This post started out as an exploration of use of the feed supplement trivalerate as a way of mimicking the beneficial effects of a fecal microbial transplant that can shift the gut microbiome to produce more valerate. How does a medium chain triglyceride differ from a long chain triglyceride?
- Does trivalerate get to the colon as the triglyceride or is it hydrolyzed to glycerol and fatty acids?
- If valerate gets to the colon, does it feed the colon enterocytes like butryate does?
- Where can we find more information if PubMed searching is not producing?
For some reason, it is hard to find papers on trivalerate, glycerol trivalerate, or trivalerin on PubMed. This post will start out refereeing papers on PubChem.
How fecal microbial transplantations work
Dr. Benjamin H Mullish is the corresponding author of the first featured paper on this post. [1] One of the first comments in the introduction was that filtered donor stool was also effective in controlling Clostridium dificile . However, a more recent pilot study demonstrated that sterile filtered donor stool (filtered through a 0.2 μm filter, small than the size of a bacterium) also effectively caused sustained remission from CDI. This study raised the intriguing possibility that soluble factors – rather than intact bacteria – were key mediators for the efficacy of FMT.[1] This was a human big data study that referenced a rodent study in which Clostridium dificile was controlled by introducing valerate as valerin/glycerol trivalerate.
Because we are more concerned about how the intestinal microbiome relates to brain health, let’s take a look at the supplemental data. Paired urine and stool samples were from a clinical trial comparing capssules vs colonoscopic FMT as a refractory C difficle infection treatment.
In the feces
Note that short chain fatty acids are almost absent in the recipients’ feces.
In the serum
Here we might be interested in brain health…Note that nothing is happening with acetate. Serum valerate seems to be increasing in the recipients post FMT.
In the urine
Are there transporters for short chain fatty acids in the kidney such that what gets filtered also gets reabsorbed?
Some Micro reactor data [2]
Clindamycin is an antibiotic used to treat aneorobic infections. Its mechanism of action is inhibition of protein synthesis.
- Chemostat cultures were grown for several weeks without manipulation
- MacDonald et al added 7.8×106 C difficile spores to each vessel to achieve an initial concentration of 3.3×106 spores/mL.to both what would be the saline control and the FMT reactors. In this particular experiment the goal was to determine how clindamycin affected short chain fatty acid production.
In McDonald 2020 clindamycin drastically reduced the valerate concentration for several weeks. 5-aminovalerate and succinate were increased. [2] Ethanol and propionate were essentially unchanged. [2] Mixed results were seen for ethanol. The bottom line is that any perturbation could alter the gut fatty acid profile. [2]
Backing up bioreactor data in a mouse model of C difficile infection [2]
Some cartoons were added to Figure 6 of McDonald 2018 [2] just to think about what is going on. The authors used oral gavage to inject the spores and trivalerate into the stomach of the mice. How close were they to the pyloric valve? Did gastric lipases have a chance to hydrolyze the trivalerate? Certainly trivalerate is hydrolyzed by pancreatic lipases in the small intestine. Internet cartoons of the mouse digestive tract reminds us that the mouse has a bacteria infested ceum. Does valerate emerge from the cecum?
The decrease in C difficile colony forming units (CFU) is pretty amazing. We just have to ask ourselves how much this bacterium colonizes the cecum versus the colon in the rodent. How much valerate was absorbed by the small intestine? If trivalerate was given some sort of small intestine coating, would lipases of the colonic bacteria have hydrodrolyzed it?
Mono and trivalerate for high fat diet fed mice [3]
For 3 weeks four groups of rats, (n = 7/group) were given:
- low-fat diet (LF)
- high-fat control diet (HFC)
- HFC with supplementation with monovalerate (5 g/kg)
- HFC with supplementation with trivalerate (5 g/kg)
Short chain fatty acids (SCFA) were measured in the caecum, blood, liver and brain. Brain acetic acid and serum valeric acid were increased. [3] The cecal microbiota composition was altered, with threefold higher abundance of Bacteroidetes and higher ratio of Bacteroidetes/Firmicutes in the MV group compared with the HFC and LF groups. Acetic acid in the brain was negatively correlated with TM7, family S24-7 and rc4-4, and positively associated to Tenericutes and Anaeroplasma.
The cecal data were edited out and not changed for butyrate and longer chain fatty acids. This suggests they were absorbed in the small intestine and/or metabolized in the cucum.
The portal serum, on the way to the liver, exhibited and increase in valerate. These data demonstrate absorption of the full length fatty acid. No change was seen in the live.
The increase in brain acetic acid in the trivalerate group is noted. We can speculate that it is coming from cecal fermentations, but why was it not also elevated in the portal vein serum? Is the pH of the CSF in the brains of MV and TV treated rates different?
