Again, what the heck... I'm all confused again! This is some pretty complex stuff...
So before I get to the really good stuff, let's focus on a few other things:
- We learned that the immune system is always in a constant state of inflammation and this is essentially regulated through the Master Channels of Dopamine and Serotonin.
- We learned and are still are learning that there is some kind of an imbalance or "dysbiosis" in bacteria within our gut and that this imbalance can not only be different in the Gut Lumen, The Mucus Membrane and Cellular (epithelial or gut lining cells cells and Immune Cells themselves) (which again I'll get to soon!)
- We learned that Pathogenic Bacteria (Food born E-coli) down regulate SERT and this causes an increase in 5HT and this is exactly how they effect our bodies and cause the symptoms they do
- We learned that levels of 5HT is for some unknown reason high in people with IBS and IBD and that SERT expression is low in people with IBS/IBD
- We learned that even commensal bacteria (common bacteria) generate an immune response and our bodies "tolerate" this. Again eventually through the Master Channels.
- We learn that Proteoacteria (such as C-diff) cause the release of IKF and NFKB and the release of TNF-a and Chemokines as an immune response and that proteobacteria are part of our normal gut microbiome but are kept under control through the series of balances and checks -Population Control "Self Regulation" due to the diversity, Adaptive or Hormonal Immune Response, and Innate Immune Response.- And this one, I currently think is REALLY, REALLY important - there is an off switch to TNF-a thought I don't know what it is and seems to be a very complex issue and I haven't looked into it fully yet. But in any case there will be one, I'm sure of this.
Now we all have these varying responses to things such as food, and we read about
things like SERT or Butyrate, or the effects of nicotine, as well as Protease
that Old Mike talks about
a lot and so on. So let's go down this path a little as they popped up when I was reading these papers and their citations. Nicotine
- Nicotine and serotonin in immune regulation and inflammatory processes: a perspective:
Nicotine and serotonin modulate the innate and adaptive immune responses and the inflammatory states. Several nicotinic cholinergic and serotonergic receptor subtypes have been characterized in B and T lymphocytes, monocytes, macrophages, and dendritic cells. The use of knockout mice has allowed a better characterization of nicotinic receptors and their role in anti-inflammatory processes in these cells. Cytokines play a crucial role in controlling inflammatory reactions. Nicotine and serotonin have been reported to regulate cytokine release. Cholinergic mechanisms also play an important role in inflammation through endogenous acetylcholine. Nicotine mimics this effect by activating the cholinergic anti-inflammatory pathways. New concepts of reciprocal interactions between nicotine and serotonin are emerging. The role of nicotine as an anti-inflammatory agent has been established, whereas that of serotonin remains more controversial.www.ncbi.nlm.nih.gov/pubmed/17108054- So now we can look at why perhaps nicotine has the suppression effects from smoking that a lot of people find, but after quitting or upon quitting, wham UC strikes as the levels of 5HT rise again. Butyrate
Absorption of SCFAs is important for colonocyte health and metabolism, epithelial integrity, as well as colonic fluid and electrolyte balance. Butyrate, a key SCFA, is known to have multiple regulatory roles in the mammalian colon, including stimulation of fluid and electrolyte absorption. Butyrate has also been implicated in suppressing mucosal inflammation (16). Decreased production or availability of butyrate has been shown to result in chronic inflammation and acute diarrhea (6). However, to date, the effects of enteric pathogens on the absorption of SCFAs have not been examined. We speculate that decreased butyrate availability caused by EPEC (Food borne e-coli - my words) infection might compromise colonic epithelial integrity, resulting in inflammation of the epitheliumeanimal.snu.ac.kr/aboutus/seminar/070110%ED%9D%AC%EC%98%81EcoilMCT12005.pdf - and here we can learn how the balance or "dysibiosis" of gut bacteria effect Butyrate and why it may be important to include resistant starch as part of a therapy. Also fiber from a resistant starch diet has been shown to prevent the adherence of e-coli and other proteobacteria to to the mucosal lining" Trypsine
Trypsine - is a serine protease found in the digestive system. This study shows that its also a signal molecule - "Mast cells containing tryptase are normally found in the intestine, and their number increases during inflammation (29), suggesting that PAR-2 mediates some effects of mast cell proteases. PAR-2 is up-regulated by interleukin 1α and tumor necrosis factor, supporting its role in inflammation (30).
