Radical Induction Theory of Ulcerative Colitis

The Radical induction theory of ulcerative colitis proposes that the disease, ulcerative colitis, is initiated by free radical damage to the membrane lining the colon. The theory was proposed in April, 2005. Although this is a comprehensive hypothesis explaining a disease of previously unknown causation, there is no scientific consensus as of yet accepting the theory. If the theory is correct there would be obvious treatment strategies. These should not, however, be considered standard treatments.

The radical induction theory proposes that ulcerative colitis is initiated by aberrant cellular metabolism that results in the production of excess hydrogen peroxide and related chemicals. The hydrogen peroxide is produced in cells in the wall of the intestine, diffuses from those cells, and accumulates between those cells and the colonic epithelial barrier, a thin membrane that separates the cells in the wall of the intestine from the digesting food and bacteria in the intestine. The hydrogen peroxide and related chemicals damage the membrane, causing it to slough off. This exposes the cells of the intestinal wall directly to the bacteria inside the intestine. The immune system then mounts an attack on the bacteria, drawing white blood cells to the intestinal wall. In attacking the bacteria, the white blood cells secrete toxins, including hydrogen peroxide, leading to progressive damage to the membrane and damage the cells in the wall of the intestine, resulting in inflammation, ulceration and bloody diarrhea.

Following treatment, or sometimes without treatment, the disease will go into remission. At that time the colonic epithelial barrier is re-established. The disease will remain in remission until the barrier is damaged again, at which time the disease will flare up.

Hydrogen peroxide

Hydrogen peroxide (H₂O₂) is familiar as a cleansing and disinfecting agent in the medicine cabinet. It is produced in the body as a side-product of the mitochondrial electron transport chain. Rather than being passed on to the next step in catabolism, an electron instead sometimes reacts with molecular oxygen in the vicinity, producing the superoxide radical, which then reacts with water, producing hydrogen peroxide.

Hydrogen peroxide is a relatively stable molecule that is capable of moving through cell membranes away from the site of generation. It is, however, capable of generating the hydroxyl radical, a highly reactive free radical that can react with many types of molecules, damaging their structure and function. Production of the hydroxyl radical is by the Haber-Weiss reaction, catalyzed by iron in the reduced, or ferrous, state.

In addition to leakage from the electron transport chain, hydrogen peroxide is also produced as a byproduct by enzymes that break down complex molecules. Excess Vitamin B6 is broken down by pyridoxine 4-oxidase, yielding hydrogen peroxide. Conversion of homocysteine to homocystine by the enzyme MTHFR also produces hydrogen peroxide.

Because hydrogen peroxide is capable of yielding damaging free radicals, the body needs mechanisms for removing it. The concentration of hydrogen peroxide reflects a balance between processes creating it, and processes removing it. Anything that increases production, or slows removal, leads to a build up of hydrogen peroxide and, under the radical induction theory, increased damage to the protective membrane.

Hydrogen peroxide removal mechanisms

The main mechanism by which cells remove hydrogen peroxide is through reduction with glutathione (GSH). This is accomplished with the enzyme glutathione peroxidase (GPx), which requires selenium as a co-factor:

2GSH + H₂O₂ → GSSG + 2H₂O

Oxidized glutathione (GSSG) is converted back to glutathione by NADPH with the enzyme glutathione disulfide reductase (GDR):

GSSG + NADPH + H⁺ → 2 GSH + NADP⁺

The electrons needed to neutralize hydrogen peroxide come from the NADPH, which is produced by the pentose phosphate pathway (PPP), which is mediated by the enzyme 6-phosphogluconate dehydrogenase (PGD)

Aberrant metabolism

A susceptibility gene has been identified on the small arm of human chromosome 1 (1p36). Persons with this aberration have a greater risk of developing ulcerative colitis. This locus codes for two enzymes that may affect hydrogen peroxide levels: MTHFR and PGD.

The variant MTHFR enzyme tends to lead to elevated levels of homocysteine, producing excess hydrogen peroxide as it is converted to homocystine. The variant PGD enzyme slows the PPP cycle, reducing the amount of NADPH available for reduction of hydrogen peroxide.

Observations consistent with the theory

If hydrogen peroxide is introduced into the colon through an enema or other procedure, a condition similar to ulcerative colitis results.

Knockout mice lacking the enzyme GPx, and therefore lacking the main mechanism for removing hydrogen peroxide, develop a condition similar to ulcerative colitis.

The barrier membrane is often missing from a larger area of the colon than the actual inflamed area, suggesting that the loss of the membrane preceded the inflammation, and that the inflammation is spreading behind the lost membrane.

The absence of protective membrane in areas that are not inflamed suggests that, rather than inflammation causing membrane loss, membrane loss causes inflammation.

The fact that ulcerative colitis is usually continuous from the rectum up the colon is consistent with the initial loss of the membrane at a weak point, followed by sloughing of the membrane from the weak point.

The radical induction theory offers an explanation for why the inflammation usually appears to begin in the rectal area.

The radical induction theory explains a fundamental difference between ulcerative colitis and Crohn's disease in which inflammation appears in patches rather than a single, continuous affected area.

The radical induction theory explains the therapeutic action of 5-ASA as that of a free radical trap as well as an anti-inflammatory drug.

