Fecal Transfusion – a treatment for UC?

http://www.paratuberculosis.org/pubs/proc9/abst185f_o4.htm

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BACKGROUND:

We have shown that the “immuno-modulators” methotrexate and 6-MP and the “anti-inflammatory” 5-ASA inhibit MAP growth (www.PLoSONE.org) and concluded that their most plausible mechanism of action in several idiopathic diseases is as antiMAP antibiotics. Thalidomide is an “immunomodulator” used in multiple “auto-immune” and “inflammatory” diseases and the mycobacterial diseases leprosy and tuberculosis. We now test the hypothesis that thalidomide inhibits MAP growth.

METHODS

Thalidomide (+-) and (+) and (-) and its two components, phthalimide and 1-hydroxy 2,6 piperidine dione (HPD) were evaluated in culture of two strains each of MAP (ATCC 19698 [bovine] & Dominic [human]) and M. avium subspecies avium (ATCC 25291 & 101.) We used a radiometric (14CO2 Bactec(R)) detection system. Inhibition is indicated by “percent decrease in cumulative Growth Index” (%-DcGI) from control.

RESULTS:

Phthalimide has no dose dependent inhibition on any strain. There was no dose dependent inhibition on either M. avium strain with thalidomide or its components. With the two MAP strains, there is dose dependent inhibition with thalidomide (+1); Dominic (31%-DcGI) and ATCC 19698 (26%-DcGI) at 64microg/ml. Thalidomide (+) is more inhibitory than (-). HPD is, on a weight for weight basis, the most inhibitory agent evaluated; Dominic (46%-DcGI) and ATCC 19698 (44%-DcGI at 64microg/ml)

CONCLUSIONS:

We show in vitro heretofore-undescribed inhibition of MAP growth by racaemic thalidomide. Thalidomide (+) is more potent than (-). Of thalidomide’s two moieties, phthalimide has no antiMAP activity and HPD is the active component in inhibiting MAP growth. We suggest that since 1942, initially with 5-ASA, the medical profession has unknowingly been treating MAP infections. These data are compatible with our concern that MAP is zoonotic. We conclude that all idiopathic “autoimmune” and “inflammatory” diseases, empirically treated with medications that we show are active against MAP, should now be evaluated for MAP as the etiological agent.

FDA approves Thalidomide for Hansen’s disease side effect, imposes unprecedented restrictions on distribution.
http://www.fda.gov/bbs/topics/ANSWERS/ANS00887.html

Redeeming thalidomide
http://pubs.acs.org/hotartcl/mdd/00/jun/mddkling.html

Remicade’s anti-TNF activity might also be useful for leprosy (a known mycobacterial disease), but there haven’t been any trials of remicade/infliximab for Leprosy (Hansen’s Disease), presumably because the manufacturers know that the average third-world leper can’t afford $30K+ a year to be maintained on remicade, and thus won’t spend the huge money necessary for the relevant clinical trials.

But Thalidomide, the poor man’s anti-TNF drug, is long out of patent, and is cheap, and so gets used for the poor lepers. But there is a fightback in the leprosy medical community, primarily because of the nasty birth defects that Thalidomide causes.

No Role for Thalidomide in Leprosy
http://www.paho.org/English/AD/DPC/CD/thalidomide.htm

Thalidomide has been trialled for Crohn’s Disease.

Thalidomide reduces tumour necrosis factor {alpha} and interleukin 12 production in patients with chronic active Crohn’s disease
http://gut.bmjjournals.com/cgi/content/abstract/50/2/196

Thalidomide: New uses for notorious drug
http://www.mayoclinic.com/health/thalidomide/HQ01507

So the relative success of treatment of Crohn’s Disease with Remicade is NOT an argument against a mycobacterial cause. In fact, if the Crohn’s Disease to Leprosy analogy that has been made by some researchers[2,3] is true, then Remicade treatment in Crohn’s could be an argument FOR a mycobacterial cause.

1. Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial.
http://bmj.bmjjournals.com/cgi/content/abstract/328/7454/1459

2. Comparisons with leprosy, tuberculosis and Johne’s disease: is Crohn’s disease caused by a mycobacterium?
http://www.paratuberculosis.org/proc7/abst6_p6.htm

3. Mycobacterium avium subspecies paratuberculosis in the causation of Crohn’s disease
http://www.wjgnet.com/1007-9327/6/630.asp

Treatment of active Crohn’s disease with recombinant human granulocyte-macrophage colony-stimulating factor.
http://www.ncbi.nlm.nih.gov/pubmed/12433518

GM-CSF treatment for Crohn’s disease: a stimulating new therapy?
http://www.ncbi.nlm.nih.gov/pubmed/12498002

Crohn’s disease: an immunodeficiency?
http://www.ncbi.nlm.nih.gov/pubmed/12840672

Sargramostim for active Crohn’s disease.
http://www.ncbi.nlm.nih.gov/pubmed/15917384

This therapy does fly in the face of current thinking in regards to how to treat Crohn’s Disease. Most attempts to treat Crohn’s Disease are targetted at suppressing the immune system, not boosting it. Here are a couple of references that discuss the importance of *reducing* GM-CSF levels.

