Hello everyone! I am researching the molecular mechanisms which drive depression in the context of gut microbiota. From what I know, depression's pathogenesis primarily relies on Tryptophan metabolism. On one hand, the pathway is perturbed to the kynurenic pathway which leads to the formation of kynurenic metabolites (KYNA, QA, XA, etc). These kynurenic metabolites exert neurotoxic effects which ultimately drive depression phenotypes. They are also able to affect the enteric nervous system, the gut millieu, and immune system which contribute to depression.
On the other hand, Tryptophan metabolism can also be driven towards serotonin synthesis. Inflammatory bowel disease and its likes (Crohn's disease, colitis) have been shown to have increased serotonin (evidenced by increased TPH expression) and decreased SERT expression. Serotonin has been shown to be pro-inflammatory and this supports the inflammatory theory of depression.
While these explanations do not completely contradict each other and that they may simultaneously contribute to depression, an "irony" still exist that one says a perturbation towards kynurenine while the other is towards serotonin. Either way, Tryptophan is consumed and surely leads towards an increased bias to one pathway (ie. increased serotogenic or increased kynurenic). Hence, do you know of any articles which settle this apparent contradiction? Or perhaps there is something I incorrectly understand?
Thank you!
Your statement raises a number of issues.
1. There is no evidence that KYNA, QA, XA, etc can have a neurotoxic effect in human brain. While animal studies may suggest a neurotoxic effect there is not even evidence that the levels of these compounds in human brain reaches levels that might have a neurotoxic effect. Furthermore, these compounds are all acids and would not be expected to cross the blood-brain barrier.
2. Low serotonin, rather than high serotonin, is thought to be associated with depressed mood. For example, giving tryptophan to depressed patients, at doses which have been shown to increase human brain serotonin synthesis, has an antidepressant effect, and giving a mixture of amino acids lacking tryptophan (which induces protein synthesis and lowers tryptophan levels as it is incorporated into protein) has been shown to lower human brain serotonin synthesis for a short period of time and can result in a lowering of mood and the temporary reversal of the effects of antidepressant drugs in patients who have responded to those drugs (Pharmacol Biochem Behav, 2002, 71:857-865).
3. Because serotonin does not cross the blood-brain barrier the status of serotonin outside the brain, in conditions such as inflammatory bowel diseases, does not necessarily reflect the status of serotonin in the brain.
3. Clinical depression is almost certainly multifactorial and probably differs somewhat in its etiology in different patients. There is certainly no evidence that altered tryptophan metabolism is the main factor responsible for clinical depression in most patients.
Simon N Young thank you for your response.
1. Yes, they cannot cross the BBB but kynurenine and tryptophan can. Trp can be converted by microglia and astrocytes using IDO to kynurenine. From thereon, they can be metabolized into these acids. Is this not a mechanism which kynurenine metabolites exert negative effects on the brain?
2. Thank you for this. I , too, am more familiar with the low serotonin associated with depression. I just asked about high serotonin and IBS because it conflicts this explanation. Perhaps inflammation and other factors caused by IBS influence increased depression incidence found in patients.
And yes, MDD is indeed multifactorial. I am interested in how gut microbiota possibly exert influence in the etiology of depression via Trp metabolism.
- Badges
- Science topic
- Similar topics
- Biological Science
- Biota
- Eukaryota
- Fungi