Microbial Factors

Although a bacterial etiology of Crohn’s disease has been postulated for decades, research has never revealed a specific responsible agent. Several possible mechanisms for a bacterial etiology in the development of Crohn's Disease have been proposed: (1) an immune response to a specific pathogen resulting in intestinal infection;⁴⁶ (2) alterations in normal bacterial content of the intestinal tract;⁴⁷ (3) a defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins;^48,49 and (4) alterations to the intestinal immune response.⁴⁶ Numerous bacteria including Escherichia coli,⁵⁰ viruses, and parasites (Table 3) have been implicated in CD, but none have been confirmed.

A 2003 study published in Lancet examined a potential bacterial etiology. French researchers examined evidence for the onset of increased rates of Crohn's Disease in Europe and North America beginning around 1940 and found a corresponding increase in household refrigeration. It appears certain bacteria, known as psychotropic bacteria, are able to grow at the temperatures maintained inside a refrigerator (-1 to +10 degrees Centigrade, or 30 to 50 degrees Fahrenheit). Referred to as the Cold Chain Hypothesis, two psychotropic bacteria - Listeria monocytogenes and Yersinia enterocolitica - have been isolated from the lesions of Crohn's Disease patients at higher rates than in controls.^51,52 Both bacteria can be found in a wide variety of foods, including meats, dairy products, and vegetables.^53,54 The researchers postulate consuming refrigerated food containing low levels of these psychotropic, pathogenic bacteria results in an over-active immune response, resulting in Crohns Disease.⁵⁵ Additional research is warranted to confirm or disprove this hypothesis.

Epidemiological data indicate an increased risk of Crohn’s disease in children with perinatal exposure to the measles virus.⁵⁶ Subsequent studies, however, have failed to detect measles-virus DNA in the intestinal tissue of Crohn's Disease patients.⁵⁷

MAP is perhaps the most researched bacterial agent implicated in Crohns Disease, with at least 20 studies investigating either its role as a pathogenic agent or the effectiveness of antimicrobial therapy to treat it. Mycobacterium species as an etiological agent for gastrointestinal inflammation is not a new theory. As early as 1895, Johne and Frothingham reported findings from tissue analysis of a cow that had died of Crohn’s-like symptoms. They identified a bacillus with much the same staining characteristics as the tubercle bacilli; the disease in cattle became known as Johne's disease.⁵⁸ In 1901, a Scottish surgeon postulated, after operating on four patients with chronic enteritis, that the disease he observed in the human intestine might be the same as Johne's disease in cattle. He was, however, unable to conclusively culture and identify the organisms from human tissue.⁵⁹

In the 1980s Chiodini successfully isolated MAP from intestinal lesions of a small number of Crohn's Disease patients.^60,61 In 1992, an internationally recognized expert in Crohns Disease, John Hermon-Taylor and colleagues confirmed Chiodini's findings. The study, involving 40 Crohn's Disease patients, 23 Ulcerative Colitis patients, and 40 controls (patients without IBD), isolated MAP in 65 percent of patients with Crohns Disease, 4.3 percent with Ulcerative Colitis, and 12.5 percent of control patients.⁶² 62 Other research has confirmed earlier findings of DNA insertion sequence (IS900) from MAP in Crohn’s diseased tissues.⁶³ Hermon-Taylor, aware MAP is ubiquitous in nature, especially in meats and dairy products, tested retail milk supplies in Great Britain. After culturing for 2.5 years, the IS900 MAP DNA sequence was isolated in 16 percent of retail milk samples, easily facilitating widespread transmission to humans.⁶⁴ Researchers in Sweden confirmed this finding in 2002 when they revealed 19.7 percent of bulk milk samples across Sweden tested positive for IS900.⁶⁵ A 2000 meta-analysis by Hermon-Taylor and colleagues of 18 peer-reviewed publications found nine other studies reporting the presence of MAP in the intestine of Crohn's Disease patients, as well as several studies in which MAP was not identified in Crohn’s patients.⁶⁶ 66 Since that time, other researchers have demonstrated MAP DNA presence in intestinal and blood samples in up to 92 percent of Crohn's Disease patients compared to 26 percent of controls.^67,68

Despite its prevalence in tissue and blood of Crohn's Disease patients, the presence of MAP DNA does not prove causality. The isolation of MAP DNA is often not reproducible with subsequent analysis of the same tissue. Conversely, MAP RNA isolation from Crohn’s-diseased tissue samples indicates the organism was viable at isolation and not from a contaminating source such as cow's milk. Isolation of the MAP RNA sequence IS900 is more reproducible in human tissue, possibly because it is a much smaller molecule. In addition, because RNA has a very short half-life (in minutes),⁶⁹ its presence cannot be attributed to environmental contaminants.⁷⁰

Antimicrobial therapy should be effective at controlling the disease, if MAP is a contributing agent. Studies examining this premise have yielded negative results.^71-74 Negative results may be because only single antibiotics or antibiotics ineffective against MAP were used. MAP is now known to be resistant to most standard antituberculous drugs. Since 1997 four open-label studies have shown efficacy with a combination of rifabutin and macrolide antibiotics for the treatment of Crohn's Disease.^75-78

Table 3. Infectious Pathogens Implicated in Crohn's Disease