“ I honestly think that we are entering a whole new frontier in our appreciation of physiology ,” said Stanley Hazen , MD , PhD , 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 .”
A direct role is evident between gut-derived metabolites and cardiometabolic disease , with the effects being both positive and negative .
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
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