Ulcerative Colitis / IBD

mattyb

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Yeah, you could take the route of directly trying to block HDC to spare histidine. I think it could work for a while, how long, I'm not sure. My guess is HDC would want to upregulate in response, or some other side effect could happen. But it could be worth a shot.
 

mattyb

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833
It's the nicotine, patches and gum work as well as smoking for improving UC.

The mechanism isn't clear yet, but nicotine helps return some function for parkin deficient animals. Parkin is a ligase that labels defective mitochondria so they can be targeted for degradation (promotes mitophagy). Loss of function mutation of the parkin gene is the most common cause of familial parkinson's disease. The mitochondria have nicotinic ACh receptors on them, and one study found that nicotine inhibits NADH dehydrogenase (complex I of mitochondria), decreasing oxygen consumption and lowering superoxide formation (inhibiting metabolism to more tolerable levels). Nicotine may also have some free radical scavenging abilities, but overall it's mechanism isn't super well defined especially in the context of UC.

And remember, it's not all about fusion/fission. It's also important to consider actual mitophagy (total reduction in mitochondrial mass and complete degradation of defective mitochondria).
 

Canari

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1,609
@HerrFisch Have you thought about the idea of a 100% protein food? A zero carb approach? Some people that were bleeding are recovering with it. Very easy diet, just go up to as much meat as you can, it will be around 2 kgs per day to keep you fit. Some people get improvement in less than a week, with stabilisation of the number of times they go to the toilets, and total remission of depression. It takes 1 month though to get totally used to it and change the gut bacterias, and up meat in more meals, to increase stomach acid. Usually they stabilise with a sort of IF and 2 meals a day.
 

Helen

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@HerrFisch

I thought about this. and looked at your case. your Dao is working and its levels are ok.( DAO has histidine in it, and copper) Your HDC is activated.

SO I think in this case you might try to bind copper with lysine instead of histidine.. Bind copper with lysine. This will increase your thyroid since lowered free copper will stop breaking down tyrosine. And this will decrease your MAO. so it will increase serotonin. This will increase ACTH and your cortisol levels.

This higher cortisol will block HDC. Lysine will also lower arginine leves which will create less ROS.
 

Helen

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You can buy simple GHK/ Or just take these 3 amino acids. You can add vitamin C to the lysine.
 
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HerrFisch

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Guys, it seems like since I took some Histidine, I keep having diarrhea. And cant really get rid of it.

I took 2g of Carnosine for over 4 weeks and I saw big improvements. Then I tried 2g of Histidine just because I thought it would be kind of similar to Carnosine. And cheaper. But the first day of Histidine diarrhea started. Thats now 2-3 weeks ago.

My thoughts on it are atm that:
- My Histamine got out of control because of little copper
- Probably to little copper for enough DAO etc
- 10-12 fold increase of HDC bc of UC, no other chance for histidine to do anything else than go into histamine

I stopped pretty much everything 2 weeks ago but am taking some Quercetin to hopefully lower somehow HDC a little / stabilize mast cells. It helps a little.

Maybe that why I had so much free copper. To keep Histamine low? Maybe thats why I felt better in flare than in remission?

I should have stopped with my "try" to lower free copper in december. Just to see where Im at. I probably did too much of the good.
But I thought by starting chelation, more copper will come out because I read so much about high copper problems while chelation.

I think binding free copper with Lysine and vit C could actually really be better than histidine in my case.

What do you guys think?
 

HerrFisch

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1,064
@mattyb

Could it be anemia in which one with UC is trapped?

Upregulated HDC -> high histidine to histamine conversion (high histamine = high inflammation markers like Tnf-alpha IL-6 etc)
No spare histidine -> too much free copper
Too much free unbound copper -> copper "toxic"
toxic -> low iron, high hepcidin, low hemoglobin, low cortisol -> low oxygen
increased H2o2 to increase oxygen transport ???
H2o2 -> upregulated HDC

Does anyone know what reaction happens when you mix hydrogen peroxide with copper?

Superoxide + SOD = H2o2. If there is no iron, there is no catalase for H2o2 to get broken down to water and oxygen.

I dont know from what side to start, but couldn't it be the other way around?
Like from too much h2o2 you go to high mitochondrial fission?
Or mitochondrial fission increases because of missing oxygen /iron?

