Is Choline Good or Bad for Your Heart? Unveiling the Gut Microbiome Link

According to new research in the Current Nutrition Reports, choline, a vital nutrient, plays a balancing act in health. Deficiency is linked to problems like NAFLD, while excess might worsen NAFLD and potentially increase cardiovascular disease (CVD) risk. Gut bacteria convert choline to TMAO, a potential CVD culprit. Individual gut microbiota composition significantly influences choline metabolism. Maintaining a balanced choline intake and promoting gut health through a healthy diet rich in fibre and prebiotics are crucial. Future research explores personalised medicine approaches based on individual factors to optimise choline metabolism and reduce cardiometabolic disorders. By understanding the complex interplay between choline, gut microbiota, and TMAO, we can develop effective strategies for promoting optimal health

Key Findings.

1. Choline: A Balancing Act: Choline is essential for health, but both deficiency and excess intake can be problematic. Deficiency links to NAFLD and cognitive decline, while excess might worsen NAFLD and potentially increase CVD risk through TMAO production by gut bacteria.

2. TMAO: The Gut Microbiota Connection: Gut bacteria can convert dietary choline to TMAO, a potential culprit in CVD. TMAO may promote atherosclerosis by increasing cholesterol uptake in macrophages, inducing endothelial dysfunction, and contributing to blood clots.

3. The Gut Microbiota's Complex Role: Gut microbiota composition significantly influences choline metabolism. Specific bacteria influence TMAO production, highlighting the importance of gut health for optimal choline utilization.

4. NAFLD and the Choline Conundrum: Choline deficiency can lead to NAFLD, but some studies suggest excess choline might worsen it through inflammation and fibrosis. Maintaining a balanced choline intake is crucial for NAFLD prevention.

5. Dietary patterns matter: Don't demonise choline-rich foods like eggs in isolation. Consider the overall dietary context. Healthy dietary patterns with fruits, vegetables, and whole grains might counteract the potential negative effects of choline on CVD risk.

6. The Future of Gut Health Modulation: Prebiotics, food sources for beneficial gut bacteria, could be a promising strategy. They might reduce TMAO production, influencing choline metabolism for improved cardiometabolic health.

7. Personalized Medicine for Optimal Choline Management: Individual genetic variations and gut microbiota profiles impact choline needs and TMAO risk. Tailoring dietary and potential probiotic interventions based on individual assessments could be a future direction for optimizing choline intake and preventing cardiometabolic disorders.

Choline, a vital nutrient for human health, plays a critical role in various biological processes. It serves as a precursor for the synthesis of phosphatidylcholine, a major phospholipid component of cell membranes. Additionally, choline is essential for the production of acetylcholine, a key neurotransmitter involved in memory, learning, and muscle function Choline also functions as a methyl donor through its conversion to S-adenosyl-L-methionine (SAM), which is crucial for DNA methylation and numerous other cellular functions. While the human body can synthesize some choline de novo, dietary intake remains the primary source. Eggs, red meat, milk, and cheese are the richest dietary sources of choline

Recommended Daily Intake and Deficiency Concerns

The Institute of Medicine (IOM) established adequate intakes (AIs) for choline in 1998, with recommendations of 550 mg for males and 425 mg for females daily. The European Food Safety Authority (EFSA) later refined these recommendations in 2016, setting AIs at 400 mg for adults, with higher intakes advised for pregnant (480 mg) and lactating women (520 mg). Choline deficiency has been linked to adverse health outcomes, including non-alcoholic fatty liver disease (NAFLD), cognitive decline, and birth defects

Metabolism and Influencing Factors

Dietary choline exists in both water-soluble (free choline, phosphocholine, glycerophosphocholine) and lipid-soluble (phosphatidylcholine, sphingomyelin) forms, impacting its absorption pathways. Water-soluble choline enters the portal circulation after absorption in the small intestine, while lipid-soluble choline is incorporated into chylomicrons and absorbed through the lymphatic system. Individual factors like age, sex, genetics, and gut microbiota composition significantly influence choline metabolism. Postmenopausal women may require higher choline intake due to decreased estrogen levels impacting choline production via the phosphatidylethanolamine-N-methyltransferase (PEMT) gene Genetic polymorphisms in PEMT can further influence individual choline needs.

The Gut Microbiota: A Complex Player in Choline Metabolism

The gut microbiota, a vast and diverse community of microorganisms residing in our intestines, plays a crucial role in choline metabolism and overall health. Disruptions in gut microbiota composition, known as dysbiosis, are increasingly linked to various diseases. Specific gut bacteria can metabolize dietary choline to trimethylamine (TMA) through a process involving enzymes like cutC and chdD. Subsequently, the liver further oxidizes TMA to trimethylamine-N-oxide (TMAO) via flavin-containing monooxygenases (FMOs) primarily located in the liver

TMAO and Emerging Cardiovascular Concerns

Recent research has highlighted a potential link between elevated TMAO levels and an increased risk of atherosclerosis, the buildup of plaque in arteries leading to cardiovascular disease (CVD). Mechanistically, TMAO may promote the formation of foam cells, pro-inflammatory macrophages that contribute to atherogenesis by increasing cholesterol uptake and inducing endothelial dysfunction, a critical step in plaque formation Additionally, TMAO might contribute to thrombosis and blood clot formation within blood vessels. However, the link between TMAO and CVD risk remains under investigation, with some studies not finding a clear association, suggesting other factors might be at play.

