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1. Tributyrin is a triglyceride made of three butyric acid molecules attached to a glycerol backbone. [1]

2. Butyric acid is a conjugate form of butyrate, a short-chain fatty acid (SCFA). SCFAs are substances produced through the fermentation of fibre in the large intestine, with many health benefits. They are associated with improved immune function, digestion, and metabolic health, among other benefits. [2]

3. As a SCFA, butyrate is an example of a postbiotic, or a substance generated through the activity of intestinal bacteria, that has a beneficial effect on the host. [2] Postbiotics help regulate the composition of the microbiome, which supports systems throughout the entire body. [2]

postbiotics vs prebiotics, probiotics and synbiotics

Where is tributyrin found?

Tributyrin can be obtained through various sources, including food. It is present in dairy products such as butter and ghee. Interestingly, the term “butyrate” originates from “βούτῡρον,” the Ancient Greek word for butter. [3]

More on the topic: Ghee and its Advantages vs Butter

Tributyrin may also be taken as a supplement. Tributyrin is a prodrug of butyrate, meaning it is converted into active butyrate within the body. [4] After it is absorbed, tributyrin releases active butyrate slowly over time, directly into the cells. [4] For this reason, it is considered to have more favorable pharmacokinetic effects than pure butyrate, which is absorbed much more rapidly. [4] Moreover, tributyrin may be taken by mouth (an accessible, minimally invasive means of administration), and it has been shown to be well tolerated in humans. [1]

Bulletproof Express 3-IN-1 ProbioticBulletproof Express 3-IN-1 Probiotic contains a science-backed dose of postbiotic Tributyrin, which helps jumpstarts the natural production of postbiotics.

Mechanism of action

The benefits of tributyrin are attributed to the actions of butyrate. Butyrate, a SCFA, is a major source of energy for the cells lining the colon. In fact, research shows that butyrate supplies over 70% of the colon cells’ energy needs. [5] One of butyrate’s mechanisms of action is increasing the integrity of the intestinal barrier. [6] This in turn protects against pathogen infection and helps maintain a favorable environment for good gut bacteria.

Layer Origin PureHMO Prebiotic and Synbiotic

Layer Origin PureHMO® Prebiotic Capsules feed the growth of healthy gut bacteria like Bifidobacterium and Akkermansia which in turn create metabolites (postbiotics) like SCFAs. For a prebiotic + probiotic combo, try PureHMO® Synbiotic.


Butyrate can also inhibit histone deacetylases (HDACs), which are enzymes that remove acetyl groups from histone proteins. [7] HDACs are involved in cancer cell growth and survival, so inhibiting these enzymes is an important anti-cancer mechanism. For instance, HDAC inhibition may trigger cancer cell death, thus minimizing tumor growth. [8]

Tributyrin may also act through antioxidant and anti-inflammatory mechanisms. For instance, butyrate has been positively associated with antioxidant enzymes like catalase, metallothionein, and glutathione S-transferases. [9,10] Butyrate has also been shown to downregulate pro-inflammatory cytokines and upregulate immunosuppressive cytokines. [11, 2] In this way, butyrate regulates the immune system, and may even protect against allergic reactions. [2]

Related:
- Prebiotics: What You Should Know
- Are Probiotics Beneficial to Human Health?

Health benefits

Tributyrin is associated with many health benefits. Perhaps the most researched is its anticarcinogenic effects. Through HDAC inhibition, butyrate can slow cancer cell proliferation and trigger cancer cell death. [7]

One study on human cancer cells found tributyrin to be even more effective than pure butyrate at inhibiting cancer cell growth, supporting tributyrin’s high bioavaiability. [4] Another study compared the effects of tributyrin and phenylbutyrate (another prodrug of butyrate) on inhibiting cancer cell growth. [12] While both drugs were effective, tributyrin was the more potent of the two. Furthermore, levels of butyrate and butyrate-producing bacteria have been found to be lower in advanced stage cancer patients compared to healthy individuals. [13]

