In the last couple of months I've had some unexpected success in reducing the inflammatory response to the various prebiotics I've been experimenting with. Instead of taking PS on its own I started combining it with psyllium.
Thank you for your insights. The reduction of inflammatory symptoms is precisely what I am looking for, and such an observation is invaluable to me. I've continued to make inroads in this regard, and I think diminishing the inflammatory response is truly how gains in your fatigue will ultimately be achieved. In my estimation, you are at an earlier junction in the process; I will tell you from personal experience that the gains in energy that you can utilize will be delayed as the natural processes designed to restore homeostatic conditions progresses.
I still think the energy losses are in large part created by the immune response to lipopolysaccharide in the extra-intestinal tissues. It's not simply about the bacterial translocation but the lack of those organisms that promote an anti-inflammatory response in the bowel and perhaps more importantly, in the reticuloendothelial system. I think I can readily correlate my symptoms with those proven symptoms of endotoxin exposure in humans. Loss of energy and the earlier onset of PEM is a feature of this. Sometimes, as the restorative processes continue without inducement by prebiotics/probiotics, you just have to "ride it out," and recognize that immune response is not within your control and the oxidative consequences of gram-negative bacterial translocation require that you minimize your energy expenditure and cut back on those carbohydrates which are so dramatically altering your microbiota and immune response.
For the benefit of those who haven't dealt with this, when endotoxins are mobilized a downward shift in mood is likely, and one of the consequences is that glutathione will be taxed resulting in earlier fatigability; as Dr. Cheney talks about the losses of energy originating in the liver, but this antioxidant resource is distributed to the skeletal muscles and beyond. One may experience lympathic pain and swelling, cytokine symptoms, sometimes headaches, etc. This is the signature of lipopolysaccharide and it will overpower even your enhanced ability to suppress inflammation. I have experienced a significant decrease in all of these symptoms, but the improvement in fatigue was slower to develop, and it frequently re-appeared along with the other symptoms. It has slowly improved both in intensity and the frequency of these "episodes" of heightened immune activation.
I firmly believe that altering gene expression to limit inflammation through manipulation of the microbiome is clearly achievable, I've made huge gains, including in fatigue and PEM, and food sensitivities, my mood continues to improve, and I only have negligible cognitive symptoms.
The prebiotic compounds that are demonstrating anti-inflammatory properties are also the ones that possess anti-tumor capabilities and modulate T regulatory cells, and they are almost universally plant compounds, rich in polysaccharides, particularly n-linked plant glycans. The idea of stimulating Cluster IV Clostridial organisms with a prebiotic is a sound one. These anaerobes, in addition to being unavailable to the masses, should be "cultured" in the intestinal environment. F. Pruasnitzii, which you mentioned is very intolerant of oxygen and can only survive for a few seconds in O2. Obviously, none of us have a good understanding of exactly what dozens or hundreds of organisms we need, so the prebiotic strategy of throwing down the substrate and providing the resources needed to repopulate sounds considerably more logical to me than probiotic supplementation, although this carries its own benefits.
"I now see that it was hypothesized in the paleo community that it shuttles RS2 to the distal colon instead of it just burning up more proximally." I can't say I understand the mechanism of this, but would like to here a bit more about the specifics. I can think of a number of possibilities, but I suspect it has more to do with providing a new mix of polysaccharides accessible by a new set of microbes that participate in the greater process of inhibiting inflammation.
There is likely a detriment to an over-reliance on resistant starch, or solely using this prebiotic because it is not going to used by a number of key organisms (and their partners) that promote the creation of anti-inflammatory molecules. Fortunately, the human intestinal microbiome is built with incredible microbial redundancy with overlapping capacity to promote the host's survival; this perhaps explain why most people never find themselves in such a quandary of being able to restore immunocompetency. I suspect that those with ME/CFS have much more pervasive disruptions of the intestinal microbiome than many other inflammatory disease processes. There are emerging microbial signatures of a number of these pathological conditions and the metabolomic/genomic tools will soon expand our understanding of these processes.
Given that humans have inhabited diverse ecosystems with equally diverse plant resources for hundreds of thousands of years, it is clear that they have survived and prospered on a variety of different plant materials that optimally promoted the intestinal microbiome. In this regard, it may be that a singular plant resource could sustain a population since most all plant matter includes not a singular type of carbohydrate but a significant number of different polysaccharides.
Some of the earliest humans appear to have consumed wood and bark, and when I look at the microbes that have been identified as those most centrally involved in the induction of anti-inflammatory processes, such as the Treg cells which have the ability to produce anti-inflammatory cytokines, I see a central role for the polysaccharides contained in this resource including, wood, bark, mushrooms and lichen growing on these trees. In other words, the organisms are richly encoded with enzymatic abilities to use these materials.
Amylose/amylopectin (starch) is of course just one part of the potato plant. The outer covering as with other whole plant matter, contains insoluble fiber or cellulose. Starch and the bacterial enzymes needed to access this are very widely distributed among the human microbiome. As far as I can tell, many more organisms can use this more "generic" substrate than some other more specialized carbohydrates that are not only resistant to human digestion but substantially resistant to most microbial degradation. Potato starch is very effective in increasing butyrate concentrations, but there is obviously a larger microbial community that requires support and I think singular supplementation can result in an "unbalanced" immune response. The connotation is not that there is anything wrong with potato starch, but the microbes that support the anti-inflammatory response are not universally able to access this starch, there are other polysaccharides or glycans of importance and I think you have likely accessed some of these by taking psyillium.
