Editorial
Crohn’s disease, TNF-α, and the leaky gut. the chicken or the egg?

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Introduction

Until the 1970s, Crohn’s disease was considered to be a relatively rare disorder. More recently, the incidence of the disease has been increasing, especially in the developed parts of the world (1). Currently, Crohn’s disease afflicts approximately 0.5% of the population, and more than 1,000,000 persons in the United States alone.

Despite the efforts of many excellent investigators, the etiology of Crohn’s disease remains unknown. However, we do glean some clues as to the etiology of the disease from several findings that are established and consistent. These findings include: 1) an abnormal T-helper lymphocytes-1 (TH-1) immunological response; 2) the necessary presence of bacteria in the intestinal lumen; 3) the increase in intestinal permeability present in most patients and some of their clinically healthy relatives; and 4) the therapeutic benefit of suppression or neutralization of tumor necrosis factor α (TNF-α). Because scientific inquiry is fragmented, and because each one of us views Crohn’s disease from our own perspective which is limited by our expertise in a narrow area of science or clinical medicine, these four consistent findings would not seem (to most of us) to be interconnected.

In this issue of the Journal(2), a group of investigators from Leuven, Belgium, headed by Professor Rutgeerts, investigated the interactions and interrelationships between two of the established factors in Crohn’s disease, namely, intestinal permeability and anti-TNF-α therapy. Intestinal permeability and TNF-α play a role in the pathogenesis and therapy of the disease. The increase in intestinal permeability in Crohn’s patients and some of their clinically healthy relatives (3) allows luminal antigens to penetrate the intestinal tissue, possibly instigating and/or perpetuating the disease. TNF-α is a proinflammatory cytokine associated with TH-1 response by the intestinal immune system in Crohn’s disease. Reduction of the activity of TNF-α is effective in improving the clinical course of patients with Crohn’s disease and in reducing intestinal inflammation 4, 5.

In the elegant study presented in this issue of the Journal, patients with active Crohn’s disease were infused with infliximab (Remicade; Centocor, Malvern, PA), a chimeric antibody to TNF-α, and their intestinal permeability was measured before and 4 wk after infusion. The patients’ intestinal permeability and disease activity both decreased significantly after infliximab administration (2). Therefore, neutralization of intrinsic TNF-α activity by infliximab was not only successful therapeutically, but also in decreasing the abnormal intestinal permeability of the patients.

Well-designed experiments raise follow-up questions and suggest future studies. The present study accomplishes this goal very well. This report stimulates us to consider whether TNF-α could also have a role in the pathogenesis of Crohn’s disease in addition to its role in intestinal inflammation. If abnormal TNF-α production were an etiological factor, it could increase intestinal permeability and increase antigenic penetration of the mucosa, thereby instigating the inflammatory process. It is established that TNF-α levels are raised in the intestinal mucosa 6, 7 and in the serum (8) of patients with active Crohn’s disease. However, it is not known whether the levels of TNF-α are elevated before the clinical onset of the disease and thus, whether it could be an etiological factor in Crohn’s disease. One possible way to approach this question would be to measure intestinal tissue levels and/or serum levels of TNF-α in the clinically healthy relatives of patients with familial Crohn’s disease. We know that approximately 20% of these relatives are likely to develop Crohn’s disease and that approximately 20% of them have increased intestinal permeability (9). If these clinically healthy relatives, especially those who have increased intestinal permeability, are also found to have elevated intestinal tissue or serum levels of TNF-α, then this pro-inflammatory cytokine could be considered as an etiological factor in the pathogenesis of Crohn’s disease.

Another possible interpretation of the present study is to assume that increased TNF-α levels in Crohn’s disease is a factor that accentuates the underlying abnormality in intestinal permeability in Crohn’s disease. Several studies of the influence of TNF-α on intestinal cell monolayers in vitro would support this possibility. In one such study, TNF-α addition to colonic cell (HT-29) monolayers resulted in disruption of the tight junctional strands (10). In an investigation using human intestinal epithelial cell monolayers (CACO-2), TNF-α caused an increase in permeability of the cell monolayers (11). TNF-α has also been shown to increase the permeability of the blood-brain barrier (12). Therefore, the available data demonstrate that TNF-α can increase intestinal permeability and could contribute to the pathogenesis of Crohn’s disease by increasing the permeability of the gut to luminal antigens. Under this scenario, the abnormality in intestinal permeability is an etiological factor, which is further accentuated by intestinal inflammation and its associated elevation in TNF-α levels.

A third follow-up consideration arising from the study is the possibility that infliximab itself could have a direct effect on intestinal permeability independent of its activity of neutralization of TNF-α activity. We do know that infliximab, in addition to its neutralization of soluble TNF-α, does cause apoptosis of activated intestinal lamina propria T lymphocytes (13). We also know of other direct effects of infliximab independent of its influence on TNF-α that include the downregulation of several adhesion molecules and a decrease in IL-4, IL-6, and IL-8 14, 15. Because infliximab does have direct effects on the intestinal milieu aside from its neutralization of TNF-α, its direct effects could include tightening of the intercellular tight junction (16) and normalization of intestinal permeability.

Bacteria and their antigenic components are detected by intestinal intracellular pattern recognition receptors possibly including the recently described NOD2 17, 18. Under normal circumstances, these receptors, when stimulated by bacterial antigens or toxins, activate nuclear factor κB, which stimulates transforming growth factor β signaling, thereby suppressing TNF-α (19). Thus, the regulation of intestinal inflammation is complicated with multiple and redundant pathways and pro- and anti-inflammatory cascades. It is virtually impossible to assess individual factors in this complex series of events in vivo in patient studies. At the same time, patient studies are extremely important in providing clues and in stimulating questions and hypothesis for follow-up studies in vitro in systems such as cell lines. This allows us to control the variables and assess the various factors in relative isolation. The study published in this issue of the Journal should stimulate many such follow-up investigations.

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