In a recent study published in the journal Contemporary Clinical Trials Communications, researchers discuss a new clinical trial that will determine the efficacy of butyrate administration in preventing colon cancer.
Study: Can butyrate prevent colon cancer? The AusFAP study: A randomised, crossover clinical trial. Image Credit: Lightspring / Shutterstock.com
What is butyrate?
Butyrate is a powerful inhibitor of histone deacetylase, which modifies the expression of certain genes involved in cellular apoptosis, deoxyribonucleic acid (DNA) repair, and cell cycle regulation.
Butylated high amylose maize starch (HAMSB) provides a significant amount of butyrate to the colons of animals and humans. The distribution of butyrate by HAMSB has been shown to induce epithelial apoptosis, prevent DNA strand breaks in colon cells, and reduce tumor burden in rat models of cancer.
Despite the advantageous properties of butyrate, excess exposure to butyrate may cause cancer cells to become resistant to its protective effects.
The AusFAP clinical trial
Familial Adenomatous Polyposis (FAP) is a condition that occurs in individuals with a rare mutation in the APC gene. This causes individuals with FAP to be at a particularly high risk of developing colorectal cancer.
Many of the mutations present in FAP tumors can also be found in the colorectal tumors that develop in otherwise healthy individuals; thus, FAP is frequently used for colorectal carcinogenesis models in research.
In the Australian FAP (AusFAP) trial, which is a double-blind, cross-over study with a timespan of 18 months for each participant, researchers plan to assess the possible chemoprotective benefits of HAMSB on polyposis in individuals with FAP.
After baseline colonoscopy examinations, individuals will be administered either low amylose maize starch (LAMS) or HAMSB for 26-28 weeks, following which a second colonoscopy is performed. The participants will subsequently ingest the alternative starch for 26-28 weeks before undergoing a third colonoscopy after 52 weeks.
This assessment is followed by a 26-28 week washout period, during which no supplements are to be consumed. A fourth endoscopy will be performed at 78 weeks. When possible, endoscopies were videotaped, and mucosal and polyp biopsies are obtained.
Individuals medically diagnosed with FAP and a prior history of polyp detection are recruited into the AusFAP trial if they are healthy, between 12 and 75 years of age, and either have an intact colon (IC) or following colectomy, an ileal pouch anal anastomosis (IPAA), or an ileorectal anastomosis (IRA). Potentially eligible participants are enrolled through state-based FAP databases, patients of the investigators, familial cancer clinics, FAP self-help organizations, and advertisements.
For about 26 weeks, AusFAP study participants will consume 40 g/day of LAMS or HAMSB in two separate doses. Independent testing for microbial, yeast, and heavy metal contamination will be performed after the two 26-week dietary interventions.
Throughout the duration of the trial, the participants, research team, and study coordinators are blinded to the therapies, as well as both the sample and data analysis. The research coordinator uses an electronic case report form (eCRF) to obtain information and allow gastroenterologists from various clinical sites to evaluate the captured videos at the conclusion of the study.
The primary outcome is the total number of polyps estimated globally across the large intestine, while secondary outcomes include the size of the global polyps, as well as the size and number of polyps at two tattoo locations placed inside the colon.
To examine polyp load, high-definition colonoscopies are performed on participants where possible. The excision of polyps or biopsies is videotaped and subsequently documented in the eCRF. At least two independent gastroenterologists will evaluate each video and assess the size and number of polyps found in every portion of the large bowel.
Dietitians will conduct telephonic interviews to record all foods and beverages ingested by FAP participants during the preceding 24 hours to determine their typical diet, baseline nutrient consumption, and the effect of the therapeutic interventions on their diet. Three to four days following the baseline colonoscopy, and between weeks 12 and 38 of the research, 24-hour dietary recalls are conducted.
The modified gastrointestinal quality of life index (GIQLI) will estimate the acceptability of the starches, as GIQLI is a validated instrument that requires one to five scaled responses ranging from "all of the time" to "never" for a total of 17 questions.
The participants will be asked to answer the questionnaires on six events, including prior to the commencement of the trial (week 0), twice throughout all the 26-week interventions (weeks 12 and 26; and weeks 38 and 52); and at the conclusion of the washout period (week 78).
The AusFAP trial intends to disseminate data in the form of reports and presentations to state-based FAP registries, FAP self-help organizations, patients of principal investigators, and familial cancer centers when eligible participants are recruited. As any favorable impact of HAMSB in FAP may potentially account for a lower frequency of sporadic CRC within the group, the team will disseminate the findings through professional presentations and peer-reviewed publications in journals.
The AusFAP trial will examine the hypothesis that HAMSB will increase the distribution of butyrate into the large bowel of FAP individuals, thus reducing the initiation and/or proliferation of polyps in these participants.
Positive findings could suggest potential advantages associated with the long-term dietary supplementation of HAMSB to mitigate CRC development risk in FAP patients. Furthermore, the trial findings could be extrapolated to sporadic CRC in the general population, wherein low dietary fiber consumption is a major contributor to the high prevalence of this disease.
- Clarke, J., Boussioutas, A., Flanders, B., et al. (2023). Can butyrate prevent colon cancer? The AusFAP study: A randomised, crossover clinical trial. Contemporary Clinical Trials Communications. doi:10.1016/j.conctc.2023.101092