Does Butyrate Lower Cholesterol? The Evidence and Mechanisms Explained

According to a 2022 study, butyrate can reduce cellular cholesterol in liver cells, showing a cholesterol-lowering effect comparable to statins in laboratory settings. This finding raises the question: does butyrate lower cholesterol in humans and what are the mechanisms at play?

Quick Summary

Butyrate, a short-chain fatty acid produced by gut bacteria, influences cholesterol metabolism through mechanisms distinct from conventional medications. Research in cell cultures and animal models demonstrates its potential to decrease cholesterol synthesis and enhance efflux, but results in human studies are mixed due to bioavailability and methodological differences.

Key Points

• Inconclusive Evidence: Human studies on whether oral butyrate supplements lower serum cholesterol have been inconsistent, despite promising findings in cell and animal studies.

• Distinct Mechanism: Butyrate influences cholesterol metabolism differently than statins, primarily by inhibiting HDACs and impairing SREBP-2 signaling to reduce cellular cholesterol synthesis.

• Enhanced Efflux: In lab and animal models, butyrate has been shown to increase cholesterol efflux from macrophages via the ABCA1 pathway, which may prevent atherosclerosis.

• Bioavailability Issues: The poor systemic availability of oral butyrate and differences in metabolism between species complicate translating animal study results to humans.

• Fiber is Key: A high-fiber diet, which increases natural butyrate production by gut bacteria, is a proven way to support gut health and may indirectly aid in cholesterol management.

• More Research Needed: Large-scale, well-controlled human clinical trials are essential to definitively understand butyrate's effects on human plasma cholesterol levels.

Butyrate and Its Impact on Cholesterol: An Overview

Butyrate is a short-chain fatty acid (SCFA) produced in the colon through the fermentation of dietary fiber by beneficial gut bacteria. It is well-known as a primary energy source for colonocytes, the cells lining the colon. Beyond its role in maintaining a healthy gut lining, butyrate acts as a signaling molecule that can influence various metabolic processes throughout the body, including those related to cardiovascular health. Its potential to modulate cholesterol levels has been a subject of scientific inquiry, exploring whether this natural compound could be a therapeutic agent for managing hypercholesterolemia.

The Mechanisms of Butyrate's Action on Cholesterol

Butyrate's effect on cholesterol metabolism is multifaceted and appears to differ from the pathway used by statins, the most common cholesterol-lowering medications. The research points to several key mechanisms:

• Inhibition of Cholesterol Synthesis: In liver cells (hepatocytes) and intestinal cells, butyrate has been shown to decrease cellular cholesterol synthesis. It achieves this by downregulating the activity of HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway, which is responsible for producing cholesterol. This is a similar end goal to statins, but butyrate accomplishes it through a different signaling route involving histone deacetylase (HDAC) inhibition and impaired SREBP-2 signaling.
• Promotion of Cholesterol Efflux: Studies on macrophages have shown that butyrate can enhance the expression of the protein ABCA1, which plays a crucial role in removing excess cholesterol from cells. By promoting ABCA1-mediated cholesterol efflux, butyrate helps prevent the formation of foam cells, a key event in the development of atherosclerotic plaques.
• Regulation of Bile Acid Metabolism: The gut microbiome, and specifically butyrate-producing bacteria, plays a role in modifying bile acids. These modified bile acids can influence liver receptors that regulate the production and excretion of bile acids, a process that utilizes cholesterol. A balanced bile acid profile can contribute to better cholesterol management.
• Modulation of SREBP-2 Signaling: In contrast to statins, which activate the SREBP-2 pathway to increase LDL receptor expression and cholesterol uptake, butyrate's effect appears to differ. Studies on human liver cells have shown that butyrate treatment is associated with decreased SREBP-2 activity, suggesting a distinct regulatory pathway.

Comparing Butyrate and Statins for Cholesterol Management

Feature	Butyrate (Produced by Gut Bacteria)	Statins (Pharmaceutical Drug)
Mechanism of Action	Inhibits histone deacetylases (HDACs), which impairs SREBP-2 signaling and directly suppresses cholesterol synthesis. Enhances cholesterol efflux via ABCA1.	Inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis.
Primary Site of Action	Produced in the colon; some absorbed butyrate reaches the liver via the portal vein.	Acts primarily in the liver.
Effect on LDL Receptor (LDLR)	In liver cells, butyrate did not increase LDL receptor expression, unlike statins.	Upregulates LDL receptor expression, increasing LDL uptake from the bloodstream.
Impact on Serum LDL	The impact on serum LDL-C in humans is inconsistent; some studies show no effect, while others report decreases or even increases. Animal studies suggest a reduction.	Proven to significantly and consistently lower serum LDL-C in humans.
Side Effects	Generally considered low toxicity, with a low dose not significantly reducing cell viability in lab studies. May have paradoxical dose-dependent effects.	Associated with potential side effects, including myopathy, liver issues, and a risk of type 2 diabetes.
Source	Produced naturally by gut bacteria from dietary fiber; also available in supplements.	Prescription medication.