We conclude that pancreatic trypsin activates PAR-2 at the apical membrane of enterocytes and regulates the intestinal epithelium. Thus, in addition to its digestive function, trypsin should also be considered an intestinal signaling molecule that specifically regulates enterocytes through PAR-2." - so now we can look at excess protease in the gut as a problem from an immune perspective in response to bacteria present in the gut and generated from the "immune cascade", not so much or further exaggerated by food source protease and protease additives
There's many others that I have crossed paths with as well... But these are some of the main ones. Same with upstream effect like Methylation... and well the list goes on again. Altering one of the The Three States of Dysbiosis:
1. Luminal Dysbiosis
2. Mucosal Dysbiosis
3. Cellular Dysbiosis or “Cellular Infection”
Altering one of the states of Dysbiosis alters any one of the main three "check and balances" as I have come to cal them.
i) Population Control - The microbiome make-up itself. Each species keeps one or more other species from being completely dominant. “Self -regulation” would be an appropriate term.
ii) Hormonal Response – or the Adaptive Immune system
iii) Innate Immune System Response
And this causes all of the wild and crazy effects we all see and and perhaps contributes to why we are all different in our responses as the bacteria make-up in us all will ultimately be unique to us.
So again, what seems so complex on the surface to us and these huge chain reactions is really, very, very simple - A normal response to an abnormal gut microbiome.
- and this is nothing new whatsoever - think SCD, GAPS, and even current traditional medical research... they all center around bacteria at the heart of the problem. I'm just trying to offer up some new or recent research and perhaps some ideas to ponder over for those interested.
Now...Cellular Dysbiosis or “Cellular Infection” as I have come to call it
First let's learn about
we learn Mucosa associated but not luminal Escherichia coli is augmented in Crohn’s disease and ulcerative colitis - Their Conclusion: In CD and UC patients only the mucosa associated population of E. coli is augmented and the proliferation is prominent in the ileum of CD and rectum and sigmoid of both UC and CD patients which are sites where the lesions usually are observed. The augmented E. coli population in these sites presented a low number of the virulence markers, possibly meaning that they are not relevant for the disease process.
- This study intrigued the heck outa me...
And based on what was learned previously from all of the above I did some more digging on this particular topic.
So from the above we see for the first time the separation between luminal and mucosa infection. i.e the balance in the lumen is perhaps normal whereas the balance in the mucosa is abnormal. And this correlates to what I keep calling the "Three States of Dysbiosis" - mainly cause I have no idea what else to call them at the moment!
Anyway - Obviously if there's an increased presence or screwy balance of e-coli in the mucosa well they had to get there somehow, and this get's back to all of the above that I wrote. There's multiple pathways set up by a variety of environmental factors and/or genetic factors etc...
Now there's many other papers suggesting not only e-coli, but other proteobacteria as well that have made their way into the mucosa. And one could go on and on, but the bottom line I think is this: They really shouldn't be there - or at least not in large quantities. At least from all of the above you can begin to see how they might get in there....
So more digging and thinking about
the effects of pathogenic e-coli as well as what we learned about
the immune response to normal c-diff and all that good stuff....
Looking into e-coli I came across a term -and at the very same time I was thinking about
the increase in TNF-a that is always talked about
from remicade discussions and papers and talks and explainations from my GI...
