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Crohn's Disease Forum » Books, Multimedia, Research & News » MAP: A Possible explanation of how Crohn's develop


 
07-01-2017, 12:43 AM   #31
OleJ
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I appriciate the reference, thank you. Very interesting stuff, that I will look more into. I also started reading up on if exercise stimulates autophagy.

No, I did not culture the blood myself. I sent two blood samples off to a laboratorium. The picture of the mother and daughter cells were in the analysis report that i got back on Tuesday.

Last edited by OleJ; 07-01-2017 at 08:33 AM.
07-01-2017, 09:41 AM   #32
wildbill_52280
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I appriciate the reference, thank you. Very interesting stuff, that I will look more into. I also started reading up on if exercise stimulates autophagy.

.
There are some studies that show exercise does stimulate autophagy and makes contributions to basal autophagy and so does all versions of fasting like intermittent fasting/caloric reduction. Fasting supposedly stimulates autophagy in the brain like alot, and exercise mainly in the muscle. Inositol inhibits autophagy and is included in some b vitamins and its pretty toxic stuff. This is One reason I think the vitamin industry should have stricter regulations. Supposedly the mechanism by which lithium stimulates autophagy is enhancing an enzyme that breaks down inositol, so you might see why a higher inositol status in the body might be a dangerous thing and taking inositol supplements are probably a bad idea and especially a bad idea when ATG protiens/genes are involved in crohn's as well as nod2 which all related to killing intracellular pathogens and autophagy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4502774/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171537/
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07-02-2017, 03:30 PM   #33
OleJ
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Thanks for the reference wildbill. I will share back my bedtime read for tonight:

A Therapeutic Role for Diet in the Treatment of Crohn’s Disease? By Dr. Gilles Monif (PDF)
07-02-2017, 10:45 PM   #34
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It's true the mycobacterium about subspecies is a huge problem for 95% or crohns patients. And it lives in the Lymph system as well. So even when you kill it in the gut it can hold out for years in your lymph


07-06-2017, 03:29 PM   #35
Crohn2357
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Take a good look at this.

In addition, you may want to read kiny's posts about MAP and Crohn's. They're very informative.

Last edited by Crohn2357; 07-06-2017 at 03:48 PM.
07-06-2017, 04:13 PM   #36
wildbill_52280
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Take a good look at this.

In addition, you may want to read kiny's posts about MAP and Crohn's. They're very informative.
Didn't know Vit d played a role in autophagy, but its a "vitamin/hormone" so I'm not surprised that it does as most vitamins play a role in almost every process, to varying degrees. I will also add that taking higher doses of vitamin d is something I will testify to helping me gain greater control over my Crohn's. It would be the #1 supplement I'd recommend.
07-07-2017, 03:48 AM   #37
OleJ
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I also did not know that, I was once treated by a GI at a university hospital who told me about a research project he had done where they gave CD patients Vitamin D, and registered the efficacy (using the CDAI score I think). He told me they concluded Vitamin D was as efficient in maintaining remission as the high dose of 5-ASA.

They did not study the mechanism, but reeding through the PubMed links you sent, it seems stimulating autophagy would be the reason.
So - does any of the established drugs like the biologics, Methotrexate and glucocorticosteroids have an impact on autophagy?

#WARNING: lengthy reply with lots of references..

I found a very interesting article, Autophagy: a new target or an old strategy for the treatment of Crohn's disease?

quote:

" Interestingly, as well as the promising introduction of direct autophagic modulators, several drugs already used in the treatment of Crohn's disease might exert at least part of their effect through the regulation of autophagy. However, whether this phenomenon contributes to or rather counteracts their therapeutic use, remains to be determined and might prove to be highly compound-specific . Here we review the complex and emerging role of autophagy modulation in the battle against Crohn's disease. Moreover, we discuss the potential benefits and deleterious effects of autophagic regulation by both new and clinically used drugs."

unfortunately the full article is not available without subscription.

Below are some articles I found dealing with autophagy and specific CD drugs. They sometime use the word "Apoptosis" which is also a programmed cell death and an important mechanism in the elimination of infected cells. It sounds a bit like autophagy, but I read that they can also be opposites, ind that autophagy can block the induction of apoptosis.

apoptosis and infliximab:
Downregulation of epithelial apoptosis and barrier repair in active Crohn’s disease by tumour necrosis factor α antibody treatment

In conclusion, we have shown a significant decrease in
epithelial cell apoptosis in CD patients after TNF-a antibody
therapy which was accompanied by an increase in epithelial
resistance. Tight junction protein expression did not contribute
to this barrier repair.

note: could this mean anti-TNFa drugs, while suppressing the inflammatory response and thus inducing a clinical improvement ("the parking lot effect" - patients getting infusions, and feeling improvement already when they exit the hospital), actually at the same time inhibit the body's attempts to clear an infection (eg. with AIEC or MAP?).

