CardioSource WorldNews | Evidence suggests that the gut microbiota plays a critical role in both the maintenance of human health and the pathogenesis of many diseases. Indeed, the supporting data are growing about as rapidly as bacteria do. Which is fast, superfast. Could dysbiosis (microbial imbalance) be causal of cardiometabolic disorders, including obesity, diabetes, and cardiovascular disease, and, if so, could the way to a healthy heart be through a man’s (or woman’s) stomach—and digestive system? It’s so exciting that renowned American biochemist Rob Knight (a professor at the University of California, San Diego and co-founder of the American Gut Project), told the journal Nature that this field offers at least as much promise as stem cell research. It’s an enthralling concept as investigators aim to unearth the mysteries of the human gut.

“I honestly think that we are entering a whole new frontier in our appreciation of physiology,” said Stanley Hazen, MD, PhD, FACC, chair of the Department of Cellular and Molecular Medicine at the Cleveland Clinic, in an interview with CardioSource WorldNews. “We used to be so focused just on Homo sapiens, but we are now realizing that much of our physiology is not just based on the Homo sapiens enzymes but also on all of the enzymes and functionality that the gut micro-community brings.”

Seems like everybody has a gut feeling about the microbiome these days. It’s not just gastroenterology that has a keen interest, but immunology, neurology, psychiatry, obstetrics and gynecology, bariatrics, rheumatology, and, yes, cardiology are all studying it as well. They are turning to our guts to better understand the mechanisms of health and disease. There are even anthropologists applying genomic and proteomic sequencing technologies to ancient human microbiomes, and to modern guts from both traditional and industrialized societies, in the hopes that they will gain a better understanding of our microbial history and its impact on human health and disease.

Food Is Medicine (Still)

No matter which way you slice it or dice it, the food we eat represents our greatest environmental exposure. Despite a tendency to avoid the topic clinically, it’s well demonstrated that food greatly impacts the organism. But what’s changing is our thinking about the ways in which food influences physiology, evolving from a fairly rudimentary assessment of calories and nutritional content, to encompass bacteria colonies numbering in the trillions who just happen to call our bodies’ home.

“It is widely accepted that obesity and associated metabolic disease, including type 2 diabetes, are intimately linked to diet,” wrote Justin L. Sonnenburg, PhD, and Fredrik Backhed, PhD, in a recent review in Nature.¹ Only in the last decade or two, however, have the gut microbiota become a prime focus for understanding the intersection of diet and metabolic health.

It is not only “reasonable to consider what proportion of metabolic problems in humans could be addressed by properly caring for the gut microbiota,” wrote Drs. Sonnenburg and Backhed, but it is also important to understand the risk of disruption of the microbial ecosystems at crucial time points, such as in early life or via repeated use of antibiotics.

Dr. Sonnenburg heads a laboratory at Stanford University Medical School dedicated to the study of the intestinal microbiome and Dr. Bäckhed is from the Wallenberg Laboratory for Cardiovascular and Metabolic Research at the University of Gothenburg, Sweden.

The Gut as Endocrine Organ

Officially the endocrine system is made up of a network of glands that secrete hormones to regulate bodily functions, including growth and metabolism. These glands include the hypothalamus, pineal gland, pituitary gland, thyroid, ovaries, testes, and more.

We don’t usually count the human gastrointestinal tract as an endocrine organ, but with 30 trillion plus bacteria encompassing hundreds or thousands of bacterial taxa, and continually converting nutritional cues into hormone-like symbols that impact the human host, it’s fair to regard the gut as a command and control center in the body.

Dr. Hazen, who also is the Cleveland Clinic’s Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis, thinks it’s time we realize that the gut microbiome is an endocrine organ. “The microbiome is constantly making compounds, some of which are biologically active and act like hormones. They fulfill all the requirements of a hormone: a biologically active entity that diffuses in the bloodstream and act on a distant site. It’s just that what gets made by this endocrine organ depends on what you feed it and what its composition is, so it’s a somewhat dynamic and plastic endocrine organ, but it still impacts host disease susceptibility.”