Note that the rats on MV and TV are eating less, but the amount of weight they gain per gram of food consumed (FER) is greater. [3] There are some slight differences in the cecal tissue weight. Other than these things, Reported rat parameters are remarkably similar. [3] This publication did report some rather sweeping changes in the microbiome. [3] If valerate is being absorbed, are there feedback loops that control GI transit times?
Supplemental data from reference [3] Prevention of high fat diet induced hypertension was one goal of this study. This post has not addressed the decreased succinate in liver or other fatty acid metabolism issues.
Glycerol trivalerrate is available from Gentaur.com It is not cheap. Healthline has a really good blog on medium chain triglyceride oils. According to the healthline post milk MCT are more likely to contain the shorter chain fatty acids closer in length to valerate than coconut oil MCT.
Glycerol Tributyrate Patent Abstract [4]
The invention discloses a preparation method for glyceryl tributyrate. The preparation method comprises: taking glycerin and n-butyric acid as raw materials, adding a catalyst and heating to 100-110 o C with stirring, performing heating reflux as well as dropwise adding butyric anhydride, stopping reaction until no water is generated in the reaction solution during dropwise adding, cooling to room temperature, and filtering, so as to obtain glyceryl tributyrate. The catalyst is a mixture of sulfonic-acid mesoporous molecular sieve and ZSM-5 acidic zeolite, and the usage amount of the catalyst is 2-10% by weight of the sum of glycerin and n-butyric acid. By taking sulfonic-acid mesoporous molecular sieve and ZSM-5 acidic zeolite as the catalyst, the selectivity is high, the reaction time is shortened, the generation of by-products is reduced and the catalyst is reusable. By employing the method, the reaction system does not need a water-carrying agent, so that the reaction cost and safe hidden trouble are reduced, the purification step of the product is simplified, the post-processing process is simple, environment is protected and energy is saved. The obtained glyceryl tributyrate is high in purity and high in yield, the reaction speed is fast, and industrial production is easy to realize.
Some Google Patents
Containing the key word “trivalerate”
CA1182725A * 1982-08-111985-02-19John C. MauckMethods, compositions and elements for the determination of lipase
US4528197A * 1983-01-261985-07-09Kabivitrum AbControlled triglyceride nutrition for hypercatabolic mammals
US4607052A * 1983-04-151986-08-19Roussel-UclafTriglycerides, dietetic and therapeutical applications and compositions containing them
US4703062A * 1984-01-161987-10-27Baxter Travenol Laboratories, Inc.Parenteral nutrition with medium and long chain triglycerides
US4847296A * 1984-09-131989-07-11Babayan Vigen K Triglyceride preparations for the prevention of catabolism
US4810726A * 1987-04-011989-03-07New England Deaconess Hospital Corporation Kernel oils and disease treatment
AT89453T * 1987-12-151993-06-15Procter & Gamble FATS WITH REDUCED CALORIES, MADE FROM FATTY ACID WITH MEDIUM AND LONG CHAIN CONTAINING TRIGLYCERIDES.
JP2925085B2 * 1988-12-101999-07-26不二製油株式会社 Dietary fats and oils and foods containing the same
DK657689D0 * 1989-12-221989-12-22Novo Nordisk As MEDICINE WITH BIOLOGICAL EFFECT ON THE GAS MILK
These patents are kind of exciting in the ways that food scientists are fractionating triglycerides from ordinary food sources.
References
- Martinez-Gili L, McDonald JAK, Liu Z, Kao D, Allegretti JR, Monaghan TM, Barker GF, Miguéns Blanco J, Williams HRT, Holmes E, Thursz MR, Marchesi JR, Mullish BH. Understanding the mechanisms of efficacy of fecal microbiota transplant in treating recurrent Clostridioides difficile infection and beyond: the contribution of gut microbial-derived metabolites. Gut Microbes. 2020 Nov 9;12(1):1810531. PMC free article
- McDonald JAK, Mullish BH, Pechlivanis A, Liu Z, Brignardello J, Kao D, Holmes E, Li JV, Clarke TB, Thursz MR, Marchesi JR. (2018) Inhibiting Growth of Clostridioides difficile by Restoring Valerate, Produced by the Intestinal Microbiota. Gastroenterology. 2018 Nov;155(5):1495-1507.e15. PMC free article
- Nguyen TD, Prykhodko O, Fåk Hållenius F, Nyman M. (2019) Monovalerin and trivalerin increase brain acetic acid, decrease liver succinic acid, and alter gut microbiota in rats fed high-fat diets. Eur J Nutr. 2019 Jun;58(4):1545-1560. PMC free article
- Short chain triglycerides https://patents.google.com/patent/EP0466768B2/en
- Preparation method for glyceryl tributyrate https://patents.google.com/patent/CN104086422A/en
