Bacterial-Metal Interactions: The Potential Role of Aluminum and Other Trace Elements in the Etiology of Chrohn’s Disease

Abstract

Despite the recent burst of excitement about the genomics of Crohn’s disease, the critical importance of environmental factors in this condition has been recognized ever since the disease was described. The chief suspects for this role have always been microorganisms and dietary constituents. Many candidate microorganisms have been proposed, evaluated and discarded over the decades, but the most persistent theories have revolved around mycobacterial infection. Among potential dietary agents, however, none has yet emerged as a favorite. An offending dietary constituent, of course, need not be conventional foodstuff; additives, preservatives, and even microparticle contaminants are plausible alternatives. With this in mind, we have arrived at an etiologic hypothesis for Crohn’s disease based on our study of a fatal outbreak of granulomatous enteritis in a group of horses sharing a common environment. The horses suffered from a disorder with many histologic similarities to human Crohn’s disease. In the evaluation of the cluster, an unexpected finding was the presence of excess aluminum in affected tissues. Microprobe elemental analysis demonstrated that aluminum was concentrated within microorganisms in the intestinal wall. Based on these observations, we propose a novel approach to etiologic concepts of Crohn’s disease. Our hypothesis is that the capability of certain microbial organisms, in particular mycobacterial species, to take up certain trace elements from environmental and host sources, may alter the pathogenicity of these organisms and exacerbate the host’s responses to them. As we will outline, mycobacteria possess potent metal chelators that provide essential metallic elements, especially iron, required for bacterial growth and virulence. We propose that in addition to iron, other metals, particularly aluminum, may use these same metal chelating systems to gain access to the organisms and this may alter their pathogenicity and ability to induce an exuberant granulomatous response. It is well established that the virulence and even survival of many bacterial organisms during infection depends on the ability of the pathogenic microbe to compete for essential nutrients, especially iron. However, in vertebrates iron remains sequestered within a number of high molecular weight binding proteins, such as transferrin, lactoferrin and ferritin. In what is essentially an iron-poor environment, microorganisms have evolved to produce ferric ion chelating agents, called siderophores, that are capable of solubilizing and transporting iron into the microbe. Siderophores contain some of the most efficient ironbinding ligands in nature and are capable of securing the metal from transferrin, ferritin, ferric hydroxide as well as from synthetic chelators such as EDTA. The affinity of siderophores for iron is remarkably strong with dissociation constants (Ks) in the range of 10 to 10.