It has been previously reported that ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduced risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colorectal cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies. Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal adenomatous polyps, we compared change in the microbiome composition after a 3‐year intervention in a subset of participants randomized to oral UDCA at 8‐10 mg/kg of body weight per day (n = 198) or placebo (n = 203). 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 reflected a UDCA‐associated shift in microbial community composition (P < 0.001), independent of sex, with no evidence of a 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. Separate analyses of microbial networks revealed an overrepresentation of Faecalibacterium prausnitzii in the post‐UDCA arm and an inverse relationship between F prausnitzii and Ruminococcus gnavus. In men who received UDCA, the overrepresentation of F prausnitzii and underrepresentation of R gnavus were more prominent in those with no adenoma recurrence at follow‐up compared to men with recurrence. This relationship was not observed in women. Daily UDCA use modestly influences the relative abundance of microbial species in stool and affects the microbial network composition with suggestive evidence for sex‐specific effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.

Background American Indians (AI) experience major colorectal cancer (CRC) screening disparities with commensurate inequity in CRC mortality and other outcomes. The purpose of this report is to describe the methods and early results of adapting a previously successful intervention for the AI community. Methods The educational content and delivery strategy of the parent intervention were adapted for AIs guided by an adaptation framework and cultural consultations with the community and clinicians. As part of the environmental scanning, we identified the need to substantively revise our data entry, collection, and tracking system and develop a REDCap database for this purpose. In this study, we staggered the implementation of the intervention in each facility to inform the process from one clinic to the next, and assess both the clinical outcomes of the tailored intervention and the implementation processes across two clinic settings, Facilities A and B. Results The REDCap database is an indispensable asset, and without it we would not have been able to obtain reliable aggregate screening data while improvements to facility electronic health records are in progress. Approximately 8% (n = 678) of screening-eligible patients have been exposed to the navigator intervention. Of those exposed to the navigator intervention, 37% completed screening. Conclusions With the small numbers of patients exposed so far to the intervention, it would be premature to draw any broad conclusions yet about intervention effects. However, early screening completion rates are substantial advances on existing rates, and we have demonstrated that a tailored navigator intervention for facilitating CRC screening was readily adapted with provider and community input for application to AIs. A REDCap database for tracking of CRC screening by navigators using tablets or laptops on- or offline is easy to use and allows for generation of aggregate, anonymized screening data. Trial registration. There was no health intervention meeting the criteria of a clinical trial. The University of Arizona Institutional Review Board granted exemption from obtaining informed consent from patients undergoing CRC screening after administration of the tailored navigation intervention as usual care.

ObjectiveWe 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.DesignUsing 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.ResultsStudy 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.ConclusionDespite 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.SUMMARYWhat 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 colonIn humans, UDCA is produced in the colon from the conjugation of primary bile acids by intestinal bacteriaIntestinal 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 PBCWhat are the new findings?Among a population of patients with colorectal adenoma, low dose oral UDCA taken daily produced modest changes in fecal bacterial compositionUDCA 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.

The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0-300 μM of soluble DU as uranyl acetate (UA) for 0-48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod® to determine UA-induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod® results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro.

Compelling evidence suggests that gut flora influences colorectal cancer risk through direct effects on colonic bile acid composition. Bile acids are widely implicated in the etiology of colorectal cancer with the strongest evidence involving a detrimental role for the secondary BA, deoxycholic acid (DCA) and a protective effect of ursodeoxycholic acid (UDCA). In a study of patients with prior colorectal adenomas who were randomized to UDCA (n=188 males, 64 females), a bile acid based intervention aimed at modulating bile acid composition, or placebo (n=162 males, 89 females), we determined effects of the intervention on the gut microbiome through 16S rRNA sequencing and bile acid composition at baseline using mass spectrometry. We observe a consistent shift in microbial composition for males (t=5.83, p=3.6e-8) and females (t=3.14, p=0.003) treated with UDCA. No effect was observed in the placebo group for either males (t=-0.08, p=0.93) or females (t=-0.09, p=0.92). There were significant correlations between the gut microbiome and BA composition (r=0.31, p&lt;0.001). This suggests that UDCA treatment had an effect on the gut microbial communities relative to the placebo group. Interestingly, the magnitude of the change in the microbiome over time is similar in the two groups, but UDCA treatment seems to drive specific microbiome changes. These results are consistent with our previously reported observation that UDCA appears to have a greater effect in men for the prevention of colorectal adenomatous polyps, while increasing risk for women. Citation Format: Talima Pearson, J Gregory Caporaso, Monica Yellowhair, Jessica A. Martinez, Betsy Wertheim, Denise Roe, Patricia Thompson-Canino, Peter Lance. Gut microbiota changes in response to treatment with ursodeoxycholic acid (UDCA). [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A18.