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.

Detailed description

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.

Interventions

• Dietary supplement 7-KLCA
  This study will be conducted as a 16 week duration parallel study. The trial will last for 112 days (16 weeks, includes a 1 month washout period and a follow up study visit to assess lasting effects) maximum, with participants assigned the intervention (400mg, taken once daily, 7-KLCA in tablet form) or maltodextrin placebo (also in matched tablet form) for 84 days.
• Dietary supplement Maltodextrin
  This study will be conducted as a 16 week duration parallel study. The trial will last for 112 days (16 weeks, includes a 1 month washout period and a follow up study visit to assess lasting effects) maximum, with participants assigned the intervention (400mg, taken once daily, 7-KLCA in tablet form) or maltodextrin placebo (also in matched tablet form) for 84 days.

Primary outcome measures

• Gut Microbiome Composition [Time frame: Baseline, Weeks 4, 12 and 16]

Secondary outcome measures (2)

• Change in production of SCFA by the gut microbiota [Time frame: Baseline, Weeks 4, 12 and 16]
• Blood markers of health [Time frame: Baseline, Weeks 4, 12 and 16]

Eligibility criteria

Inclusion criteria

• Volunteer is healthy (good physical and mental condition, disease-free, with haemoglobin levels between 138 - 172 g/L for male and between 121 and 151 g/L for female) at the time of pre-examination
• Volunteer is aged ≥ 18 to ≤ 65 years for the duration of the study
• Volunteer is able and willing to comply with the study instructions
• Volunteer is suitable for participation in the study according to the investigator/study personnel
• Volunteer is able to give informed consent
• Volunteer must be following a non-restrictive diet according to the investigator/study personnel (no vegan, keto or fasting diets)
• Volunteer has not consumed pro- or prebiotic supplements or food products for a minimum of 4 weeks prior to starting the intervention.
• Volunteer has no gastrointestinal disorders

Exclusion criteria

• No command of any local language
• Gastrointestinal disorders including IBS, IBD or other conditions that might affect the gut environment
• Food allergies or intolerances
• Using drugs (e.g. antibiotics) influencing gastrointestinal function (12 weeks before intervention)
• Use of laxatives
• Clinically significant diabetes (plasma glucose test, fasting blood glucose > 6.5 mmol/l (120 mg/dL)
• Volunteers currently involved or will be involved in another clinical/ food study for the duration of this study
• History of drug (pharmaceutical or recreational) or alcohol abuse.
• If participants are pregnant or are lactating
• Regular intake of probiotic or prebiotic supplements
• Smoker
• Those who follow extreme diets (Keto-diet, Atkins diet, vegan)
• Those taking prescribed medication for existing health condition(s)
• Those with a pacemaker

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Prevention

Study locations

United Kingdom · 1 center

• Hugh Sinclair Unit, Harry Nursten Building, University of Reading, Whiteknights Campus, RG — Reading

Identifiers

NCT: NCT07499414 · BioMet-7

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