The Effects of the Bile Acid Supplement, 7-keto Lithocholic Acid, on Human Gut Microbiota and Risk Factors for Disease.

Overview

In humans and most mammals, bile acids play a role in the metabolism of glucose and the transport and absorption of lipids (such as cholesterol and triglycerides), vitamins, and nutrients by allowing for emulsification (mixing) and absorption of fatty molecules that are consumed. More recently, bile acids have been discovered to influence the composition and quantity of the microorganisms in the gut microbiome. Bile acids also act as signalling molecules (like hormones) in the body, regulating important metabolic pathways and digestion. While the majority of bile acids are recycled back to the liver, a small proportion of these bile acids enter the colon and interact with the gut microbiota. Primary bile acids, synthesized in the liver, are essential for the absorption of fat- and fat-soluble vitamins, as part of the digestive process. These primary bile acids are converted to secondary bile acids by gut bacteria, which have been shown to have benefits to health. This provides the rationale for exploring the use of a bile acid, in this case 7-keto lithocholic acid (7-KLCA), as a beneficial modulator of the gut microbiome, to help regulate metabolic and potentially other disease pathways.

Bile acids are small, naturally occurring molecules that play a vital role in the metabolism of glucose and lipids. Bile acids are classified as primary or secondary. Primary bile acids are made from cholesterol in the liver, where they form bile salts and are transported into the gall bladder before finally being secreted into the stomach, as part of the digestive process. \~95% of bile acids are recycled back to the liver, but a small proportion enters the colon and interacts with our gut microbiome. In the gut, these primary bile acids are converted to secondary bile acids (by our gut bacteria), and act as secondary signalling molecules that can affect health. Recent discoveries show that bile acids directly affect the gut microbiome. In fact, ursodeoxycholic acid (UDCA), a secondary bile acid, has a long history in medicine. Though currently used to treat liver diseases, treatment with UDCA has been found to increase the beneficial bacteria Faecalibacterium prausnitzii and reduce levels of hydrogen- and methane-producing bacteria in the gut. Therefore, there is potential to use UDCA (and UDCA-like molecules) as a prebiotic-like molecule that can be used by our gut microorganisms to promote beneficial bacteria in the gut and lead to a health benefit. The bile acid 7-keto lithocholic acid (7-KLCA) is metabolised in the gut to produce UDCA. Using our in vitro fermentation models, UDCA and 7-KLCA were evaluated and found to increase the incidence of the beneficial microorganisms: Lactobacillus, Eubacterium rectale and Bifidobacterium spp. Changes in downstream bacterial metabolites and increases in short chain fatty acids also were observed. Our in vitro fermentation results, coupled with our in vitro cell culture studies, suggest there may be additional mechanisms by which UDCA and UDCA-like molecules exert their beneficial effects. This study aims to assess in vivo, via a human intervention study, the prebiotic potential of 7-KLCA, as a bile acid supplement, and how microbial changes in the gut can improve biomarkers, indicative of beneficial metabolic and microbiome function and reduce risk factors of disease. In preparation for this study, 7-KLCA has undergone toxicology, absorption, and bioavailability studies to ensure it is safe for human consumption. Blood faecal and urine samples will be obtained at key points in the study, to assess microbial changes (bacterial count and composition, as well as metabolite profiling analysis; fatty acid, bile acid and lipids) and monitor key biomarkers (blood glucose and cholesterol, and indicators of inflammation and immune response), to address our primary and secondary research questions.