Kelly Heim, PhD, is a nutritional pharmacologist at Pure Encapsulations and a graduate of Dartmouth Medical School, where he studied molecular pharmacology, epigenetics, and functional genomics. His publications and lectures have highlighted evolving concepts in polyphenol biochemistry, nutritional endocrinology, and nutrigenomics. (Altern Ther Health Med. 2014;20(suppl 1):62-64.)
Alternative Therapies in Health and Medicine (ATHM): What first drew your attention to the cardiovascular benefits of healthy gut flora?
Dr Heim: It has been known for many years that gut bacteria affect metabolism and energy balance. Those are very important determinants of cardiometabolic health. There have been a number of human and animal studies that have determined links between the microbiota composition and how the body harvests and disposes of caloric energy and nutrients. This is a really complex, very interesting, and rapidly evolving area of research, and because of its complexity, focusing on specific strains against really well-defined outcomes, such as the lipid profile, is critical to the development of probiotic products with clear and measurable benefits.
Last spring, we were introduced to some really compelling clinical research on a strain of Lactobacillus reuteri, called NCIMB 30242. This strain was specifically developed for cardiovascular applications because it expressed a high level of an enzyme called BSH, or bile salt hydrolase. There were a number of recent randomized clinical studies—double-blind, placebo-controlled trials—over the past 2 years, and I reviewed them carefully. The studies document very consistent and significant favorable changes in the lipid profile in as little as 6 weeks of supplementation.
ATHM: Can you back up a step and discuss the role of microbiota as a whole and how that might impact cardiovascular health?
Dr Heim: The microbiome, which is the sum total of microbial genes, is an extraordinarily complex organ system that harbors genes that the human genome does not have. These genes encode enzymes, proteins, and many kinds of molecules that allow bacteria to do things that humans cannot do. When we think of the gut bacterial population, it is very overwhelming because there are so many strains there. We are not at the point in research where we can clearly assess the effect of the total microbiome on specific cardiovascular outcomes. We do not have the tools yet, but they are being developed. It is a cross-disciplinary field called systems biology, or OMICS biology. It involves metabolomics, genomics, proteomics, and others.
ATHM: How does that complexity, and the fact that the tools necessary to assess the situation are still being developed, impact the use of probiotics to influence health at this point?
Dr Heim: While the complexity of the microbiome is considerable, we already have a basic, yet powerful tool that brings important scientific findings into clinical practice every day. Probiotics, like any modality, are amenable to the randomized, double-blind, placebo-controlled trial. When this gold standard design evaluates a specific strain against clinically relevant outcomes, we get a clear indication of whether a probiotic is useful for a defined application, at a specified dose. In that order, all principles of evidence-based medicine can be rationally extended to probiotics for enhancement of patient outcomes. While a randomized, controlled clinical trial can yield some insight into mechanism of action, a comprehensive mechanistic understanding requires the newer, more complex systems biology approaches, which are more challenging in terms of methodology, validation, statistical analysis, and interpretation of enormous data sets.
ATHM: So returning to this specific strain for cardiovascular health that was identified, tell us a little more about the mechanism involved in the beneficial effects.
Dr Heim: The bile salt hydrolase enzyme is expressed at relatively high levels in the L reuteri, NCIMB 30242. A lot of lactobacilli do have the gene that encodes this enzyme. But this strain encodes the gene and expresses quite a lot of it relative to other strains. So the result of that enzyme activity is deconjugation of bile acids. The bile acids are made by the liver from cholesterol as a substrate, and they are released into the gut. Deconjugation attenuates the reuptake and reintroduction of the cholesterol.
ATHM: There has been some debate recently over the role of cholesterol in cardiovascular disease and its markers. How does this finding impact that debate?
Dr Heim: Cholesterol is an important, yet limited, component of assessment and monitoring in clinical cardiology and in medicine in general. It is one piece of a large puzzle. The studies on the NCIMB strain have focused on the lipid profile. But it is entirely rational to speculate that, like other lactobacilli, this microorganism might be exerting other cardiovascular benefits, or other metabolic benefits—for example, lactobacilli as a genus. Within that genus, species have been shown to produce peptides that can target angiotensin converting enzyme, or ACE, a very well-known regulator of endothelial function. That is just one of many potential mechanisms by which probiotics can support cardiovascular health. Hopefully research exploring the strain in the current repertoire, which is the NCIMB 30242, against other cardiometabolic measurements, will be forthcoming in the research.
ATHM: Recent literature has supported the idea of inflammation playing a greater role in cardiovascular dysfunction. Have probiotics shown any promise in influencing systemic inflammation?
Dr Heim: We are fascinated by the role of inflammation in the etiology of metabolic syndrome. This is a key component of our ongoing applied clinical research program. It is clear that probiotics do influence inflammatory responses. However, the specific role of probiotics in mitigating inflammation in terms of cardiometabolic health outcomes has yet to be determined.