My line of thinking was quite simple - I thought to myself "it's obvious there's some kind of infection going on in my body" and it probably has to do with a response to bacteria being were they should not be - OR, simply a higher number of certain bacteria that is constantly throwing the normal "check and balance" procedure out of whack. And this is causing an influx or higher amount of TNF-a to be present where it normally shouldn't be or preventing the "off" switch for inflammation from activating causing a cascade of crazy effects... and now knowing the effects of TNF-a on the SERT expression and how this causes the increase in 5HT and how things all go really wonky from this first "chick and balance" point - and I'm crapping mucus all the time but this AA therapy seems to have tackled that to a degree and.... well, I became curious about
e-coli and came across the following term: Adherent and Invasive Escherichia Coli (AIEC)THIS SCARED THE CRAP OUT OF ME....
I had not seen or heard of this before, even when i was reading about
E-coli effects on SERT
Firstly, before you even read this let's remember that for sure we all have to much TNF-a. Which has always assumed to be from the immune cascade that people get lot's in as Old Mike says and wich is more likely from the immune response and all the stuff we learned from above... Also let's remember once again that TNF-a Down-regulates SERT and causes and increase in 5HT....
And we all have talked about
or read about
the increase of macrophages and so on... and we all (or at least I have) been told many times that there is a wonky autoimmune response going on and that our body does not know how to shut off inflammation 'Flip the off switch".... And this is why I need to take Remicade and so on... to deal with the chronic inflammation and prevent further damage. And so on and so on...Soooooooo, in the words of Old Mike: "Let's look at this mess"
and ugggg.... this is NOT good at all!
"Adherent and invasive Escherichia coli (AIEC) associated with Crohn's disease are able to survive and to replicate extensively in active phagolysosomes within macrophages. AIEC-infected macrophages release large amounts of tumour necrosis factor-alpha (TNF-α) and do not undergo cell death.
The aim of the present study was to determine what benefit AIEC bacteria could gain from inducing the release of large amounts of TNF-α by infected macrophages and to what extent the neutralization of TNF-α could affect AIEC intramacrophagic replication. Our results showed that the amount of TNF-α released by infected macrophages is correlated with the load of intramacrophagic AIEC bacteria and their intracellular replication. TNF-α secretion was not related to the number of bacteria entering host cells because when the number of bacteria internalized in macrophage was decreased by blocking lipid raft-dependent and clathrin-coated pits-dependent endocytosis, the amount of TNF-α secreted by infected macrophages was not modified. Interestingly, dose-dependent increases in the number of intracellular AIEC LF82 bacteria were observed when infected macrophages were stimulated with exogenous TNF-α, and neutralization of TNF-α secreted by AIEC-infected macrophages using anti-TNF-α antibodies induced a significant decrease in the number of intramacrophagic bacteria. These results indicate that AIEC bacteria use TNF-α as a Trojan horse to ensure their intracellular replication because replication of AIEC bacteria within macrophages induces the release of TNF-α, which in turn increases the intramacrophagic replication of AIEC. Neutralizing TNF-α secreted by infected macrophages may represent an effective strategy to control AIEC intracellular replication.www.nature.com/labinvest/journal/v92/n3/full/labinvest2011156a.html
I don't like were this mess is going one bit.... the whole Crohn's-Coltis thing I have and all... Seriously... this is bad news.
On the plus side - I have read that fiber prevents this adhesion... but really, aside from that how does one deal immediately with an issue like this inside the immune cells themselves...
PS - this all took me nine bazillion hours to type out so please excuse any spelling and grammar etc...
Just my thoughts on an extension of what Old Mike has been saying.
My only thought as of today is really to continue with this Amino Acid Therapy to see if I can relieve some of the symptoms and get the 5HT things under control, then use diet and health and maybe fecal transplant or something to try and correct an imbalance.
ALSO one last thing. Adherent and invasive Escherichia coli (AIEC) and other Adhesive and Invasive Bacteria are found in normal people as well... So maybe a fecal transplant when in a major flare from someone with these present in it leads to infection and a dramatic worsening of symptoms??? MAYBE...