Your GI tract is home to an incredibly diverse ecosystem made up of bacteria, archaea, viruses, fungi, and other microeukaryotes. Scientists estimate that the average human gut encompasses over a thousand species of bacteria,1 and we’ve only just begun to understand the significant role they play in our immune system.
More recently, the scientific and medical communities have been abuzz regarding the topic of gut microbiome due to its potential role as a link between the gut and the heart. Specifically, some believe that a metabolic pathway involving choline and the gut microbiota could contribute to the development of heart disease in humans.
But choline is recognized as an essential nutrient for humans. So why does it have some scientists and doctors concerned? And what do fish and red meat have to do with it? Keep reading to find out!
The Importance of Choline
Choline is an essential nutrient naturally present in some foods. It contributes to various metabolic processes in the body, ranging from methyl-group metabolism to neurotransmitter synthesis. Choline is a major dietary source of methyl groups for S-adenosylmethionine (AdoMet), an enzyme substrate required in at least 50 reactions in mammals.2 Choline is also required to make components of cell membranes — phosphatidylcholine, lysophosphatidylcholine, choline plasmalogen, and sphingomyelin.3
Phosphatidylcholine (also known as lecithin) synthesis is important because it is required for the assembly and secretion of very-low-density lipoproteins (VLDL) from the liver. Inadequate phosphatidylcholine can lead to abnormal fatty deposits in the liver, which in turn can result in nonalcoholic fatty liver disease (NAFLD). This disease is the leading cause of liver transplant in the United States. One study of healthy adult subjects showed that 77% of men and 80% of postmenopausal women developed fatty liver and muscle damage when deprived of choline.4 Fortunately, the damage was reversed when the subjects consumed a high-choline diet.
Other studies have shown that animals fed a choline-deficient diet also experienced:5
- Growth impairment
- Renal dysfunction and hemorrhage
- Bone abnormalities
So how do you make sure that you get enough choline?
The good news is that some amount of choline can be acquired through de novo biosynthesis via the methylation of phosphatidylethanolamine to phosphatidylcholine. However, this alone does not meet human requirements. You’ll also want to eat a diet rich in choline. Som choline-rich foods include:6
- Beef liver
- Chicken liver
- Beef top round
- Chicken breast
- Ground beef
- Shiitake mushrooms
- Wheat germ
- Kidney beans
Based on studies reporting liver damage from lower choline intakes, the Institute of Medicine, Food and Nutrition Board recommends 425 milligrams of choline per day for women 19 years of age and older, and 550 milligrams of choline per day for men of the same age group.3
Choline and the Gut Microbiome
By now, you may be wondering, what does the gut microbiome have to do with choline?
It turns out that choline and carnitine are major dietary precursors of a bacterial metabolite called trimethylamine (TMA). Recent studies have identified nine bacterial strains in the human intestine that are capable of producing TMA from choline,7 including:
- Anaerococcus hydrogenalis
- Clostridium asparagiforme
- C. hathewayi
- C. sporogenes
- Escherichia fergusonii
- Proteus penneri
- Providencia rettgeri
- Edwardsiella tarda
- Desulfovibrio desulfuricans
Liver enzymes flavin monooxygenases (FMO1 and FMO3) further convert TMA into another compound known as trimethylamine N-oxide (TMAO), which is then either transported to the tissues or cleared by the kidneys.
In humans, a mutation of FMO3 causes trimethylaminuria, a condition that results in the affected individuals secreting TMA, not TMAO. Trimethylaminuria is also known as the “fish odor syndrome” because it is characterized by a fishy body odor in urine, sweat, breath, and other bodily excretions.8
Scientists once believed that TMAO was just a waste product of choline metabolism, a substance that had no action or significance in the human body. However, there is now a growing body of evidence that suggests a link between TMAO and inflammation.9101112 Other studies have reported that TMAO generated by gut microbiome aggravates impaired glucose tolerance and inhibits insulin signaling, suggesting that it could play a role in the development of type-2 diabetes.1314
In the last decade or so, TMAO has been in the limelight for another reason: cardiovascular disease (CVD).
TMAO and Cardiovascular Disease
In 2011, the scientific journal Nature published a paper titled, “Gut Flora Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease.”15 In it, the researchers stated that supplementation with the three metabolites of phosphatidylcholine — choline, TMAO, and betaine — promoted atherosclerosis, or the buildup of plaque in the arteries. And because atherosclerosis is a major risk factor for heart disease and stroke, some researchers believe that TMAO should be considered a key player.
The mechanism by which TMAO increases the risk of CVD remains unclear. There are several hypotheses, but one of the more popular proposals suggest that higher TMAO levels up-regulates multiple macrophage scavenger receptors that are linked to atherosclerosis.16 It is also believed that TMAO alters the enterohepatic cholesterol and bile acid metabolism, a major pathway by which cholesterol is eliminated from the body.17
When more macrophage scavenger receptors are present, this increases the likelihood of their binding low-density lipoprotein (LDL), leading to the formation of foam cells, known for the foamy appearance they get from ingesting LDLs.16 Foam cells secrete various substances that can lead to plaque growth, and their deaths result in inflammation, both of which contribute to CVD.18
Since the 2011 paper, several studies have supported these findings. Furthermore, recent systematic reviews and meta-analyses of prospective studies reported that TMAO not only increased CVD risk, but that it also raised all-cause mortality risk.192021
As you can imagine, the results from these studies have stirred up debate in the medical and scientific community, with some doctors suggesting dietary adjustments to reduce consumption of TMAO precursors choline and L-carnitine.