ATHM: Other sources discuss infection as another variety of insult that can manifest as cardiovascular disease. Might the gut biome also play a role here?
Dr Heim: This is a plausible question. It has a complex answer that is currently elusive and demands considerable cross-disciplinary research. The gut bacteria account for a large part of our natural immune defenses, and the immune system is highly relevant to cardiology. But whether the gut biome lies at the functional confluence of infection and cardiovascular risk remains unknown. Speculation of a 3-part relationship here is reasonable, theoretically. We know that the immune system, when it is activated and stimulated by something, orchestrates the release of cytokines, chemokines, and reactive oxygen species, all of which can affect the vascular endothelium and critical aspects of metabolism, glucose homeostasis, and energy balance. So perhaps there is a relationship, but it is very early in the investigational process, so we can only speculate.
ATHM: Might there be any other pathways that might tie cardiovascular dysfunction to gut health?
Dr Heim: Yes, very possibly. The digestive tract is the most complex system in the body, and its health ramifies globally to systemic physiology through a number of pathways that include neuronal, immunologic, endocrine, and other types of signaling networks. Whether the link between the gut and cardiovascular health involves these types of mechanisms is still a question at this point.
ATHM: What has research shown about our ability to modulate these types of responses with diet and/or supplementation? Should we be looking at these more from a preventative perspective, or more for therapeutic potential?
Dr Heim: Obviously the randomized controlled trials on the NCIMB 30242 strain have not addressed prevention. We know that the strain is very effective for maintaining a healthy lipid profile over a short 6- to 9-week course of supplementation. But ideally, in the preventive scheme of good health, it is ideal to combine a supplement with a healthy diet and lifestyle, because these are backed by very large studies and epidemiological data that strongly support preventive value.
ATHM: How does diet work to drive the impact of the microbiome?
Dr Heim: What you eat can definitely affect the ability of probiotics and the gut bacteria that are already there to work optimally. Eating a healthful diet that is rich in polyphenols is one example. Polyphenols are potentially highly selective prebiotics and synbiotics that can support favorable shifts in the gut microbial community, and some of the health benefits might be due to that shift. We know this because these large, high molecular weight compounds that we get in fruits and vegetables, many of which are polyphenols, do not get absorbed. So how could they be working? We know they are working because they work in clinical studies. But you cannot see them in plasma. So at the interface of these very powerful compounds that appear to have 0% bioavailability—we are talking about tannins and proanthocyanidins, with 0% bioavailability—how can they exert these very consistently documented health benefits? They are basically altering the gut microbial communities in a favorable, healthy way. So that is an exciting area of research, and it brings together dietary supplements that we would not ordinarily think of being useful in supporting the microbial population and ecosystem in our intestinal tract. But we are all familiar with prebiotics like fructo-oligosaccharides, or FOS, and they definitely have a place here. But I think in the course of discovery of new strains that are useful clinically, we will also discover new synbiotics that can help support the bacteria that are already there and help them to work in a way that makes us healthier.
ATHM: When considering probiotics for therapeutic use, what should a clinician’s main concerns include?
Dr Heim: With probiotics, it is definitely important to look at the research. For general digestive and immune applications, efficacy has been documented across a range of species and strains. Both single strains and multistrain formulations have value in clinical practice. For specific applications like cardiovascular health, it is prudent to look at researched strains that have produced relevant clinical benefits in studies. You want the right strain at the right dose, and the evidence to support how much to use, and for how long, and what to expect. A final take-home message is the importance of product stability and quality. Stability ensures full label claim by the time the patient takes the product, which can sometimes be 6 months after the product has been in the patient’s kitchen or refrigerator.
ATHM: When taking a probiotic for a specified period, will the seeded strain sustain itself once supplementation is discontinued? How do the influences of dietary contaminants, such as pesticides or antibiotics, affect the need to repeat supplementation cycles or even require continuous supplementation?
Dr Heim: This is a very important point to make when talking about probiotic research and translating the research to the clinic. Research is limited for a number of reasons. We are limited in the conclusions that we can make. One hurdle is the considerable interindividual variations of the microbiome. So it is difficult to recruit subjects, or a cohort of individuals, and expect baseline levels of microbial metabolites to be the same. So there is considerable interindividual variability in the microbiome. Secondly, the microbiome is constantly interacting with a person’s diet, their lifestyle, and their genetics. So it fluctuates in terms of what it is doing, the metabolites that it is making, and the proteins that it is expressing. If researchers can ultimately identify and validate biomarkers of a healthy microbiome and an unhealthy microbiome, that would be wonderful. But we have a long way to go. So we do not have clear data on how the microbial communities shift in response to supplementation. It seems to be different in everyone. To really make a broad statement about what to expect in terms of colonization, there is not enough information available. When antibiotic use enters the picture, an evidence-based approach is prudent. Some specific strain combinations have been studied in conjunction with antibiotic use and have demonstrated maintenance of microbial diversity. Again, it is important to follow the data and look for measured outcomes attributed to specifically defined interventions.