Increased production of granulocyte-macrophage colony-stimulating factor in Crohn’s disease–a possible target for infliximab treatment.
http://www.ncbi.nlm.nih.gov/pubmed/15201577

Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease.
http://www.ncbi.nlm.nih.gov/pubmed/15201575

How to resolve the apparent paradox, i.e. whether to treat Crohn’s by boosting or by suppressing the immune system? The answer to that probably lies in the fact Crohn’s may be several different diseases presenting the same or a similar profile of symptoms: Crohn’s is not a disease but a SYNDROME. Until we can differentiate between the different underlying disease causes, we’ll be stuck with the current situation of one-size-fits-all therapy. It is to be hoped that the Sargramostim/Leukine/GM-CSF trials will not only seek to treat CD, but also to determine *why* a significant percentage (~40%) of Crohn’s patients experience improvement when their immune systems are so boosted, while the rest experience insignificant change. If some clear indicator can be found that differentiates between the two groups, then that would be a huge leap forward in the clinical treatment of Crohn’s Disease.

Although the mainstream medical community may be surprised by the GM-CSF results, I for one am not. After all, one of the primary effects of Granulocyte-Macrophage Colony-Stimulating-Factor (GM-CSF) is to boost the activity of Macrophages, the key anti-microbial component of the innate immune system. Ineffectiveness of macrophages to phagocytose mycobacteria is the key failure of the immune system that leads to granuloma formation in mycobacterial disease.

MECHANISMS OF BACTERIAL PATHOGENICITY: Bacterial Defense Against Phagocytes
http://textbookofbacteriology.net/antiphago.html

Immune Evasion by bacteria
http://crohn.ie/archive/primer/imunevad.htm

It is quite likely that in the short term, both suppressive and booster therapies will work in relieving Crohn’s Disease symptoms. However, in the longer term, the outcomes would be very different.

1. Therapy which boosts the immune system would ideally result in elimination of the infection causing inflammation.

2. Suppression, on the other hand, would result in a failure of the Th1 immune response, and thus failure to eliminate the causative infection. This would result in the immune system response changing to a Th2 response, mediated by the humoral arm of the immune system, which is
almost always ineffective in controlling mycobacterial infections.

Check the references below.

The bit I find most interesting is the reliance on human opinion and experience to differentiate between the diseases. The reason for this is because we’re dealing with diseases that are classified by the damage that results from having them, not by what causes them.

Personal opinion: The vast majority of “autoimmune” diseases are caused by infections with one or more of a range of bacteria, and where the symptoms can be extremely similar.

Research into all of these diseases needs a fundamental shift in paradigm. Looking solely at the body, its reactions, and how those reactions result in tissue damage is incapable of delivering a cure.

Consider if you drove your car home every day along a road that was covered in shards of glass. When you get home, you see that you have flat tyres. You examine the car, you examine the tyres, you work out the weight distribution on the wheels, trying to imagine a situation where the car tyres “spontaneously” blow out. You spend a fortune, getting an army of “experts” to try to figure out why your tyres keep blowing out. They spend a fortune in money and time trying to figure the huge range of parameters that can affect the car, even going so far as to revisit the production process for the car, watching how it is constructed in the factory, and trying to discover the “design flaw” that results in the tyres spontaneously bursting.

And you still keep getting flat tyres everyday.

Until you look at the surface of the road you’re driving on, and realise that it’s covered in glass, which damages your rubber tyres, you’re not going to have the faintest clue as to why your tyres are flat everyday.

1. An unusual presentation of Behcet’s disease: intestinal perforation.
Pirildar T, Keser G, Tunc E, Alkanat M, Tuncyurek M, Doganavsargil E.
http://www.ncbi.nlm.nih.gov/pubmed/11254244

2. Crohn’s disease with Behcet’s syndrome like appearance: a case report.
Kallinowski B, Noldge G, Stiehl A.
http://www.ncbi.nlm.nih.gov/pubmed/7886973

3. Pathology of chronic inflammatory bowel disease in children.
Domizio P.
http://www.ncbi.nlm.nih.gov/pubmed/8003743

4. Bechet’s colitis: a differential diagnosis in inflammations of the large intestine.
Kyle SM, Yeong ML, Isbister WH, Clark SP.
http://www.ncbi.nlm.nih.gov/pubmed/1859318

5. Prerequisites for therapy of inflammatory bowel diseases. Pathophysiology–symptomatology–diagnosis
Haag K, Scholmerich J.
http://www.ncbi.nlm.nih.gov/pubmed/1855748

Actually no, no way has yet been found of shortening the duration of RMAT.

Prof John Hermon-Taylor, as reported in his “Two year outcomes analysis…” treated patients for between 6 and 35 months, with a median of around 18 months. It is only a small percentage of patients that are treated for as little as six months.

Dr. T.J. Borody in Australia treats *all* of his patients for a minimum of 24 months, and adds Clofazimine (Lamprene) to the basic regime. This is the protocol upon which the Australian clinical trial is based.

Dr. Shafran is attempting to lower both the dosages and the duration of treatment, with good reason, because these drugs can be difficult to tolerate, especially for such long periods of time, not to mention the expense (approx US$500/month), a vital consideration if you have very little/very poor medical insurance. However, one must be very careful when treating bacterial infections with antibiotics at too low a dosage, because resistance can develop. Dr. Shafran is also adding probiotics to his regime, I believe to improve tolerance and assist in the reduction of inflammation.

There are other conceivable ways to reduce the duration of treatment.

1. By vaccination with a harmless mycobacterium, e.g. M. phlei or M. vaccae. Such a vaccination would assist in antigen uptake by the immune system, which would hopefully increase the efficacy of any antibiotic treatment. More on this interesting approach at

http://crohn.ie/archive/research/vaccine/m_vaccae.htm

Prof. JHT is also pursuing the possibility of a subunit vaccine, using raw DNA vaccination.

2. Hyperbaric Oxygen Therapy. Although no one is following up this possibility, I firmly believe that it could be of enormous benefit. If I ever hear of any work in this area, I’ll report on it.