Ulcerative colitis is more common in people with genetic variants involving metabolic pathways that could produce elevated levels of hydrogen peroxide and related chemicals.

Ulcerative colitis has been reported following administration of vitamin B6, which is metabolized with generation of hydrogen peroxide as a by-product.

Ulcerative colitis has been reported following administration of iron as a dietary supplement. Iron catalyzes the conversion of hydrogen peroxide to the more active hydroxyl radical.

The radical induction theory offers a straightforward explanation for the intermittent nature of ulcerative colitis: the disease starts when the membrane sloughs off. Following treatment, or of its own accord, the membrane is restablished. The disease remains in remission until the membrane is damaged again.

The radical induction theory offers a biochemical basis for the effect of psychological stress in initiation of the disease.

Removal of the colon usually cures ulcerative colitis, including the extra-intestinal manifestations of this systemic disease. This suggests that the cause of the disease is in the intestine itself, and not in the immune system or some other part of the body.Am Coll Gastroenterology, Practice Guidelines, ^*

Comparison with other theories

The radical induction theory appears to be the first comprehensive theory attempting to explain ulcerative colitis, the prior theories attempting to explain only certain aspects of the disease. It is therefore not seeking to displace any prior theory.

Under the radical induction theory, loss of the barrier membrane plays the central role in initiation of the disease. The membrane is not much discussed in the other leading theories, which appear to regard loss of the membrane as a consequence of inflammation, rather than the cause of it.

Although ulcerative colitis is often treated as an autoimmune disease, there is no consensus as to whether the disease is in fact an autoimmune disease. See List of Autoimmune Diseases. The fact that removal of the colon cures the disease, including the extra-intestinal manifestations, suggests that ulcerative colitis is not an autoimmune disease. The radical induction theory is more consistent with the disappearance of all symptoms upon removal of the colon.

Related to the autoimmune theory is the theory that the immune system is mounting an exaggerated response to an actual, but unknown, infection, which could be either in the intestine, or in some other part of the body. The radical induction theory identifies the "infection" as the infiltration of bacteria into the wall of the intestine following loss of the protective membrane.

The radical induction theory offers an explanation for the genetic component of the disease. Persons with known aberrant genes controlling enzymes involved in the production or elimination of hydrogen peroxide have a greater incidence of the disease.

The radical induction theory is also consistent with the theory that environmental factors may trigger the disease in a person predisposed to it: foods, medicines and contaminants may affect the metabolic reactions that result in the production or removal of hydrogen peroxide. Many of the environmental factors previously suggested seem, however, to be only remotely related to this mechanism; and, obvious factors may have been overlooked.

Administration of vitamin B-6 has been identified as a trigger, and the theory explains this in terms of hydrogen peroxide production as a byproduct of metabolism of the vitamin. Administration of iron has likewise been identified as a trigger, and the theory explains this in terms of catalyzing the conversion of peroxide to the more active hydroxyl radical.

What is not well-explained?

Although the radical induction theory is much more comprehensive than any other explanation for ulcerative colitis, there are some aspects of the disease that are not well-explained. These include:

Ulcerative colitis is more common in developed countries than underdeveloped countries.

The theory seems to contemplate that persons in remission on immume-suppressing drugs may be experiencing episodes of membrane loss, without inflammation. Wouldn't such people be at risk for life-threatening infections in the intestinal wall?

There is no explanation under this theory for the correlation between ulcerative colitis and high levels of sulfate-reducing bacteria.*Roediger et al. "Colonic sulfide in pathogenesis and treatment of ulcerative colitis.", Dig Dis Sci. 1997 Aug;42(8):1571-9. PMID 9286219*Levine et al. "Fecal hydrogen sulfide production in ulcerative colitis.", Am J Gastroenterol. 1998 Jan;93(1):83-7. PMID 9448181

Status as a scientific theory

As a scientific theory, the radical induction theory is subject to attack under the scientific method:

Are there logical contradictions in the theory?
Is the theory consistent the observed facts about the disease?
The build up of peroxide under the epithelial membrane and the initial rupture without prior inflammation have not been directly observed. Is the theory making too many assumptions?
Does the theory subsume the prior theories of the disease?
Does the theory make predictions that could be tested by experiment?

Possible Treatment

Although treatment is not a part of the radical induction theory, there is an obvious implied treatment strategy that might work, to the extent the theory may be valid. This should not be viewed as a standard or accepted treatment, and it has not been endorsed or recommended by any person.

5-ASA would continue as the main drug, although its role would be as a free radical trap as well as an anti-inflammatory. It may still be necessary to use corticosteroids to obtain and maintain remission.

Restoration and maintenance of the protective membrane should be a main goal of treatment. Things that would increase hydrogen peroxide production should be avoided, and the enzyme systems that remove hydrogen peroxide and other free radicals supported. Anti-oxidative dietary supplements include:

Coenzyme Q10 is also often cited as an antioxidant.

Quantities of any dietary supplements in excess of recommended daily amounts should be approached with caution. Large quantities of vitamin B-6 and iron should be especially avoided, since they may be triggers for the disease. Large quantities of copper may also be associated with the disease.

External links

References

Autoimmune diseases | Gastroenterology | Inflammations

Gourt Home::Gourt :: Radical Induction Theory of Ulcerative Colitis