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Crohn's Disease- Pathophysiology and Conventional and Alternative Treatment Options
Intestinal Permeability (SIP) or Leaky Gut Syndrome
Considerable evidence supports the presence of increased small intestinal permeability (SIP) or leaky gut syndrome in Crohn’s disease. However, whether it is a contributing factor to the pathogenesis or a consequence of inflammation is not entirely clear.
Evidence for Genetic- and/or Environmentally-Induced Intestinal Hyperpermeability Preceding Disease Manifestation
Evidence that SIP precedes actual disease manifestation has been put forth by a number of researchers. Studies of Crohn's Disease patients and their firstdegree relatives point to the possibility of a genetic- and/or environmentally-induced defect in intestinal permeability preceding the onset of fullblown disease. A case report in Gastroenterology describes a woman with a positive family history of Crohn's Disease and a positive personal history of increased SIP since age 13; at age 24 she developed Crohn's Disease. In this case, SIP appeared to precede disease manifestation by at least 10 years.102
Examination of intestinal permeability or leaky gut syndrome in relatives of Crohn's Disease patients sheds light on the potential genetic influence of increased intestinal permeability in the pathogenesis of Crohn's Disease. A study examined intestinal permeability in 16 Crohns Disease patients and 26 first-degree relatives with whom they lived, compared with 32 healthy controls and their family members. Increased SIP was found in 37 percent of patients and 11 percent of first-degree relatives, significantly greater than controls. Because the patients were living with the relatives tested, it is impossible to know from this data whether the increased permeability was genetically or environmentally induced. However, it does provide evidence of a defect in SIP, possibly preceding the onset of inflammation.103 Interestingly, another study found a small increase in SIP or leaky gut syndrome in spouses of Crohn's Disease patients, pointing to a possible environmental cause.104
Another group of researchers, studying the familial connections in SIP and Crohns Disease, tested SIP in 39 Crohn's Disease patients, 34 healthy first-degree relatives, 22 spouses, and 29 healthy controls, using the lactulose:mannitol test (Table 4). SIP was tested at baseline and then after dosing with acetylsalicylic acid (aspirin) to induce increased permeability. The baseline SIP results found elevations in 36 percent of Crohn's Disease patients, 23 percent of spouses, 18 percent of relatives, and three percent of controls, indicating environment may play a greater role than genetics. On the other hand, after aspirin provocation, all participants experienced an increase in permeability with 32 percent of patients, 41 percent of first-degree relatives, 14 percent of spouses, and three percent of controls demonstrating an abnormally high response. This latter data seems to point to genetic factors. The researchers suggest that baseline permeability may be determined by environmental factors, whereas reaction to provocation by gut toxins such as aspirin may be genetically determined.105 A similar study found exaggerated response to provocation by ibuprofen ingestion in first-degree relatives of pediatric Crohns Disease patients, with a greater increase in SIP in relatives than in healthy controls.106
An in vitro study provides a potential mechanism by which increased SIP or leaky gur syndrome could contribute to the etiology of Crohns Disease. Mucosal samples from non-inflamed portions of the ileum of Crohn's Disease patients had increased permeability to the common food allergen ovalbumin. The authors suggest this could increase the antigen load in the mucosa leading to disease initiation.107
Evidence for Inflammation as Causative Factor of Increased SIP
Other research points to inflammation as the causative factor for increased SIP in Crohn's Disease, implying the disease itself caused the increased permeability. TNF-alpha appears to cause a rearrangement in key proteins associated with the tight junctions in the intestines of Crohn's Disease patients, resulting in increased permeability.108 Inhibition of TNF-alpha has been found to reverse increased tight junction permeability.109
Common medications used to treat Crohn's Disease, including prednisone110 and infliximab,111 decrease inflammatory cytokines including TNF-alpha and normalize gut permeability.
SIP as a Predictor of Disease Activity and Potential for Relapse
Several studies indicate the permeability of the small intestine seems to be reflective of disease activity and potential for relapse in Crohns Disease. One study of 39 Crohn's Disease patients found the effect of an elemental diet on SIP was similar to SIP seen during disease remission in both instances significantly lower than during active disease.112
Wyatt et al followed 72 patients with inactive Crohn’s disease for one year, evaluating SIP using the lactulose:mannitol ratio, and found 26 of 37 patients with increased permeability experienced relapse, compared to only six of 35 with normal permeability.113
Another study examined absorption of macromolecules (horseradish peroxidase) as a reflection of increased intestinal permeability in moderate-to-severe Crohn's Disease compared to mild disease and controls. The researchers found significantly increased permeability in moderate-to-severe Crohns Disease but not mild disease or controls. The authors conclude disease activation seems to be associated with increased permeability, which they hypothesize is secondary to the disease process.114
Another study examined 50 patients with inactive Crohn's Disease; defined as a CDAI 150. SIP was assessed via the lactulose:rhamnose ratio. Of 18 patients with increased permeability, eight relapsed during the one-year study, while only one of 31 with normal SIP experienced a relapse.115
Evaluation of 132 Crohn's Disease patients in remission who were followed every four months for two years supports the use of intestinal permeability as a predictor of relapse. Forty percent of patients relapsed during this period and increased lactulose:mannitol ratio (signifying increased permeability) and decreased serum iron were associated with relapse. There was no association between tendency to relapse and other disease parameters such as white blood count, ESR, CRP, or other signs of inflammation.116
Another study of 27 Crohns Disease patients in remission, compared to 22 healthy controls, failed to conclude intestinal permeability was a good predictor of relapse.117
A Generalized Permeability Defect in Crohn's Disease?
Whether SIP typically precedes disease manifestation or is a result of inflammation remains to be determined. It is probable increased SIP precedes disease manifestation, but inflammation associated with active disease exacerbates the problem. However, the permeability defect may be more generalized, as increased permeability has been noted in other tissues of Crohn's Disease patients. One group of researchers found increased pulmonary permeability in patients with Crohn’s disease. Unlike intestinal permeability, pulmonary permeability did not seem to be affected by disease activity.118
Gastroduodenal permeability (GDP), tested by sucrose excretion, has been found by two groups of researchers to be increased in Crohns Disease patients. One study of 100 patients found GDP was significantly higher in Crohn's Disease patients than controls, and increased GDP was predictive of gastroduodenal involvement.119 Another study found similar results in a group of 50 Crohns Disease patients. The researchers also found higher gastric and intestinal permeability were associated with a greater likelihood of granulomatous involvement.120 Nutrients for the treatment of increased intestinal permeability in Crohns Disease are discussed below in the treatment section.
Table 4. The Lactulose: Mannitol Test for Small Intestinal Hyperpermeability
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