- Without enough oxygen, increase in NADH and glycolysis, ETC not working properly, high lactic acid

H2o2 Iron uptake

"Under these conditions, iron becomes especially harmful because it catalyzes the generation of free radicals from reactive oxygen species released by inflammatory cells. Here, we show that the exposure of various cell types to sustained H2O2 results in the up-regulation of TfR1 expression and accumulation of iron."

Seems like the body does not want to use iron, but then stays with excess h2o2 and accumulated iron.

Iron and Copper toxicity?
 

mattyb

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833
During inflammation the body will retain iron and bind it with ferritin, which prevents it from oxidizing. So iron is present but biounavailable. You see this all types of inflammatory conditions ranging from UC/IBS to rheumatoid arthritis. So the body largely controls things so iron toxicity doesn't go overboard. The body also retains iron because this inflammation is telling the body there's bacteria and viruses present, so it restricts access to iron because iron is often the limiting mineral needed for these infections to spread further.

I think H202 is upregulated because the superoxide anion is formed from several sources - excessive mitochondria from fission with impaired metabolism, and from inflammation via NADPH oxidase. Although H2O2 can serve as a source of oxygen for oxygenation of tissues, you have to remember that the rate of formation of H2O2 outpaces the rate of degradation of it. The body also has other more efficient means of providing oxygen when low oxygenation is present, and this is why angiogenic factors are often upregulated in inflammatory diseases, which causes more bloodflow and therefore more oxygen to be delivered to the tissues.

The order of operation here isn't very important. Missing oxygen or iron (or too much of each) could drive mitochondrial fission, or too much H202 could drive fission, or too much fission can drive too much H202. It doesn't really matter. You could have a heavy metal toxicity that was driving this process. Or it could be radiation causing excess formation of superoxide and H2O2 which caused fission to occur. Maybe it could even start from a histidine deficiency. Maybe copper poisoning itself could cause it. Tons of ways to get that cycle started. Your cycle of things overall looks to be right, but it just doesn't really matter that much as long as you have too much mitochondrial mass at some point because that's the one issue that won't fix itself over time (other issues will fix themselves as long as you limit exposure to the cause, like in the case of copper poisoning or heavy metal exposure). Once the cycle starts, the start doesn't matter as much.

What you end up with is a condition of too much fission, too much mitochondrial mass, and too many defective mitochondria, and it can only be treated by upregulating mitophagy. All the other problems won't get fixed once this problem has arisen. It's the blockade in the way of healing. You can't get iron or copper metabolism back on track when it's being fudged up from this.

You need to force the body to eat those guys up. Just check out r/fasting on reddit, I've found quite a few success stories on there of people fixing IBS with longer fasts.
 

HerrFisch

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Thanks really nice writing! Appreciate it.

But UC most likely is not viral or bacterial, so what if UC is just the body failing at determining the pathogen and being stuck with consequences? And maybe even that consequence is mitochondrial fission.

And what if there is more behind just upregulated fission? Maybe there is a reason for that? Like missing cortisol production due to missing iron or something?

And if there is upregulation of mitochondrial fission, maybe this upregulation can go away as easy as it started?
[I thought damaged mitochondria is more like diseases of old people?]

Though I want to dig deeper and I think there is the possibility for maybe another explanation or way out.
Even with my little understanding of those things, there are so many things that fit together. I guess I just need more time to actually grab it.

Autophagy is required during cycling hypoxia to lower production of reactive oxygen species
Serum hepcidin in inflammatory bowel diseases

"Therefore, Drp1-induced mitophagy may account largely for the metabolic reprograming and cancer cell survival.Overactivation of mitochondrial fission was recently shown to promote tumorigenesis and cancer invasion"

There are so many ways how this could start, that make sense to me. I just need more knowledge. Lol

Pathogenic inflammation, dont want / cant use iron, chronic inflammation, cortisol deficiency, histamine & inflammation markers increase, more inflammation, metabolism increases to increase cortisol

Its just a cycle needed to be stopped.
 

mattyb

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833
That's exactly it, it's a cycle that just needs to be broken. And also just like you said at the beginning of your post, this is the body responding to something it think is a pathogen, but it isn't. So it's stuck. It's doing everything right to combat a pathogen, because that's the only problem it knows how to solve.