Already gut microbes have been implicated in a broad range of physical, neurological, inflammatory and autoimmune conditions, including allergy, inflammatory bowel disorder, Crohn’s disease, and asthma. We also can gorge on a substantial amount of evidence that links the gut to metabolic disease and our microbiota are causally linked to fat gain and impaired glucose metabolism.² Indeed, gut bacteria appear to influence appetite, fat creation, and insulin sensitivity through varying mechanisms, suggesting that direct targeting of the gut microbiome could offer an effective means of treating cardiometabolic disease.

A direct role is evident between gut-derived metabolites and cardiometabolic disease, with the effects being both positive and negative. One example: the metabolism of carbohydrates by gut bacteria results in the production of short-chain fatty acids, such as butyrate and propionate, which provide an important source of nutrients as well as regulatory control of the host digestive system. Another example: microbiota-derived metabolites that enter circulation and stimulate inflammation.

The Microbiome and CVD

Metabolic products produced by the gut appear to induce an inflammatory response that may be causal for insulin resistance, metabolic syndrome, obesity, diabetes, and atherogenesis. With the gut playing such a key role in the inflammatory status of the host, it seems highly unlikely that it would not also exert an effect on the King of Inflammatory Disease: cardiovascular disease.

Dr. Hazen has served as principal author on a series of key clinical and mechanistic studies linking the gut microbiome to CVD risks. Using a metabolomics approach as a discovery tool, his team has shown how resident gut commensal microbes (normal microflora) in subjects at risk for cardiac disease are more apt to turn dietary phosphatidylcholine – mostly obtained by eating eggs, meat, and fish – into trimethylamine (TMA), which is further oxidized in the liver into trimethylamine N-oxide (TMAO).

Choline, a semi-essential nutrient found in every cell in the human body, holds various metabolic roles, including serving as a building block of cell membranes and assisting in the production of the neurotransmitter acetylcholine. But TMAO, as has been shown in a Dr. Hazen’s studies, appears to be causally related to cardiovascular disease.

Dr. Hazen’s group has published an array of TMAO studies since 2011, and, more recently, other groups are adding their two bits to the mix. Here are some key TMAO studies to date:

Gut microbes convert dietary choline (think liver, egg yolk, and peanuts) into TMAO, and elevated circulating TMAO accelerates atherosclerosis in mouse models. In humans, elevated plasma TMAO is associated with cardiovascular disease risk.³

Measurement of phosphatidylcholine-converted TMAO levels in more than 4,000 subjects followed over time revealed that plasma levels predict future risk of myocardial infarction, stroke and death risk.⁴ Gut microbes also figure into TMAO formation from dietary L-carnitine; another large-scale clinical study linked plasma carnitine levels to incident cardiovascular risks, but only among those with concurrently high TMAO.⁵ The researchers also found that omnivorous participants produced more TMAO than did vegans or vegetarians after ingestion of L-carnitine, which is found mostly in red meat and is metabolized in the gut into TMA and TMAO.

Fasting plasma levels of choline and carnitine levels were predictive of an increased risk of major cardiovascular events after adjusting for traditional risk factors in stable cardiac patients undergoing elective coronary angiography—but, again, only if TMAO levels are high. That certainly is consistent with TMAO driving the association with CVD risks.⁶

High TMAO levels are elevated in heart failure patients (compared to subjects without HF) and are associated with a 3.4-fold increased mortality risk independent of traditional risk factors and cardiorenal indices.⁷

In a mouse model, atherosclerosis susceptibility (as defined by plaque burden) was transmitted using fecal microbial transplantation.⁸

Plasma TMAO levels are elevated in patients with chronic kidney disease and are associated with poorer survival and CVD risks, and chronic choline or TMAO feeding in mice resulted in impaired renal function.⁹

The TMAO-generating enzyme flavin monooxygenase 3 (FMO3) is a key regulator of cholesterol/lipid metabolism and inflammation.¹⁰

TMAO levels correlated with thrombosis potential in > 4,000 patients and increased platelet activation. In mice fed an excess of choline, gut-generated TMAO heightened platelet hyper-reactivity and thrombosis potential in vivo.¹¹

In a prospective study, fasting TMAO levels were independently predictive of coronary vessel atherosclerotic burden as quantified by SYNTAX scores and lesion characteristics,¹² while another study showed that elevated TMAO increased mortality risk among patients with stable CAD managed with optimal medical treatment.¹³

Dietary phosphatidylcholine intake has been linked to an increased risk of type 2 diabetes in three U.S. populations¹⁴ and to increased all-cause and CVD mortality in >100,000 women and men—especially in those with diabetes—who were followed for over a quarter century while enrolled in the Nurses’ Heath Study and the Health Professionals Follow-up Study.¹⁵

OK, so how do you change the situation? Inhibiting microbial TMA formation reduces the formation of atherosclerotic lesions.¹⁶ A compound called 3,3-dimethyl-1-butanol (DMB) inhibits TMA and DMB is found naturally in many foods included in the Mediterranean diet plan, including some balsamic vinegars, cold-pressed extra virgin olive oils, grapeseed oils, and red wine.

