical of the germ-free mice as a model for at risk CRC patients. Their abiotic gut could be more susceptible to transplantation, eliciting a stronger onco-epigenetic response than would be seen in at-risk patients. Furthermore, the study did not demonstrate a strong correlation between CRC-µ and inflammation, which is a key hallmark of the CRC disease. This could be attributed to the lack of red meat contained within the diet of the mice. Furthermore, the investigators presented a story that suggests CRC is a result of microbiota composition. However, the hosts highlight that the reverse may be true in that a tumor may establish an environment in which harmful bacteria would flourish, and perhaps exacerbate tumor progression. In addition to mechanistic questions, the podcast hosts debated on the medical application of a blood plasma assay to detect altered DNA modifications. Would it be used in addition to, preceding, or after the standard colonoscopy exam? Furthermore, how does a patient’s diet factor into the medical decision-making assessing when to use and how to interpret DNA modification results? Nevertheless, this model provides a new avenue for further research into the dynamic relationship between the microbiome, cancer, and epigenetic alterations during a disease state, from which early testing can aid medical practitioners with preventative treatment strategies.
References
J. Guinney et al., The consensus molecular subtypes of colorectal cancer. Nat. Med. 21,
1350–1356 (2015).
R. V. Purcell, M. Visnovska, P. J. Biggs, S. Schmeier, F. A. Frizelle, Distinct gut micro- biome patterns associate with consensus molecular subtypes of colorectal cancer. Sci. Rep. 7, 11590 (2017).
Rosshart SP, Vassallo BG, Angeletti D, et al. Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell 2017; 171:1015–28.e13.
Sobhani, I., Bergsten, E., Couffin, S., Amiot, A., Nebbad, B., Barau, C., … Sansonetti, P. (2019). Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. PNAS, 116(48), 24285–24295. https://doi.org/10.1073/pnas.1912129116
