Fig. 2

Bile acids, TMAO and tryptophan metabolic pathways and their links to the brain. Primary bile acids are produced from cholesterol breakdown in the liver. They can be conjugated with taurine or glycine residues before travelling to the gut, where they are deconjugated and converted to secondary bile acids via microbial action. Bile acids have been found in the brain of humans and rodents suggesting they can cross the blood–brain barrier via either diffusion (unconjugated) or active transport (conjugated) and influence the central nervous system. TMAO is produced via a two-stage process. TMA is first formed from the microbial conversion of choline in the gut. TMA then travels to the liver, where the FMO1/3 enzyme converts it to TMAO. Recent evidence found TMAO in human brains, indicating it can cross the blood–brain barrier. Tryptophan can be metabolised via three key pathways. Firstly, via gut microbial action, tryptophan can be converted via the indole pathway into numerous indole derivatives, or into the amino acid, tryptamine. Indoles and tryptamine are known to cross the BBB. Secondly, around 3% of dietary tryptophan is metabolised into serotonin and melatonin via numerous enzymes in the serotonin pathway. Notably, serotonin produced in the gut cannot cross the blood–brain barrier. However, the serotonin precursor, 5-hydroxytryptophan, and serotonin derivatives, N-acetylserotonin and melatonin, can cross the blood–brain barrier and influence the central nervous system. Finally, the majority of tryptophan (~ 90–95%) is metabolised via the kynurenine pathway, of which 90% occurs in the liver. This pathway is initiated by the TDO enzyme in the liver and the IDO enzyme in the brain. Only kynurenine, 3-hydroxykynurenine and tryptophan itself can cross the blood–brain barrier. However, once in the brain, tryptophan can be metabolised via both the kynurenine and serotonin pathways to form the pathway’s intermediates