Another article, however, concludes the opposite, namely that infliximab increases apoptosis:

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease

conclusions:
Conclusions: Our data indicate that infliximab treatment causes a rapid and specific increase in apoptosis of T lymphocytes in the gut mucosa. These findings may explain the rapid and sustained therapeutic effects of infliximab in Crohn's disease.
Infliximab induced activation dependent apoptosis of Jurkat T lymphocytes, possibly altering the Bax/Bcl-2 ratio. In patients with Crohn's disease, infliximab rapidly increased the number of apoptotic T cells in the inflamed mucosa, without affecting peripheral blood mononuclear cells. These data indicate that infliximab functions, in part, as an “immunotoxin” that specifically targets the mucosal T lymphocytes that are involved in the pathogenesis of Crohn's disease



On apoptosis and Methotrexate:

One way MTX works is that it is a competitive inhibitor of many enzymes that use folates, inhibiting synthesis of DNA, RNA, thymidylates, and proteins.
The article Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis however, concludes that MTX also upregulates autophagy, at least in patients with rheumatoid arthritis:

Results:
MTX-induced apoptosis was increased in OA-FLS compared with RA-FLS. However, MTX stimulated the autophagy response in RA-FLS by inducing autophagosome formation, but not in OA-FLS. In RA-FLS, transfection with Beclin-1 small interfering RNA inhibited autophagy and increased susceptibility to MTX, which induces cell death. MTX upregulated autophagy through its ability to enhance the expression of HMGB1 and Beclin-1 rather than through the Akt/mTOR pathway.

Conclusions:
Autophagy induction contributes to resistance to MTX treatment in fibroblasts from patients with rheumatoid arthritis.



Another study on MTX that describe apoptosis:

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

Results:
MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN.

Conclusions:
Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease.


Glucocorticosteriods (Prednisone) and apoptosis :

Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease

From the abstract:
Glucocorticoid hormones (GCH) induce apoptosis in PHA-primed peripheral blood T lymphocytes (PBL) and down-regulate membrane-bound proteins involved in the immune response.

Another one on glucocorticosteroids:

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

From the abstract:
Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents

In summary, it does not seem far fetched to propose that upregulating autophagy and/or apoptosis may explain why usual CD drugs help inducing remission. Further, it makes the case for investing natural ways of stimulating these processes, to see if it can be done without the need for these drugs, in order to avoid the side effects.

Please note: I realise I may be mixing pears and apples in citing studies that describe either Autophagy or Apoptosis. Any thoughts on this?

Also, I realise I could be causing thread drift into the topic "CD and autophagy / apoptosis". Should we maybe start a new thread on this?? Kiny started one in 2012, but it is re. a specific article on autophagy and AIEC. http://www.crohnsforum.com/showthread.php?t=44825
07-07-2017, 08:23 AM   #38
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There's more. There are animal model studies showing that the deletion of VDR gene strongly correlates with an increased disease severity.
07-07-2017, 12:19 PM   #39
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Another thought is how a pathogen would ever get as far as reaching the epithelial surface of the gi tract because it has to get past alot of protective layers , I think the mucus layer and all the good bacteria that are supposed to be protecting and limiting pathogen invasion in the first place. or even when pathogens gain access to immune cells which are supposed to be able to kill them, microbiome also can affect immune cell functions too, lack of signals from microbiome that limit autophagy might allow a pathogen to persist intracellularly.

I don't recall the specifics of GI anatomy at the moment, but before we talk about problems with intracellular bacteria, we also have to address other weaknesses that allowed a bacteria to get that far, it makes you wonder which came first and which is more important. Maybe autophagy and pathogens are all minor details to IBD, at least that's kind of how I feel now. It's the protective factors and perhaps all the beneficial functions of the microbiome. My current opinion is still that genes and pathogens don't matter much in regards to what causes the disease, microbiome might explain it all and possibly not just bacteria but viruses and fungus too.