Tributyrin is also beneficial for gut health. By strengthening the gut barrier, butyrate helps prevent pathogenic bacteria from entering the bloodstream. [6] This is crucial for preventing “leaky gut,” a syndrome that occurs when toxic materials from the intestine spill into the blood. [14] Leaky gut may cause inflammation throughout the entire body, including the brain. This happens when harmful substances cross the blood brain barrier (a border that separates the brain from the blood circulation) and cause damage in the brain. [14] In fact, leaky gut may contribute to nervous system disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). [14]

leaky gut

By strengthening the gut barrier as well as the blood brain barrier, butyrate may protect against such diseases. For example, in mice that have been genetically modified to carry ALS genes, butyrate supplementation has been shown to improve neuromuscular function and slow disease progression. [15] Additionally, lower levels of butyrate-producing bacteria have been observed in ALS patients compared to healthy controls. [16]

As the main fuel source for colon cells, butyrate can also promote the movement of intestinal contents through the digestive tract. For instance, butyrate supplementation has been shown to increase colonic motility. [17] These findings highlight butyrate’s potential in treating gastrointestinal disorders.

Related: Biohacking Digestion and Optimising Gut Health

For instance, there is evidence supporting butyrate’s role in the treatment of irritable bowel syndrome (IBS). In a double-blind, randomized, placebo-controlled study of 66 adults with IBS, butyrate supplementation reduced the frequency of abdominal pain, with benefits seen after just four weeks. [18] Studies have also shown lower levels of butyrate or butyrate-producing bacteria in patients with inflammatory bowel disease. [19, 20]

Principle effects of butyrate
Summary of principle effects of butyrate and its potential mechanisms of action in the colon and peripheral tissues; liver, skeletal muscle and adipose tissue.
Source: ResearchGate

 

Additionally, tributyrin may help promote a healthy body weight. In a recent study, mice that received tributyrin had a lower weight gain and more favorable blood glucose levels compared to those fed a placebo. [21] Consistent with these findings, another study found butyrate to be effective at reducing food intake and preventing obesity in mice. [22] This study also reported increased fat oxidation among the butyrate-fed mice, further supporting butyrate’s role in weight management and obesity prevention.

While much of this research is limited to animal models, there is also some supporting evidence from human studies. For example, in a randomized, double-blind, crossover study of 13 overweight or obese men, butyrate administration significantly increased fat oxidation and satiety hormone concentrations. [23]

Takeaways

In summary, tributyrin is an efficient tool to raise butyrate levels in the body. Butyrate is an important postbiotic that is associated with many health benefits, including digestive and nervous system support. Butyrate may also support a healthy body weight by regulating satiety and increasing fat metabolism. There is even research supporting butyrate’s role as an anti-cancer agent.

Tributyrin has been shown to be more potent than natural butyrate, due to its slower release after absorption. While further research is needed to clarify tributyrin’s mechanisms of action and efficacy, there is promising evidence to support its health-promoting properties.

 

References

1. Edelman MJ, Bauer K, Khanwani S, et al. Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug. Cancer Chemother Pharmacol. 2003;51(5):439-444. doi:10.1007/s00280-003-0580-5

2. Żółkiewicz J, Marzec A, Ruszczyński M, Feleszko W. Postbiotics-A Step Beyond Pre- and Probiotics. Nutrients. 2020;12(8):2189. doi:10.3390/nu12082189

3. https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:30772

4. Gaschott T, Steinhilber D, Milovic V, Stein J. Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells. J Nutr. 2001;131(6):1839-1843. doi:10.1093/jn/131.6.1839

5. Roediger WE. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut. 1980;21(9):793-798. doi:10.1136/gut.21.9.793

6. Fachi JL, Felipe JS, Pral LP, et al. Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism. Cell Rep. 2019;27(3):750-761.e7. doi:10.1016/j.celrep.2019.03.054