Choline and Cardiometabolic Disorders: A Two-Sided Coin

The relationship between choline and cardiometabolic disorders like NAFLD, CVD, and chronic kidney disease (CKD) is complex and multifaceted. Here's a deeper dive into the potential mechanisms involved:

1. Non-Alcoholic Fatty Liver Disease (NAFLD):

• Choline Deficiency and NAFLD: Choline deficiency can lead to NAFLD development. Choline is a precursor for phosphatidylcholine, which plays a crucial role in exporting triglycerides from the liver. Deficiency disrupts this process, leading to fat accumulation in the liver cells (steatosis), a hallmark feature of NAFLD.

• Excess Choline Intake and NAFLD: Conversely, some studies suggest that excess choline intake might worsen NAFLD by promoting inflammatory pathways and fibrosis, the development of scar tissue in the liver, potentially leading to NAFLD progression

Choline, NAFLD, and the Gut Microbiota Connection

The seemingly contradictory effects of choline on NAFLD highlight the complex interplay between dietary intake, gut microbiota composition, and host metabolism. Here are some potential mechanisms for how excess choline might contribute to NAFLD progression:

• Increased Choline Metabolite Production: High choline intake can lead to increased production of TMAO by gut bacteria. Studies suggest TMAO might exacerbate hepatic steatosis and inflammation in animal models. The exact mechanisms are still under investigation, but TMAO might interfere with lipid metabolism in the liver, promoting fat accumulation.

• Bile Acid Dysregulation: Choline metabolism is intricately linked with bile acid synthesis. Excess choline intake can potentially disrupt bile acid homeostasis, leading to the production of secondary bile acids that might be more hepatotoxic (toxic to liver cells) and contribute to steatosis and inflammation.

• Gut microbiota dysbiosis and inflammatory pathways: high choline intake might promote the growth of certain gut bacteria that are less efficient at metabolizing choline, leading to increased levels of free choline metabolites in the gut lumen. These metabolites can then activate inflammatory signaling pathways in the gut epithelium, potentially contributing to low-grade systemic inflammation and NAFLD progression.

2. Cardiovascular Disease (CVD):

• TMAO and Atherosclerosis: As discussed earlier, TMAO derived from gut microbiota-mediated choline metabolism is a potential culprit in CVD. While the exact mechanisms are still being elucidated, TMAO appears to promote atherogenesis through various pathways:

  • Increased Cholesterol Uptake: TMAO can increase cholesterol uptake by macrophages, leading to the formation of foam cells, the building blocks of atherosclerotic plaques.

  • Endothelial Dysfunction: TMAO might impair the function of the endothelium, the inner lining of blood vessels. This dysfunction can contribute to plaque formation and progression.

  • Thrombosis: TMAO might also influence platelet aggregation, potentially increasing the risk of blood clots within blood vessels.

• Dietary context matters: It's important to consider the overall dietary pattern when evaluating the potential cardiovascular risks associated with choline intake. Choline-rich foods like eggs are often part of healthy dietary patterns that include fruits, vegetables, and whole grains. These components might counteract the potential negative effects of choline on CVD risk through various mechanisms, including reducing inflammation and improving endothelial function.

3. Chronic Kidney Disease (CKD) and the TMAO Conundrum:

• Impaired TMAO Excretion: In individuals with CKD, impaired kidney function can lead to reduced excretion of TMAO, potentially contributing to its accumulation and increased CVD risk. This highlights the importance of considering kidney health when evaluating the potential cardiovascular risks associated with choline intake.

• Potential Role of Choline in CKD Progression: Emerging evidence suggests that high choline intake might be associated with a faster decline in kidney function in CKD patients. However, more research is needed to confirm and clarify the underlying mechanisms.

Dietary Considerations:

• Focus on a Balanced Diet: Maintaining a balanced diet with moderate choline intake is crucial. While choline is an essential nutrient, excessive intake can potentially lead to adverse health outcomes. Including a variety of fruits, vegetables, and whole grains in the diet can help mitigate the potential negative effects of choline on cardiometabolic health.

• Prioritize Gut Health: Promoting a healthy gut microbiota composition through a diet rich in fiber and prebiotics is a promising strategy. Prebiotics are selectively fermented by beneficial gut bacteria, potentially reducing TMAO production by these microbes. Examples of prebiotic fibers include inulin, fructooligosaccharides (FOS), and resistant starches, which are found in fruits, vegetables, legumes, and whole grains.

Future Directions:

• Personalized Medicine: Individual genetic variations and gut microbiota profiles can significantly influence choline metabolism and CVD risk. Tailoring dietary recommendations and potential probiotic interventions based on individual assessments could be a future direction for personalized medicine approaches. This might involve genetic testing and analysis of gut microbiota composition to guide choline intake and probiotic supplementation strategies for optimal health.

Conclusion:

Choline is an essential nutrient with a complex role in human health. While choline deficiency can lead to health problems, a delicate balance needs to be maintained to avoid potential downsides associated with excess choline intake and TMAO production. Future research focusing on dietary patterns, gut health modulation through prebiotics and targeted probiotics, and personalized medicine approaches holds promise for optimizing choline intake for overall health and preventing cardiometabolic disorders. By unraveling the intricate interplay between choline, gut microbiota, and TMAO, we can develop effective strategies to promote optimal choline metabolism and reduce the risk of cardiovascular disease and other chronic conditions.

Journal Reference

Vallianou, N.G., Kounatidis, D., Psallida, S. et al. The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence. Curr Nutr Rep (2024). https://doi.org/10.1007/s13668-024-00521-3

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