Last edited by wildbill_52280; 07-07-2017 at 04:41 PM.
07-12-2017, 12:20 PM   #40
OleJ
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Exciting news from Redhill: in the beginning of August they will announce the result of an interim analysis of the efficacy of their antibiotics regimen for atypical mycobacterium infection.
Redhill RHB-104 news (12 July, 2017)
07-21-2017, 06:21 AM   #41
OleJ
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My proposal for a dream study:
1000 crohn's patients in a current state of active disease, confirmed by elevated calprotectin, measured each month for six month(say, average above 200 mg/kg). All of them confirmed positive for MAP infection by culture and PCR, and tested for gut bacteria diversity and - count. 500 remain on their current treatment, 500 participants are put on a treatment that:

a) strengthen the immune system by boosting vitamin and mineral consumption and omega-3 fats intake.
b) adds live, good bacteria to the diet through the consumption of fermented foods (probiotics), along with foods for those bacteria (Prebiotics)
c) reduce the risk of MAP exposure.
d) stimulate autophagy / apoptosis to help the body deal with the infection.

Such a diet treatment could be:
All unprocessed foods. Almost exclusively organic fruit and vegetables, nuts and berries, unheated honey as sweetener, good sources of fatty acids such as coconut and hemp oil, a little fish, a little wholegrain. Fermented foods (such as kimchi and sauerkraut). Prebiotics (such as jerusalem archichokes). Vitamin D supplements.
No processed foods, no dairy, no meat from cows.
Three days of cycling per week, 10km each time.

Then after six month and one year the trends in calprotectin, MAP incidence, and gut bacteris diversity are compared between the two groups.

Who will fund a study like that I wonder. Heck, we should to it here in the forum!
Who wants to join

Even though such a study can never be done blinded I still think the results would tell alot about whether MAP, gut bacteria, and food plays a role in CD.

Regarding antibiotics, by the way, an article recently published on this topic:

Resolution of Crohn's with antibiotics - What are the next steps?

Excerpt:


1) The first step should be for the medical and research communities to move forward in unison with the recognition that Map is another zoonotic mycobacterial pathogen similar to M. tuberculosis

2) The second step should be reevaluation of methods for diagnosis of patients infected with Map. Diagnostic tests have not been standardized for use in humans. Current methods of testing for the presence of Map in blood and other tissues should be improved and should be robust and sensitive. The current diagnostic tests in humans are not approved by the US FDA and are probably relatively insensitive. Based on prevalence studies such as Naser’s culture of blood samples from CD patients, it is estimated that at least 50% of CD patients are infected with Map

3) The third step should be implementing a study on the effects of all antimycobacterial antibiotics (current and experimental) on Map. Numerous clinical trials of antibiotics in CD [... references ...] have been conducted on the theory that Map or some other bacterium is the etiologic agent. Several meta-analyses of controlled trials comparing antibiotics to placebo have concluded that antibiotic therapy has a significant effect of superiority to placebo

4) Although a large randomized controlled clinical trial is under way sponsored by RedHill Biopharma Limited, Tel Aviv, Israel, ‘[...] there is an urgent need for a trial without restrictions on evaluating different combinations of antibiotics for treatment of clinically ill patients infected with Map. The focus of the RedHill trial is on the use of a proprietary drug formula RHB-104. [...] Many of the parameters of the trial would overlap those of the RedHill trial, but the trial would be restricted to patients clearly infected with Map


Last edited by OleJ; 07-21-2017 at 09:57 AM.
07-21-2017, 05:15 PM   #42
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This may sound silly but i think my crohns was brought on by a heavy dose of antibiotics. Had cellulitis. multiple shots in the rear. and 2 or 3 oral antibiotics. Was not 2-3 months later my symptoms started. Anything? First time post
07-21-2017, 11:05 PM   #43
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This may sound silly but i think my crohns was brought on by a heavy dose of antibiotics. Had cellulitis. multiple shots in the rear. and 2 or 3 oral antibiotics. Was not 2-3 months later my symptoms started. Anything? First time post
I don't think that's silly at all. I'm convinced that mine was caused by overuse of antibiotics. I had chronic sinus problems in my late teens and early twenties and was given 2-3 courses of antibiotics per year. I was diagnosed with IBD at 24.

I wish I had known better and requested an evaluation from an ENT to explore the constant sinus problems, rather than just taking the antibiotics my GP prescribed. I was always sensitive to the antibiotics. I would end up having cramping and diarrhea with almost every one I took. I definitely think the frequent courses of antibiotics over a long period of time triggered by Crohn's.

What's done is done, I can't do anything to reverse it now, but I do stay away from antibiotics when possible. And it's definitely something I'll be conscious of with my daughter. Antibiotics will only be used when absolutely necessary.
07-22-2017, 12:09 AM   #44
OleJ
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I agree, it would make sense that the usually given antibiotics would erradicate some of the good bacteris and thus protective layers in the gut.
MAP, AIEC and other pathogen bacteria would then have the conditions needed to multiply and cause inflammation which destroy the protective layers of the gut wall. Maybe, because of the gut wall damage, partially digested food items are able to reach the deeper layers of the gut wall where they and no supposed to be, causing even more inflammation.
This would explain why enteral nutrition works - then the latter mechanism stops.

