Abstract
Objective We previously reported that Ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduces risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colon cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies.
Design Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal neoplasia, we compared change in the microbiome composition after 3 years intervention in a subset of participants randomized to 8–10 mg/kg of body weight UDCA (n=198) to placebo (n=203). UDCA effects on the microbiome, sex and adenoma outcome were investigated.
Results Study participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This change reflected an UDCA-associated shift in microbial community distance metrics (P <0.001), independent of sex, with no evidence of UDCA effect on microbial richness (P > 0.05). These UDCA-associated shifts in microbial community distance metrics from baseline to end-of-study were not associated with risk of any or advanced adenoma (all P> 0.05) in men or women.
Conclusion Despite a large sampling of randomized clinical trial participants, daily UDCA use only modestly influenced the relative abundance of microbial species in stool with no evidence for effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.
What is already known about this subject?
Ursodeoxycholic acid (UDCA) is a therapeutic bile acid used in the treatment of primary biliary cirrhosis (PBC) and investigated for anti-cancer activity in the colon
In humans, UDCA is produced in the colon from the conjugation of primary bile acids by intestinal bacteria
Intestinal bacteria play a critical role in human intestinal health and disease including a hypothesized role in the development of colorectal cancer.
UDCA was found to reduce the risk of more advanced colorectal adenoma with effects present in men but not women.
Therapeutic UDCA was recently shown to reduce the extent of bacterial dysbiosis in patients with PBC
What are the new findings?
Among a population of patients with colorectal adenoma, low dose oral UDCA taken daily produced modest changes in fecal bacterial composition
UDCA associated changes in the gut microbiome were similar in men and women.
UDCA associated changes in the gut micobiome were not associated with risk of any or advanced colorectal adenoma in the patient population.
How might it impact on clinical practice in the foreseeable future?
These findings confirm effects of oral UDCA on the microbiome that may be beneficial for patients with PBC.
These findings suggest that the anti-cancer effects of UDCA for colorectal adenoma prevention are not due to major effects of UDCA on the gut microbiome.
- Abbreviations
- UDCA
- Ursodeoxycholic acid
- CRC
- Colorectal cancer
- DSS
- Dextran sodium sulfate
- AOM
- Azoxymethane
- PBC
- Primary biliary cirrhosis
- OTU
- Operational taxonomic unit
- ASV
- amplicon sequence variant
Footnotes
↵* Authors share first authorship.
↵** Authors share senior authorship
Grant support: This project was funded by the Partnership for Native American Cancer Prevention (NIH/NCI U54CA143924 and U54CA143925). The microbiome bioinformatics work was supported in part by NSF Award 1565100 to JGC. The fecal archive for this study was supported in part by R01 CA151708 (to PAT and PL). Research in this manuscript was directly supported by the Biostatistics and Tissue Acquisition and Cellular/Molecular Analysis Shared Resources Funded by the NCI Award P30CA023074.
Disclosures: The authors declare no conflicts of interest.
Data access: Raw sequence data is currently being deposited in the Qiita microbiome meta-analysis repository, and the ENA sequence read archive. Accession numbers will be included in the final version of this manuscript, after they have been generated. For review purposes, data can be anonymously accessed through dropbox using the following link: https://www.dropbox.com/sh/49115v1mukwjtc3/AABdB8hx33ogeheILLmvom9na?dl=0