“I think the coolest thing about the thrombosis paper in Cell¹¹ was that we pretty much showed that you could transfer an elevated risk of thrombosis by taking gut microbes from a high TMAO-producing, thrombosis-prone mouse and transplanting them into germ-free mice,” said Dr. Hazen in an interview. “It’s such a weird idea to think our gut microbes are impacting how much we might be at risk for hemorrhaging after an injury, or, literally, thrombosis potential. These studies show our risk for MI and stroke are linked to our diets and dependent on our gut microbes.”

Of course, the million-dollar question is: what do you do with a high TMAO level? (There is now a commercially available clinical assay for it.) It remains to be seen whether there is clinical benefit to altering diet to reduce TMAO or whether we find other factors besides diet and microbiota that influence TMAO levels or their effect on the vasculature. But studies have already shown that subjects adhering to a Mediterranean diet have lower TMAO and this diet reduces heart disease risks.

Dr. Hazen, who is also section head of Preventive Cardiology at the Cleveland Clinic, noted that high blood TMAO levels serve as a strong and independent predictor of incident CVD risk; consequently, he thinks more aggressive global preventive efforts with a high TMAO would seem reasonable. To be clear, Dr. Hazen says much more research is needed, and he and others are looking at numerous gut-mediated pathways to atherogenesis and inflammation; it is just that TMAO is the furthest along.

What About Inflammation?

Does TMAO link the gut and atherogenesis? It may be part of the connection, but there is likely more, according to Peter Libby, MD, FACC, the Mallinckrodt Professor of Medicine at Harvard Medical School, Boston, MA.

Oxidized lipids have been thought to be an important initiating stimulus for atherosclerosis; however, the evidence to show this in humans is actually “awfully slim,” he said in an interview. Besides being a cardiologist at Brigham and Women’s Hospital in Boston, MA, Dr. Libby is an editor of Braunwald’s Heart Disease and a world leader in the area of atherogenesis, inflammation, and vascular biology.

“For want of better guesses, we all—including myself and all textbooks and review articles—show that oxidized LDL is the initiating stimulus, but I don’t think that the evidence that supports that is rock solid,” said Dr. Libby.

“And that’s why it’s intriguing that we have a greater understanding of the human microbiome, not just in the gut but also in places like the periodontal space, and that an alternative or complementary hypothesis to the oxidized LDL hypothesis as a trigger for inflammation in atherosclerosis might be products of infectious agents.”

Dr. Libby suspects that leakage of gut microbial products, due to impaired barrier function in the intestinal epithelium, may switch on inflammatory signaling networks that can be identified and targeted clinically.¹⁷

This doesn’t mean TMAO is out. On the contrary, Dr. Hazen’s work has been “eye-opening” said Dr. Libby, but he suspects there are other important aspects of the relationship we have with our commensal microbial organisms that interact with vascular cells and inflammatory cells.

Any Recommendations?

Fecal microbial transplantation offers one possibility for repairing or rehabilitating a dysfunctional microbiome, but—let’s face it—that’s not one likely to be embraced by the masses any time soon [see the sidebar Sharing Your Microbes with Friends]. Let’s all imagine being asked to come up with a glossy ad campaign to support that service.

The appeal of fixing your health by fixing your microbiome through dietary means is more than enough of a catalyst to drive industry into a bug-feeding frenzy. But is the science advanced enough to establish clinical guidelines, or even suggestions? CSWN asked Drs. Hazen, Sonnenburg, and Libby what clinical recommendations they feel can be made based on the evidence we have today:

The Mediterranean diet is “the way to go,” said Dr. Hazen, citing the PREDIMED trial.¹⁸ PREDIMED showed a 30% reduction in adverse cardiovascular events with a Mediterranean dietary pattern supplemented with extra virgin olive oil or nuts compared to a low-fat, low-cholesterol diet. He added that most people should probably not be taking probiotics for cardiovascular disease prevention purposes.

