Bile acids and the gut microbiota: metabolic interactions and impacts on disease

Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis.

Studies of host-associated and environmental microbiomes often incorporate longitudinal sampling or paired samples in their experimental design. Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity, offering advantages over cross-sectional and pre-post study designs. To support the needs of microbiome researchers performing longitudinal studies, we developed q2-longitudinal, a software plugin for the QIIME 2 microbiome analysis platform (https://qiime2.org). The q2-longitudinal plugin incorporates multiple methods for analysis of longitudinal and paired-sample data, including interactive plotting, linear mixed-effects models, paired differences and distances, microbial interdependence testing, first differencing, longitudinal feature selection, and volatility analyses. The q2-longitudinal package (https://github.com/qiime2/q2-longitudinal) is open-source software released under a 3-clause Berkeley Software Distribution (BSD) license and is freely available, including for commercial use. IMPORTANCE Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity. We describe q2-longitudinal, a software plugin for longitudinal analysis of microbiome data sets in QIIME 2. The availability of longitudinal statistics and visualizations in the QIIME 2 framework will make the analysis of longitudinal data more accessible to microbiome researchers.

q2-longitudinal: Longitudinal and Paired-Sample Analyses of Microbiome Data.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metabolism) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concentration of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid-gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.

Bile Acid-Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside.

Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy.

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 0.05). 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.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1965

Effects of ursodeoxycholic acid on the gut microbiome and colorectal adenoma development.

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 0.05). 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. SUMMARY 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.

/pdf/lack-of-evidence-that-ursodeoxycholic-acid-s-effects-on-the-jkh269ysw2.pdf

Lack of Evidence that Ursodeoxycholic Acid’s Effects on the Gut Microbiome Influence Colorectal Adenoma Risk

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Effects of ursodeoxycholic acid on the gut microbiome and colorectal adenoma development.

Lack of Evidence that Ursodeoxycholic Acid’s Effects on the Gut Microbiome Influence Colorectal Adenoma Risk