Inconsistencies in TMAO Research
But not all studies have demonstrated similar findings. In one study involving 339 patients, researchers noted that while plasma concentration inTMAO were higher in diabetic patients than non-diabetic patients, higher levels were not associated with increased cardiovascular events during eight years of follow-up.22
Another study examined patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack. And what they found was quite surprising. The patients with asymptomatic atherosclerosis showed no obvious differences in the gut microbiota and TMAO levels. However, stroke and ischemic attack patients had significantly more opportunistic bacteria, including many of the strains listed above. Interestingly, this group of patients showed lower, not higher, blood TMAO levels than the asymptomatic group.23
The mixed results from these studies indicate that we do not yet know whether TMAO can accurately predict CVD risk. Therefore, using TMAO as a biomarker to determine the necessity of medical intervention could lead to undesirable effects.
TMAO and Fish — Is Fish Still Good for Your Heart?
One of the most interesting debates that has come out of this research is regarding TMAO and seafood. Most of us have probably been told that eating fish is good for us. It’s lower in fat than other animal meat, it’s a great source of protein, and it’s also high in those heart-healthy omega-3 fatty acids.
So why do some researchers and physicians say fish may not be good for your heart, and why are they pointing their fingers at TMAO? The debate started when studies started reporting increases in urinary TMAO and TMA levels among people who consume fish.24 A study published in 2016 reported that mice fed fish protein had higher serum levels of TMAO than other groups, and that the increase was accompanied by a larger atherosclerotic plaque area in the aorta.25
The increase in circulating TMAO has been replicated in human studies. In particular, one study showed that fish yielded greater increases in circulating and urinary concentrations of TMAO than eggs and beef did. Furthermore, the augmented circulating TMAO levels were measurable within 15 minutes of food consumption, which suggests that TMAO can be absorbed without processing by gut microbes.26
Therefore, if TMAO was associated with increased risk of heart disease, it would only make sense to advise patients to reduce seafood consumption.
However, some disagreed. In a letter to the Journal of the American College of Cardiology, a team of researchers wrote that “the hypothesis that TMAO is directly involved in development of atherosclerosis…seems like a paradox, as intake of seafood is generally accepted as cardioprotective.” They suggested that the conversion of TMA to TMAO may be a detoxifying mechanism by gut bacteria and that the ingestion of TMAO by seafood consumption should not be regarded as “fishy business.”27
Drs. Wilson Tang and Stanley Hazen of the Cleveland Clinic published a response to the letter in the same journal. They argued that many species of fish have virtually no TMAO, and just as how blubber from a fish can have similar fatty acid composition to bacon fat, they warned against the “oversimplification that anything and everything derived from the sea and ingested in any quantity must be ‘heart healthy.’”27
Indeed, while some species of fish have pre-formed TMAO, not all do. From currently available studies, it appears that deep-water fish (such as those found in Arctic waters) tend to have significantly higher levels of TMAO content than shallow-water species (ex: trout).28 Tang and Hazen also pointed out that they were not arguing for or against any specific food types, but that there are certain components (phosphatidylcholine, carnitine) that could contribute to atherosclerotic burden.
The Key to the Heart is in Your Gut
The TMAO and fish debate has not yet been settled. Still, if there is one conclusion we can gather from all of these conflicting studies, it’s that the health and diversity of the gut microbiome could be risk factors for heart disease.
I’ve written extensively about how to heal and/or maintain a healthy gut. You can check out some of my tips in 9 Simple Steps to Heal Leaky Gut Syndrome Fast and Diagnosis and Treatment of Leaky Gut: Part II.
If you are concerned about TMAO, the Cleveland Clinic also recommends eating a diet rich in plant foods and fiber. Another approach is to eat a Mediterranean diet. One study found that 3,3-dimethyl-1-butanol (DMB) — a compound found in olive oil, red wine, and other foods — blocked the formation of TMA and reduced TMAO levels in mice fed a high choline or carnitine diet.29 If future clinical trials show similar results in humans, it could result in a new strategy to treat or even prevent CVD.
Should You Stop Eating Red Meat and Fish?
The bottom line is that even if red meat, fish, and eggs were to raise TMAO substantially, we should remember that these foods have thousands of components that have many biological effects; focusing on one biological effect of a single component simply does not make sense. In addition, the real conversion to TMAO is related more to the microbiome than anything else. I have several cases in my clinic that an elevated TMAO was reversed not simply by changing the diet but by restoring a healthy gut microbiome!
As always, I recommend eating an organic, whole food-based diet and maintaining a healthy gut microbiome. While more research needs to be done to elucidate the link between TMAO and heart disease, I don’t believe that there is enough reason to eliminate red meat and deep water fish completely from your diet.
Now that we’ve discussed the association between TMAO and heart disease, it’s time to hear from you. Have you ever been tested for TMAO? Are you concerned about the research findings showing increased risk of heart disease? Will you be adjusting your diet? Share your thoughts in the comments below!