Microbial control of intestinal innate immunity

Intestinal innate immunity, a critical component of the intestinal barrier to noxious agents, is a master regulator of intestinal health. Dysregulation of intestinal innate immune features are pathognomonic of disease states such as inflammation and cancer [1]. The implication of loss of intestinal barrier function to human health is broad and goes beyond oncogenesis [2, 3]. Thus, a complete understanding of the molecular pathways governing the regulation of innate immunity in the intestines is a prerequisite towards finding cures. In a recent paper, our group defined a unique aspect of the regulation of intestinal innate immunity by microbial metabolites, in that, indole tryptophan metabolites (e.g., indole propionic acid) control intestinal barrier function via a host cellular pathway involving the Pregnane X Receptor (PXR) and Toll-like receptor (TLR4) [4]. Based on the evidence presented, we speculate that the following model best describes this regulatory pathway (Figure 1). The model derives from data obtained from rodents (mice) and thus requires confirmation in humans. To better understand the general implications, however, some further discussion of available data from human and other rodent studies supports the foundations of our model. In specific bacteria, with the availability of L-tryptophan, the repressed tryptophanase operon (trp ABCDE) and tna operon (tnaCAB), are induced, and indole concentrations rise [5]. Indoles generated in one species can cross cell membrane boundaries of permissive cells and participate in interkingdom signaling [5]. There is also a significant influence of the environment, other than the availability of L-tryptophan on TnaA expression (e.g., cell density, high pH, low glucose availability) [5]. The indoles have been implicated in interkingdom signaling among bacteria and in regulating (inhibiting) biofilm formation, motility, chemotaxis, and cell adherence. L-tryptophan supplementation of mice exposed to inflammatory toxins (DSS, TNBS) ameliorates inflammatory indices in the intestines and liver fat. Colitic mice have reduced indole metabolites [6]. In humans, urinary excretion of tryptophan is increased, and Editorial