Molecular mechanisms of colorectal cancer development, with Prof. Alberto Martin PhD

This episode features Prof. Christophe Courtin from KU Leuven (Belgium), speaking about the European HealthFerm initiative. HealthFerm began in September 2022 and brought together multiple institutions and companies to advance the project with a grant of 30 million Euros. The main aim of the project was to improve public acceptance of plant-based foods through fermentation. A citizen science component of the project involved gathering fermented food samples from all over Europe, both home fermenters and small bakeries, to analyze the microorganisms. The researchers received over 650 sourdough starter samples and around 200 other fermented foods samples; from these, they identified some new species that still need to be named. Another part of the project involved a clinical trial on how the body responds if short-chain fatty acids are released in the small intestine versus in the colon. They found that small intestinal release increased GLP-1 levels more than PYY; the opposite happened with colonic release. Another study in the project compared oat to fermented oat, and found that the fermentation changed the fiber (degree of polymerization), and also led to positive health effects. Prof. Courtin says the potential for future research in this area is to find out how to add nutritional benefits through fermentation (for example, vitamin B12 in plant-based foods), as well as how to change the fiber profile in a food to yield specific health benefits.

This episode features Dr. Mingyang Song ScD from Harvard University (USA), speaking about epidemiological evidence connecting the gut microbiota to colorectal cancer (CRC) and whether the evidence supports the gut microbiota as a ‘driver’ or a ‘passenger. Dr. Song explains how he and colleagues studied the gut microbiome in a subset of people from the Nurses’ Health Study. It’s known that adenoma removal reduces CRC risk, but doesn’t eliminate it. Does the gut microbiome contribute to this remaining risk? The researchers found that many years after adenoma removal, individuals had a different gut microbiota compared with healthy controls, indicating that the microbiome profile is not fully restored by adenoma removal. People with past adenoma removal had a gut microbiota that overlapped with that of current CRC patients, with the caveat that lots of heterogeneity was observed. Diet and lifestyle also correlate with both CRC development and gut microbiome composition, with some of the main factors reducing CRC risk being dietary fiber, fruits, vegetables, whole grains, and calcium. These and other healthy lifestyle factors were associated with fewer of the gut microbial members typically seen in CRC. Next, prospective studies are needed to determine whether gut microbiota changes truly precede CRC and independently contribute to risk. This line of research could also lead to a more tailored approach to CRC screening, with risk factors being taken into account.

This episode features Dr. Georg Zeller PhD from Leiden University Medical Center (the Netherlands), speaking about gut microbiome signatures of colorectal cancer across global populations. An early study Dr. Zeller completed in Peer Bork’s lab suggested that the gut microbiomes of people with colorectal cancer are distinct from controls. This signature, as well as work on the tumor microbiome, all pointed toward Fusobacterium as particularly important. Subsequent studies exploring this idea show wide variation in geography and methods. Accounting for these factors, meta-analyses have confirmed several gut microbiome characteristics that are enriched in colorectal cancer across the global population. Dr. Zeller was interested to see that bile acid metabolism is consistently enriched in the cancer metagenome. The taxonomic profile, however, appears better than the functional profile in distinguishing colorectal cancer from control samples. He emphasizes the importance of linking his insights from bioinformatic efforts to the mechanistic work being done. Initially he was hopeful that a gut microbiome diagnostic could be developed, but currently the highest achievable AUC for the classification models is around 0.85 or 0.9, which may not be adequate for enhancing current clinical tools. The possibility remains for a gut microbiome test to complement existing diagnostics. The most promising area may be targeted gut microbiome modulation for prevention of colorectal cancer, perhaps through diet. His group is also exploring the gut microbiome for early diagnosis of pancreatic cancer, possibly by combining fecal markers with other diagnostic tools.

This episode features Prof. Cynthia L. Sears, MD from the Johns Hopkins University School of Medicine and the Bloomberg School of Public Health (USA), speaking about both biofilms and specific gut microorganisms that may contribute to colorectal cancer development. Initially, Prof. Sears became interested in enterotoxigenic Bacteroides fragilis in connection with colon cancer. Further investigation found complex biofilms with multiple bacteria fixed to the surface of the tumor. The biofilms were shown to be oncogenic, and they reassembled very quickly after antibiotic treatment. Interestingly, the biofilms were found to have C. difficile. A subset of the biofilms have a dominant amount of Fusobacterium, and the latest work shows that these bacteria are associated with advancing cancer, stage 2 or beyond. These bacteria and/or biofilms don’t necessarily trigger the onset of mutations that lead to colon cancer, but they accelerate tumor growth. Over time, the gut microbiota may be perturbed in various ways (including by antibiotics), allowing the organisms to create a niche for themselves that ultimately harms the colonic epithelial cells. Prof. Sears is optimistic about prevention strategies for colorectal cancer, such as a tool that helps predict risk in younger populations. Targeted prebiotics, too, show promise for encouraging the growth of beneficial bacteria that prevent the oncogenic species from finding a niche.

This episode features Dr. Anne Salonen PhD from University of Helsinki (Finland) speaking about her studies on the gut microbiota in early life and how it relates to health and disease. She noted that while mode of delivery (C-section or vaginal birth) is the largest factor affecting microbiota composition for the first weeks and months of life, the immunological and functional microbiota consequences of this are still unknown. However, there appear to be ‘windows of opportunity’ in which microorganisms can influence the development of the immune system, which have lasting consequences for health. Dr. Salonen describes her Finnish HELMi birth cohort, a longitudinal, prospective general population birth cohort, set up to identify factors that modify the gut microbiota and how they relate to child health and wellbeing. Children from 1055 families were sampled frequently in the first 2 years of life and followed as they grew older. The findings confirmed that early-life microbiota composition was a risk factor (among others) for certain diseases as the children developed. Prof. Salonen also described her study on inoculating the infant gut with maternal gut microbiota via milk feeding after C-section birth. They found, in an initial small study, that the gut microbiota of the infants became similar to vaginally born infants. She sees this type of inoculation as a research tool, and says the field will progress toward standardized, reproducible interventions in this area.