The Evidence: What the Studies Say

While laboratory and animal studies have shown promising results for butyrate's cholesterol-lowering potential, the evidence from human trials is currently inconclusive and mixed.

• In Vitro and Animal Studies: In cell cultures and animal models, researchers have observed a reduction in cellular and serum cholesterol levels with butyrate administration. Specifically, studies in mice on a high-fat diet found that butyrate significantly decreased total cholesterol and LDL-C, while also inhibiting atherosclerosis. This effect was linked to the upregulation of ABCA1-mediated cholesterol efflux.
• Challenges in Translating to Humans: The poor systemic availability of oral butyrate and differences in cholesterol metabolism between rodents and humans present significant challenges. In contrast to humans, rodents predominantly carry cholesterol on HDL rather than LDL, which complicates direct comparisons.
• Human Clinical Trials: Small human studies have yielded conflicting results. One placebo-controlled trial found no significant change in plasma cholesterol after 45 days of butyrate supplementation, although GLP-1 secretion (a hormone involved in glucose and lipid metabolism) increased. Another small study showed an unexpected increase in LDL-C levels in subjects with metabolic syndrome. Larger, well-designed clinical trials are necessary to determine if oral butyrate supplementation can reliably alter plasma LDL-C in humans.

Conclusion: A Promising but Unproven Supplement

In summary, while there is compelling evidence from laboratory and animal studies suggesting that butyrate can lower cellular cholesterol and influence lipid metabolism through distinct mechanisms, the same effect has not been conclusively demonstrated in human trials. The potential benefits are promising, particularly regarding the reduction of hepatic fat and atherosclerosis seen in animal models. However, factors such as poor bioavailability and inconsistencies between species mean that robust, large-scale human clinical trials are still needed to determine if butyrate can effectively lower serum cholesterol in people. For now, the most reliable way to boost butyrate production naturally is by consuming a high-fiber diet, which feeds the beneficial gut bacteria that produce it.

Natural ways to increase butyrate production

• Eat More Dietary Fiber: Focus on a diet rich in fruits, vegetables, whole grains, and legumes to provide fermentable fiber for your gut bacteria.
• Include Probiotic Foods: Yogurt, kefir, and fermented vegetables contain beneficial bacteria that can contribute to a healthy gut environment.
• Consider Prebiotics: Prebiotic foods and supplements, which are types of fiber that feed gut bacteria, can help increase butyrate production.
• Focus on Polyphenols: Compounds in foods like tea, cocoa, and red wine can support the growth of SCFA-producing bacteria.
• Maintain Overall Gut Health: A diverse and balanced gut microbiota is key to consistent butyrate production.

References

• Butyrate Lowers Cellular Cholesterol through HDAC Inhibition and Impaired SREBP-2 Signalling: https://www.mdpi.com/1422-0067/23/24/15506
• Butyrate protects against high‐fat diet‐induced atherosclerosis via up-regulating ABCA1 expression in apolipoprotein E-deficiency mice: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.14933
• Short-Chain Fatty Acids Suppress Cholesterol Synthesis in the Liver and Intestine and Lower Plasma Cholesterol in Rats: https://www.sciencedirect.com/science/article/pii/S0022316623020370

Frequently Asked Questions

How does butyrate get produced naturally in the body?

Butyrate is produced by beneficial bacteria in the colon through the fermentation of indigestible dietary fiber, found in foods like fruits, vegetables, and whole grains.

Is butyrate a better option than statins for lowering cholesterol?

Butyrate and statins operate through different mechanisms, and the cholesterol-lowering effects of statins in humans are well-established, whereas butyrate's effects are still under investigation and inconsistent in human studies.

Can I get butyrate from supplements instead of food?

Butyrate supplements are available, but studies indicate poor bioavailability, meaning the body does not absorb them efficiently. Increasing fiber intake is generally considered a more reliable method for boosting natural production.

Why do animal studies on butyrate and cholesterol show different results from human studies?

One reason for the discrepancies is that animal models like rodents have different cholesterol metabolism from humans, primarily carrying cholesterol on HDL rather than LDL. Combined with poor oral bioavailability in humans, this makes direct translation difficult.

Does butyrate affect HDL (good) cholesterol?

Some studies have shown butyrate can influence HDL-related proteins, like ABCA1 and SRB1, but the effect varies depending on the cell type. It is not clear how this impacts overall HDL metabolism and cholesterol levels in humans.

Is increasing butyrate production through diet a good idea?

Yes, increasing butyrate production naturally by eating a high-fiber diet is generally beneficial for gut health, anti-inflammatory effects, and overall metabolism. It is a safe and well-supported strategy for health improvement.

What is the key difference in how butyrate and statins affect liver cells?

While both can lower cellular cholesterol, statins increase the expression of LDL receptors on liver cells to pull cholesterol from the blood, whereas butyrate does not; it acts through a different signaling pathway involving HDAC inhibition.