“I would argue that we are way far away from being able to say ‘Okay let’s absorb this set of microbes and it’s going to be healthy for your heart,’” said Dr. Hazen. “The microbial community is so complicated—I give the analogy of taking a probiotic and assuming it’s going to end up in the right location to delivering mail just to the front door of the Empire State Building. You deliver the mail by shoving it through the mail slot at the front door and hope that all the envelopes go to their right address in the building.”

Microbiologist, Erica Sonnenburg, PhD, the other half of the Sonnenburg team that wrote The Good Gut [see sidebar Field Notes: Further Reading], feels that one of the problems is the American diet, which is high in processed foods that the Sonnenburgs say has led to a “mass extinction event,” affecting species of bacteria that had lived in our bodies for most of human history. We can do better, she said, and admits to being incredulous as to why more people haven’t adopted a Mediterranean diet pattern. Also, based on current understanding of the microbiota, she agrees that there is “very little evidence” to say people should be taking probiotics for most conditions.

“What is so shocking to me is that there has been every type of study, including the gold standard prospective, blinded, placebo-controlled trials, showing that consumption of dietary fiber reduces the risk of all-cause mortality and we know that dietary fiber influences the gut microbiota, even if we haven’t figured out the exact details yet. So, we often wonder if after we do all of this work charting the microbiota and developing therapeutics, if there is going to be anything that we develop that’s going to be better than just eating more dietary fiber. I don’t think so.”

For his part, Dr. Libby favors prevention: “We use antibiotics promiscuously in our society; they are abused both in agriculture and in medicine,” he said. Beyond the issue of antibiotic resistance, “we know that antibiotics change our microbial flora and the health consequences of that need to be considered. […] So, rather than trying to repair an altered microbiome, why don’t we learn to use antibiotics more appropriately, both in agriculture and in medicine?”

There may not be any earth-shattering clinical recommendations to be made at this point in the microbiome game, but most who are involved feel we are fast approaching a time when the gut will become an important treatment target for multiple conditions, and perhaps offer some “cures” hitherto undiscovered.

As Valentin Fuster, MD, PhD, MACC, physician-in-chief of the Mount Sinai Medical Hospital and editor-in-chief of JACC, recently summarized, referring specifically to the gut metabolite TMAO: “I’m not entirely certain how far this field will go, but better we watch it.”

References:

1. Sonnenburg JL, Bäckhed F. Nature. 2016;535:56-64.
2. Backhed F, et al. Proc Natl Acad Sci U S A. 2004;101:15718-23.
3. Wang Z, et al. Nature. 2011;472:57-63.
4. Tang WH, et al. N Engl J Med. 2013;368:1575-84.
5. Koeth RA, et al. Nat Med. 2013;19:576-85.
6. Wang Z, et al. Eur Heart J. 2014;35:904-10.
7. Tang WH, et al. J Am Coll Cardiol. 2014;64:1908-14.
8. Gregory JC, et al. J Biol Chem. 2015;290:5647-60.
9. Tang WH, et al. Circ Res. 2015;116:448-55.
10. Warrier M, et al. Cell Rep. 2015. pii: S2211-1247(14)01065-1.
11. Zhu W, et al. Cell. 2016;165:111-24.
12. Senthong V, et al. J Am Coll Cardiol. 2016;67:2620-8.
13. Senthong V, et al. J Am Heart Assoc. 2016;5. pii: e002816.
14. Li Y, et al. Diabetes Care. 2015;38:e13-4.
15. Zheng Y, et al. Am J Clin Nutr. 2016;104:173-80.
16. Wang Z, et al. Cell. 2015;163:1585-95.
17. Libby P, et al. J Am Coll Cardiol. 2016;67:1091-103.
18. Estruch R, et al. N Engl J Med. 2013; 368:1279-90.

Read the full August issue of CardioSource WorldNews at ACC.org/CSWN

Keywords: CardioSource WorldNews, Bacteria, Cardiovascular Diseases, Diabetes Mellitus, Dysbiosis, Stomach, Gastrointestinal Contents

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