7. Xu, W., Parmigiani, R. & Marks, P. Histone deacetylase inhibitors: molecular mechanisms of action.Oncogene 26, 5541–5552 (2007). https://doi.org/10.1038/sj.onc.1210620

8. Vrzáčková N, Ruml T, Zelenka J. Postbiotics, Metabolic Signaling, and Cancer. Molecules. 2021;26(6):1528. doi:10.3390/molecules26061528

9. Sauer J, Richter KK, Pool-Zobel BL. Physiological concentrations of butyrate favorably modulate genes of oxidative and metabolic stress in primary human colon cells. J Nutr Biochem. 2007;18(11):736-745. doi:10.1016/j.jnutbio.2006.12.012

10. Stein J, Schröder O, Bonk M, Oremek G, Lorenz M, Caspary WF. Induction of glutathione-S-transferase-pi by short-chain fatty acids in the intestinal cell line Caco-2. Eur J Clin Invest. 1996;26(1):84-87. doi:10.1046/j.1365-2362.1996.113252.x

11. Załęski A, Banaszkiewicz A, Walkowiak J. Butyric acid in irritable bowel syndrome. Prz Gastroenterol. 2013;8(6):350-353. doi:10.5114/pg.2013.39917

12. Clarke KO, Feinman R, Harrison LE. Tributyrin, an oral butyrate analogue, induces apoptosis through the activation of caspase-3. Cancer Lett. 2001;171(1):57-65. doi:10.1016/s0304-3835(01)00574-2

13. Chen HM, Yu YN, Wang JL, et al. Decreased dietary fiber intake and structural alteration of gut microbiota in patients with advanced colorectal adenoma. Am J Clin Nutr. 2013;97(5):1044-1052. doi:10.3945/ajcn.112.046607

14. Obrenovich MEM. Leaky Gut, Leaky Brain?. Microorganisms. 2018;6(4):107. doi:10.3390/microorganisms6040107

15. Zhang YG, Wu S, Yi J, et al. Target Intestinal Microbiota to Alleviate Disease Progression in Amyotrophic Lateral Sclerosis. Clin Ther. 2017;39(2):322-336. doi:10.1016/j.clinthera.2016.12.014

16. Nicholson K, Bjornevik K, Abu-Ali G, et al. The human gut microbiota in people with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(3-4):186-194. doi:10.1080/21678421.2020.1828475

17. Soret R, Chevalier J, De Coppet P, et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology. 2010;138(5):1772-1782. doi:10.1053/j.gastro.2010.01.053

18. Banasiewicz T, Krokowicz Ł, Stojcev Z, et al. Microencapsulated sodium butyrate reduces the frequency of abdominal pain in patients with irritable bowel syndrome. Colorectal Dis. 2013;15(2):204-209. doi:10.1111/j.1463-1318.2012.03152.x

19. Takaishi H, Matsuki T, Nakazawa A, et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int J Med Microbiol. 2008;298(5-6):463-472. doi:10.1016/j.ijmm.2007.07.016

20. Huda-Faujan N, Abdulamir AS, Fatimah AB, et al. The impact of the level of the intestinal short chain Fatty acids in inflammatory bowel disease patients versus healthy subjects. Open Biochem J. 2010;4:53-58. doi:10.2174/1874091X01004010053

21. Sato FT, Yap YA, Crisma AR, et al. Tributyrin Attenuates Metabolic and Inflammatory Changes Associated with Obesity through a GPR109A-Dependent Mechanism. Cells. 2020;9(9):2007. doi:10.3390/cells9092007

22. Li Z, Yi CX, Katiraei S, et al. Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit. Gut. 2018;67(7):1269-1279. doi:10.1136/gutjnl-2017-314050

23. Canfora EE, van der Beek CM, Jocken JWE, et al. Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial. Sci Rep. 2017;7(1):2360. doi:10.1038/s41598-017-02546-x

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