Sorry one of those long posts:
I think knowing a bit more about the tryptophan metabolism helps understand the bigger picture, the inter-related nature of biological processes, and how this all relates to exposure to gram negative bacteria.
Elevated kynurenic acid is what I was talking about with LPS interfering in the tryptophan metabolism and causing depressive symptoms. Depression is only one symptomatic expression of the effects the endotoxins produce, but it does illustrate some of the important underlying processes. (Unfortunately, like other inflammatory and immune markers, there is never going to be consistent disease-wide metabolite elevation because there are so many variables that can come into play. Amino acid metabolism will be influenced at so many places to attempt to mediate the immune response and people with ME/CFS are at many stages of immunocompetency. An elevated ratio of kynurenine/tryptophan, might interesting to see, at certain stages, but overall, there are going to be more useful tests).
When exposed to LPS, the depressive symptoms in animals are marked by an elevation of the kynurenines, which would include both kynurenine and one of its metabolites, kynurenic acid. Some of the metabolites can by themselves, like quinolinic acid, cause significant ROS, so this likely contributes to these symptoms. As the information you linked indicates, these diversions of tryptophan are also found in bacterial infections in humans.
In our murine friends, who have a dissimilar BBB but similar mammalian tryptophan metabolism, when LPS is injected directly into the brain, to at least overcome the confounding effects of BBB dissimilarity, this causes activation of the enzyme, IDO. The depressive effects are in part mediated by this enzyme IDO. Similar upregulation of IDO has now been established in a number of inflammatory disorders, autoimmune disease, cancer, asthma. I believe this is the same mechanism whereby Interferon can induce Depression, since Interferon has been shown to very potently activate IDO. So what does IDO do?
IDO is Indoleamine-PYRROLE- 2,3-dioxygenase and it catalyzes the breakdown of L-Tryptophan into N-formylkynurenine. Kynurenine pathways lead to niacin (NAD+) biosynthesis. By enhancing the biosynthesis of metabolites of kynurenine, however, this has the effect of limiting tryptophan availability for making your brain feel happier. As you know, tryptophan has more than one use, it doesn't just get fed into the kynurenine metabolism, it's collateral pathways is necessary for 5-HTP and biosynthesized into serotonin and then melatonin. Serotonin synthesis from tryptophan starts out with tryptophan hydroxylase, one of those enzymes that I think is going to start working better with RS supplementation. This enzyme, tryptophan hydroxylase, also uses tetrahydrobiopterin (BH4), and at the root level all these problems go back to the capacity to synthesize DNA.
So, the first question I was thinking about is, why, evolutionarily speaking, is tryptophan being diverted away from the serotonin/5-HTP pathways? One of the tested behaviors in mice they examined was the that the LPS inhibited their desire to consume sucrose. The other was that the mice were more immobile. So why would mice not want sugar or do they simply lack the desire to pursue anything (anhedonia) because the serotonin biosynthesis was inhibited? Also what purpose would this serve. From a pure evolutionary perspective, this sounds contradictory. On one hand, the immobility relates to caloric preservation and not wasting energy, but the failure to feed represents caloric deprivation. Of course, sucrose can quickly escalate serotonin levels, which would reinforce this decision to pursue sucrose, and depressed humans often resort to this compensatory strategy to self-medicate. Unfortunately, sucrose is not the sort of saccharide, a disaccharide, that is going to nurture the organisms we want and, in fact, the availability of sucrose would seem to favor a dysbiotic state, more gram negative organisms, and more LPS.
In ME/CFS, glucose can make matters worse by increasing lactate concentrations. Glycolysis is the way in which glucose is converted to usable energy, and in the process of doing so, pyruvate and lactate is produced. This can exacerbate oxidative stress. Certain forms of bacterial fermentation use these same basic chemical reactions, they produce much more lactate than Bifidobacteria, for example, and they don't readily yield reducing molecules we need to quench oxidative stress. This is the reason I generally think homolactic fermentation is not a good idea in ME/CFS.
So getting back to tryptophan, one of the really interesting things with mice is that when they are exposed to LPS and then given tryptophan, the tryptophan potentiates the toxicity of the LPS. The murine model has its limitations, including that humans are far more sensitive to LPS than mice, but I still think the combination of increasing the concentration of this amino acid should have the same effect in upregulating expression of IDO, regardless of the species. We have studies that have demonstrated that the availability of this amino acid (tryptophan) has the effect of significantly amplifying the endotoxin (LPS) toxicity often making non-lethal doses, lethal. Recall that I have talked about the many controls in place to limit the catabolism of proteins; and I think this is in part because the amino acids that become available via catabolism of proteins can amplify a immune response and initiate a dangerous, if not at least a symptomatically unpleasant immune cascade.
The counter-regulatory mechanisms are unbelievably complicated, and I am only familiar with a handful, but the redundancy is brilliantly engineered. Tryptophan is just one example, and seems to parallel the many other components of the metabolism, particularly the nitrogen/cysteine metabolism that simultaneously potentiate and suppress the immune response and hence inflammation. Just glancing at this page, the effect of thiamine, a sulfur-based compound, and the often mentioned problems introducing modifiers of the sulfur metabolism can readily stimulate the immune response. This is the paradox of immunomodulation; attempts to stimulate a response are often met with very adverse symptoms as they are also met with favorable symptomatic responses. It is about finding a tolerable balance as this is what the human body is trying to maintain.
The enzymatic reactions mediate varying responses to achieve a balance. IDO, for example, is activated by the endotoxins but it doesn't just divert flow from tryptophan, it also induces B cell activation. It plays a critical role in moderating the effects of the endotoxins to protect us. It seemingly, simultaneously influences our own actions via neurotransmitter inhibition. In this regard, Depression as induced by LPS, would seem to have a function, or evolutionary role.
Less melatonin, less serotonin, and more cytokines and kynurenine and QA is what you may get when you challenge the gram-negative organisms.
I should clarify a bit more...even though I had a very strong immune reaction, it definitely felt like a positive thing one on level as I very rarely get flu type symptoms and when I do, my ME symptoms abate somewhat, and that happened on this occasion too, so obviously it was reawakening part of my immune system that is normally very suppressed. Even though I felt pretty rough with the flu, my fatigue was not as severe and my brain was less inflamed (which is one of my worst symptoms by far).
