The dark matter of the gastrointestinal microbiome, where yet to be fully discovered bacteria reside, is being steadily explored and some of the related inhabitants have been linked to the production of an enzyme that can convert artery clogging cholesterol into a more harmless form that is not absorbed by the body.
In two groundbreaking studies published in Nature Microbiology and Cell, researchers have uncovered the potential of specific gut bacteria to reduce cholesterol levels, paving the way for novel therapeutic approaches to combat cardiovascular disease. The Nature study focused on a bacterial strain, Bacteroides SP3-5A3, isolated from an individual with exceptionally low cholesterol. Subsequent experiments in mice revealed that this strain could convert cholesterol into coprostanol, a non-absorbable form, that is excreted in faeces effectively lowering cholesterol levels.
Complementing these findings, the Cell paper identified another bacterial species, Oscillibacter, that plays a crucial role in cholesterol metabolism. Researchers discovered that individuals with higher levels of Oscillibacter in their gut microbiome had significantly lower levels of blood cholesterol.
Through a series of experiments, the team found that Oscillibacter produces an enzyme called cholesterol dehydrogenase/isomerase, which initiates the breakdown of cholesterol into metabolites that can also be excreted from the body. Notably, when Oscillibacter was introduced into the gut microbiome of mice, their cholesterol levels decreased substantially.
These discoveries further highlight the evolving understanding of the intricate relationship between the gut microbiome and cholesterol homeostasis, opening up new avenues for developing microbiome-based therapies. Potential applications (subject to any adverse related changes in the microbiome) include probiotic supplements containing cholesterol-metabolising bacteria or targeted nutritional interventions to modulate the gut microbiome composition.
These interventions offer a natural and potentially safer alternative to existing cholesterol-lowering medications, which can have adverse side effects. Moreover, they underscore the importance of maintaining a balanced and diverse gut bacterial community for overall health.
Gut Microbiota in health and CVD
Accumulating evidence, much of which is well presented in this paper published in Mol Biomed in 2022, point to a pivotal role of gut microbiota and their metabolites in the development and potential treatment of cardiovascular diseases (CVDs) and type 2 diabetes (T2D)[1]. Dysbiosis, an imbalance in the gut microbial community, has long been linked to chronic inflammation, production of harmful metabolites, and disease progression, suggesting that modulating the gut microbiome to restore eubiosis (a balanced gut microbiome promoting optimal digestive health and function) could be a novel therapeutic target[2]. The gut microbiota are known to influence various physiological processes, including energy intake, metabolism, and insulin sensitivity, which are closely associated with the pathogenesis of CVDs and T2D.
Several safe interventions have shown promise in regulating gut microbiota composition and their metabolic byproducts, potentially offering new therapeutic strategies for these conditions. Exercise training and dietary modifications to include fibrous foods and probiotics have been demonstrated to favourably modulate the gut microbiome[3].
Faecal microbiota transplantation (FMT), the transfer of gut microbiota from a healthy donor to a recipient, has emerged as a promising approach for treating CVDs[4]. FMT has been shown to alter the gut microbiome composition, improve glucose homeostasis, and reduce blood pressure. However, its widespread application is currently limited due to potential adverse effects and the need for further safety evaluations.
The role of bile acids (BAs), metabolites produced by the gut microbiota, in CVDs remains controversial, with some studies suggesting beneficial effects, while others do not support such associations. Further research is needed to elucidate the mechanisms by which gut microbiota-derived metabolites, including BAs, influence disease susceptibility and to develop targeted therapies for CVDs and T2D[5].
Microbial immune impacts on CVD
The connection between the immune system and cardiovascular disease, as well as the role of gut microbiota, is a key area for research and revolves around the dynamic interactions among the gut microbiota, their by-products, and the host’s immune defences[6]. These interactions can trigger the onset of prevalent CVDs, such as coronary artery disease and high blood pressure.
The gut microbiota contributes to nutrient absorption, metabolic processes, and immune functions. Alterations in its composition can impact the host’s metabolism, immune system, and the integrity of the gut barrier. The immune system, which consists of the innate and adaptive branches, engages with the gut microbiota and its metabolic products, affecting the cardiovascular health of the host and promoting the development of CVD[7].
For example, atherosclerosis is linked to an increase in inflammation-promoting microbiota and a decrease in those that produce fermentation, resulting in lower levels of short-chain fatty acids (SCFAs) that help prevent plaque build-up. Furthermore, hypertension is associated with changes in the gut microbiota composition, such as reduced diversity and a higher ratio of Firmicutes to Bacteroidetes, which can influence blood pressure control. In essence, the gut microbiota and its metabolic outputs are pivotal in the immune-related mechanisms driving the progression of CVD.
The concept of the microbe-gut-heart axis succinctly illustrates how the gut microbiota is linked to cardiovascular diseases through theories of dysbiosis and bacterial translocation. Consequently, treatments like dietary modifications, the use of antibiotics, probiotics, and faecal microbiota transplantation from healthy donors are currently being applied or will be strategically employed in clinical practices. These approaches aim to mitigate symptoms and slow the progression of CVDs in patients.
Ultimately the creation and sustaining of a healthy gastrointestinal bacterial community is becoming harder, as we lose key species due to changes in dietary practices and loss of bacterial diversity in soils. Consuming fermented foods and probiotics derived from well-studied strains is considered a positive move, as well as the ingestion of a multitude of fibrous foods as part of a consistent food choice[8].
High protein intake such as recommended by the paleolitic diet may also be of benefit but the quality of studies have created some confusion[9]. A meta-analysis published in 2022 was able to parse out a clearer set of clinically relevant benefits, albeit the impact on the microbiome and its upstream effects are not included[10].
Conclusion
Studies have demonstrated that probiotics can lower levels of LDL (low-density lipoprotein) cholesterol and total cholesterol in individuals with diverse cholesterol profiles, in addition to promoting better gut health and metabolic activity.
The current available probiotic strains identified for these benefits include Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus reuteri NCIMB 30242, and a composite probiotic mix that includes Bacillus, Saccharomyces, Streptococcus, Clostridium, Lactobacillus.
These probiotics contribute to cholesterol reduction through several mechanisms, one of which is the activity of bile salt hydrolase that interferes with micelle formation, leading to reduced cholesterol absorption. They also generate short-chain fatty acids (SCFAs) that suppress cholesterol synthesis and enhance lipid metabolism. Furthermore, probiotics have a positive effect on the gut barrier’s integrity, alter the composition of gut microbiota, and play a role in immune regulation[11].
References
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[9] Ghaedi E, Mohammadi M, Mohammadi H, Ramezani-Jolfaie N, Malekzadeh J, Hosseinzadeh M, Salehi-Abargouei A. Effects of a Paleolithic Diet on Cardiovascular Disease Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Adv Nutr. 2019 Jul 1;10(4):634-646.
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