The colonic microbiome is completely built around carbohydrate metabolism, in this regard so is the host immune system. The commensal, anaerboic, predominantly gram-positive organisms have special chemical abilities to sever the bonds of these carbohydrates that provide a raw material myriad processes. This resistance to human digestion of course gives these carbohydrates special functional abilities, and it is increasingly becoming clear that these organisms shape the entire immune response in ways that has been under-appreciated.
Theoretically a handful of certain microbes involved in the critical role of dampening inflammation could shut down a host of processes that can inhibit the efficacy of the entire community. The restoration of this system involves not only restoring a group of organisms but a host of incredibly complex and interdependent manufacturing process that keep these communities of microbes thriving in times of scare food resources. Carbohydrates are synthesized and interconverted to keep chemical processes moving that keep us and our microbes alive. Some of these products or byproducts are only made available by a limited number of microbes. This includes some of these special carbohydrates that support these critical pieces of the anti-inflammatory network of microbes that are microbially-converted or hydrolyzed into other forms of polysaccharides that can be used as part of the network thereby obviating the need to consume these in the diet regularly.
I don't have time to go into the depression thing now, but when one looks closely at the microbial metabolism of tryptophan/indoleamine and the interrelationships of the organisms that participate in this he or she can visualize the roles of these organisms in suppressing inflammation and neutralizing the effects of LPS. (I think I previously wrote about indoleamine 2, 3 dioxgenase the rate-limiting enzyme in the tryptophan metabolism via kynurenine and LPS...which is central to modulating the immune response, particularly T-cells.) Anyway, a loss of key tryptophan metabolizer (like non-pathological e. coli) would have effects on those microbes that hydrolyze tryptophan to indole because the concentration of indole in the colon serves to amplify the expression of genes involved in strengthening the mucosal barrier an enhancing mucin biosynthesis.
So, for example, someone might get a great boost in mood from commensal e coli (mutaflor) but without one of the indole metabolic partners, it may have no effect. Their are thousands of these relationships. Without looking at the capabilities of C. Butyricium, (AOR 3) I'm willing to bet this organisms plays a major role in the tryptophan metabolism simply based upon the indole odor that stuff creates.
This of course is just one more piece of the puzzle; this redundant engineering designed to counter the inflammatory response is exquisitely engineered, but broken, this breakdown centers around the organisms that maintain the intestinal epithelium. In this example, the network of organisms helps restore intestinal barrier function and suppress the peripheral immune response by keeping endotoxins from these extraintestinal tissues that precipitate such a strong pro-inflammatory response.
So psyillium is interesting, I think this fits the equation of expanding that core group of microbes that has collapsed. It is a mucillage, something I happen to be using now. Folks will likely find that this list (types of mucillage rich plants) is pretty well-tolerated. This plant also contains some of the other staple substrates for our anti-inflammatory microbes and their microbial partners. Not psyillium per se, but the structural polysaccharides that compose this plant. I can't say I know anything about psyillium or much about botany, or glycobiology, or chemistry for that matter, but a "husk" certainly means you are consuming structural (vs. storage) polysaccharides, I'm assuming it contains hemicellulose and xylan and it certainly includes some polysaccharides that are "resistant" to human digestion and ecologically preserved for microbial use. Other microbes (see Bifidobacteria) will play a role in making this substrate available.
Chitin is another structural polysaccharide along with cellulose, cellobiose, and then there are hemicelluloses such as, mannans, pectins, and glucuronoarabinoxylans...some of these are both storage and structural polysaccharides. (Honestly, I get confused about the categories of all of these materials, so hopefully I got it right). Still, there is a reason I have been talking about XOS and chitin and cellulose derivatives, and that is because these are the resources that best stimulate the expansion of the counter-inflammatory response. Looking at the organisms that have proven to play a part in inducing an anti-inflammatory response, at least in terms of T-regulatory cell differentiation/function, and their enzymatic capabilities, I think that these storage polysaccharides are the most specific substrate for this community. In fact I've been getting very good results from very modest doses of acetylated mannan from aloe vera, for about two months.
I do suspect the effects of psyillium will be highly variable depending upon such factors as ones "immunocompetency" and his or her's own individual microbial balances. Like other resistant prebiotics, it may need to be taken in very modest quantities, and still in others no appreciable effect, perhaps because this does not contain the "missing" polysaccharides. Nevertheless, I think this is likely to be a helpful addition for many and is worth trying. I'll give it a try after looking to see what is in it.
I'm still looking for that optimal mix/dosage of prebiotics that minimizes the inflammatory response. The evidence that particle size of certain polysaccharides can dramatically influence pro vs. anti-inflammatory response is still very intriguing, and I have to wonder how much of this relates to the ability of these molecules to counteract the proinflammatory response in the periphery. Highly sulfated/acetylated may have a role. I think we are looking at a function of the differences in n-linked glycosylation, which is rare among bacteria, and the plant n-glycans mannan, xylose, NAG, fucose, etc., are likely going to be involved.