And don't think of the problem as purely JUST fission. Fission is just when one mitochondria splits into 2, often times to separate the defective part of a large mitochondria from the working parts. Then the defective parts are supposed to be broken down, but in inflammatory diseases they often aren't. A better focus is on the increase in mitochondrial mass. Re-fusing the split mitochondria will still keep the mitochondrial mass the same, so looking just at things like DRP-1 regulation is not sufficient to address the real issue. What we really want are those defective parts of the mitochondria to be consumed through mitophagy, decreasing total mitochondrial mass. Upregulating mitophagy is hard, mainly because it's reliant on several processes working together (AMPk, DRP-1, parkin, PINK1), and my suspicion is that in the gut there is also cross-talk between bacteria and mitochondrial regulation. The only 100% reliable way I know of upregulating this entire pathway is through nutrient deprivation (fasting), and possibly nitrogen deprivation (no protein). And without this problem being fixed, you can't break the cycle - because once this starts it will always keep kicking that cycle into gear, even if you fix other aspects of the cycle.

This is an interesting article on how two genes for autophagy are implicated in raising risk of developing Crohn's disease. In one part, they mention that one of these genes is part of a triad of genes that raise the risk of developing CD by 20x.
Role of Autophagy and Autophagy Genes in Inflammatory Bowel Disease
 

mattyb

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833
Given that nitrogen deprivation can upregulate mitophagy, a juice fast (consuming as many calories as you want through juice) could be enough to break the cycle in IBD/Crohn's/UC. I've definitely heard lots of anecdotes of people doing juice fasts to treat gut disorders.
 

mattyb

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833
Basically. At most, 500mL of veggie/fruit juice will have 2-5g of protein. I imagine if you lifted weights during this time too it would drive any protein towards muscle synthesis and keep it away from the gut. We want to maximize auto/mito-phagy in the gut and minimize it elsewhere.

I don't think it would be a good idea to do it mid-flare. Probably best to wait until things calm down, I think it could make a flare worse.
 

HerrFisch

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1,064
Im not sure if i'm in a flare right now or not. Its weird. It feels like its high histamine only.
I tried loratadine for some days now and it calms everything down pretty good.

I saw some articles about antihistamine being better than prednisolone for UC.
I still wonder if there is any chance to lower HDC / Histamine in the middle of inflammation.

Antihistamines just work on the receptors. And DAO supplements only on the histamine from food right?
So are there any other ways to lower Histamine in the body or in the cell?

Of course histidine depletion, lowering immune system, fasting, lowering ROS would be the obvious ways.
 

mattyb

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833
That's a really good question!

Antihistamines would be great for mid-flare. The problem is when you go off usually the body is more sensitized to histamine. But if you went off and mid-fast (even a short 3 day fast) I would imagine the histamine would have limited ability to exercise it's function since immune cells wouldn't have sufficient energy to function and would be getting consumed via autophagy.

Epicatechin gallate was the first thing that came up when I looked up dietary HDC inhibitors. It's very high in green tea and carob flour, and also found in buckwheat, grapes, blackberries, and apples.
 
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mattyb

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833
EGCG sounds really promising.

A pilot study to evaluate the safety and efficacy of an oral dose of (-)-epigallocatechin-3-gallate-rich polyphenon E in patients with mild to mode... - PubMed - NCBI

"Twenty patients were randomized to active therapy or placebo in a 4:1 ratio. Nineteen subjects received >1 dose of study medication (15 Polyphenon E, 4 placebo). The mean UC disease activity index score at study entry was 6.5 ± 1.9 in the treatment group and 7.3 ± 1.7 in the placebo group. After 56 days of therapy, the response rate was 66.7% (10 of 15) in the Polyphenon E group and 0% (0 of 4) in the placebo group (P = 0.03). The active treatment remission rate was 53.3% (8 of 15) compared with 0% (0 of 4) for placebo (P = 0.10). Polyphenon E treatment resulted in only minor side effects."

Other:
[Protective effect of epigallocatechin-3-gallate on inflammatory bowel disease: experiment with rat models of induced colitis]. - PubMed - NCBI