One of the important questions is if antibiotics against intercellular bacteria such as MAP will have a similar effect? It would be very interesting to hear from someone on Anti-MAP therapy.
07-22-2017, 10:50 AM   #45
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OleJ, as I said earlier, you may want to read kiny's posts about the pathogenesis of Crohn's Disease, and related topics.

This.

Read the whole of this article, published in 2009.

Although CD is immune mediated, it is not an autoimmune disease, as the immunological process appears to be triggered by the content of the gut lumen rather than a self-antigen.
To date, CD is widely accepted as a genetically determined immunological disease that manifests principally in the gut and is triggered by bowel contents. But this is as far as scientific consensus and certainty go.
The first breakthrough toward an understanding of the pathogenesis of CD came in 1976 when Anthony Segal demonstrated impaired influx of granulocytes into skin windows in CD patients (Segal and Loewi, 1976), a finding that was confirmed and extended to the gut in 2006 (Marks et al., 2006). As CD is an inflammatory disease, it was hard to imagine a more paradoxical and provocative finding than impaired inflammation (Korzenik, 2007). Moreover, although CD is principally localized to the gut, these studies claimed that the inflammatory defect was systemic and affected various tissues, such as the skin, that were not affected clinically. However, as the Hungarian physiologist Albert Szent-Györgyi pointed out, “a discovery is a discovery because it is at variance with accepted knowledge.”

In a clinical investigation reported by Smith et al. (2009) in this issue, Segal's group studied inflammation in response to skin wounded with heat-killed bacteria. Consistent with their past studies, patients with CD had impaired inflammation at the wound site, as demonstrated by tracking intravenously injected, radio-labeled granulocytes. Clearance of Escherichia coli at the sites of injection was also impaired in patients with CD, but not in those with another inflammatory disease, ulcerative colitis, or in healthy subjects. Notably, impaired bacterial clearance was evident for high, but not low, bacterial doses. Overall, these experiments suggest a causal link between impaired inflammation and impaired bacterial clearance. The intestine was not wounded with bacteria, but the skin defect was proposed to be systemic and to involve the gut in particular. In fact, E. coli was chosen for these studies because of its abundance in the intestinal flora. It is important to reiterate that the defect was seen only with high bacterial loads, given that the highest bacterial load in the human body is found in the intestinal tract, which is the primary target of CD. Impaired bacterial clearance presumably results in chronic inflammatory responses, accompanied by accumulation of granulomas consisting of macrophages and T lymphocytes. Therefore, in this model, excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of CD pathogenesis
Macrophages from the patients are intrinsically defective, with impaired secretion of cytokines that are normally translated but internally degraded. Because of insufficient production of cytokines and chemokines, there is impaired attraction of granulocytes to mucosal breaches. Impaired acute, granulocytic inflammation results in impaired clearance of bacteria and debris from the gut wall, itself resulting in chronic, granulomatous inflammation.
and so on...

Read the discussions in these topics, for example:
http://www.crohnsforum.com/showthread.php?t=71588
http://www.crohnsforum.com/showthread.php?t=65923
http://www.crohnsforum.com/showthread.php?t=47428
http://www.crohnsforum.com/showthread.php?t=45026

There are many others that might be of interest to you.


On a side note, I agree with kiny on the fecal transplants; and not only that, I think it may be very dangerous for someone with Crohn's Disease, considering the immunodeficiency hypothesis, the use of immunosuppressants, leaky gut, impaired gut flora, malnutrition etc...

"and do you believe fecal transplants are worth trying?"

I think they are worthwile for C Difficile and perhaps UC. If crohn's disease is related to AIEC or MAP they wouldn't be very effective, AIEC are present in submucosa and both are intracellular, fecal transplants wouldn't be an effective treatment for them.
07-22-2017, 05:00 PM   #46
OleJ
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thanks Crohn2357. There is some very interesting discussion points and knowledge in those threads.
07-31-2017, 04:22 PM   #47
OleJ
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another announcement from Redhill just came out. I wonder if this is their interim safety/efficacy report due in august 2017? If so I am a little disappointed, nothing is revealed about the efficacy of their antibiotics-regimen RHB-104, as far as I can see..

31th JULY 2017:
RedHill Biopharma Announces Unanimous Positive DSMB Recommendation for Continuation of the Phase III Study with RHB-104 for Crohn’s Disease
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