Tributyrin

Tributyrin is a precursor or prodrug of the endogenous short-chain fatty acid (SCFA) butyric acid (butyrate).^[4][2][5] It is stable and is rapidly absorbed and gradually converted into butyric acid.^[2][5][11] Tributyrin is not broken down by gastric juice and is slowly converted into butyric acid and glycerol by pancreatic lipases in the gut.^[12] In addition, tributyrin is more lipophilic than butyric acid and is taken up into cells much more readily in comparison.^[4] Butyric acid itself has an extremely short elimination half-life of seconds to minutes among other limitations, which makes its own use impractical.^{[2][3][13][14]} For comparison, tributyrin has considerably longer half-life of 40 minutes with oral administration in rodents.^[2][5]

Butyric acid, the active form of tributyrin, has a large variety of biological effects.^[10] It is an agonist of the FFAR2 (GPR43), FFAR3 (GPR41), and GPR109A and a histone deacetylase (HDAC) inhibitor of HDAC classes I and II.^[10] In addition, butyric acid is the preferred energy source for colonocytes, and has been found to provide approximately 70% of total energy needs for colonocytes in mice.^[10] Butyrate plays a key role in gut homeostasis and has anti-inflammatory effects among others.^[10] Tributyrin is described as an HDAC inhibitor similarly to butyric acid.^[15][16]

Tributyrin has been found to reverse gut microbiota dysbiosis and intestinal injury and inflammation induced by antibiotics in rodents.^[4][12][17] This included increasing potentially beneficial SCFA-producing bacteria such as Muribaculaceae and Bifidobacterium and decreasing potentially pathogenic bacteria such as Bacteroidetes and Enterococcus.^[12] One means by which SCFAs like butyrate may mediate such effects is by decreasing intestinal pH.^[18] In accordance with the observed intestinal bacterial changes, tributyrin increased levels of the SFCAs butyric acid, acetic acid (acetate), and propionic acid (propionate).^[12] The effects of tributyrin and butyrate appear to be dose-dependent, with low concentrations promoting the intestinal barrier and inhibiting inflammation while high concentrations can do the opposite via induction of apoptosis.^[4][12] In addition to reversing antibiotic-induced dysbiosis, tributyrin has been found to strongly reduce Clostridium difficile infection in rodents.^[4][19] Coadministration of tributyrin with the probiotics Limosilactobacillus reuteri and Lacticaseibacillus rhamnosus has been found to synergistically increase butyrate levels in humans ex vivo as well.^[20][21]

Butyric acid is known to activate the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) signaling pathway via its HDAC inhibition.^[22][23] Tributyrin has been found to modulate hippocampal synaptic plasticity and improve memory in rodents.^[24][25] It has also been found to enhance sleep and increase slow wave sleep (SWS) in rodents.^{[26][27][28][29][30]} Beneficial effects of butyric acid on sleep in rodents have been found to be mediated by activation of the BDNF–TrkB pathway.^[31]

The pharmacokinetics of tributyrin in rodents have been studied.^{[2][5][32][33][34][35]} In addition, tributyrin has been clinically studied in people with solid tumors.^[13][14] Oral administration of high doses of tributyrin (50–400 mg/kg) has been found to maintain elevated circulating butyrate levels for up to 4 hours.^{[2][3][13][14]} This was insufficient for once-daily administration, so thrice daily administration was subsequently pursued instead, though butyrate levels during therapy remained erratic.^{[2][3][13][14]} The elimination half-life of tributyrin in humans could not be determined due to levels being too erratic.^[14][13] On the other hand, its time to peak levels was median 2.75 hours and range 2.0 to 3.5 hours.^[14] The time to peak levels for butyrate specifically (with tributyrin) is median 0.5 to 1.5 hours and range 0.5 to 4.0 hours.^[14][13]

Tributyrin is sold as an over-the-counter supplement under names like CoreBiome, ButyraGen and TauBiotic among others and has been referred to as a "postbiotic"—that is, a microorganism metabolite that has biological effects and potentially therapeutic benefits.^{[6][7][36][37][9][8]} The compound has a mild, lingering odor and bitter taste, but this is overcome with supplements via formulation in soft gelatin capsules.^[5] Tributyrin has greater encapsulation efficacy than sodium butyrate.^[8] As a result, higher doses of tributyrin can be contained in capsules than sodium butyrate—500 mg per capsule and 150 mg sodium butyrate per capsule.^[8] The reduced number of capsules needed may make tributyrin more acceptable in comparison to sodium butyrate, in addition to its more favorable pharmacokinetic properties.^[8] Side effects of tributyrin include mild gastrointestinal upset or bloating.^[9]

Tributyrin is used in microbiological laboratories to identify the bacterium Moraxella catarrhalis.^[38]

Tributyrin was under formal clinical development for the treatment of solid tumors in the late 1990s, but no further development was subsequently reported.^[39] It is also being clinically studied in the treatment of depression (4 g/day)^[8] and Parkinson's disease (1.5 g/day).^{[9][40][41][42]} In a preliminary phase 1b clinical trial for Parkinson's disease, tributyrin demonstrated target engagement (increased butyric acid levels in the brain and other organs), produced systemic anti-inflammatory effects, showed improvements in cognitive and motor symptoms, and increased deep sleep by about 22% or approximately 15 minutes per night.^{[43][9][40][42]} A larger phase 2 trial of tributyrin for Parkinson's disease, known as BUTTER2, is now underway.^{[9][40][42][41]} The proper dosage of tributyrin and butyrate for therapeutic use, based on extrapolation from endogenous intestinal butyrate production (~1–10 g/day), has been studied and reviewed.^[8][44]

• 1,2,3-Tris(4-hydroxybutyroyloxy)propane
• Butyric acid
• SerBut (O-butyryl-L-serine)
• Glyceryl-tris-3-hydroxybutyrate (3GHB)
• Triacetin
• Tripropionin
• List of investigational Parkinson's disease drugs