Introduction

We read with interest the paper entitled "Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88" by Larsson et al (1). The role of microbiota in health and disease is the sub-ject of rigorous investigation. Several studies have demonstrated that microbiota and the Pattern-Recognition Receptors (PRRs) contri-bute to intestinal tumourigenesis; the exact mechanism of which is still obscure. Larsson et al have studied the effect of microbiota on the intestinal epithelial cell gene expression through a systematically microarray experi-ment in germfree vs. colonised mice. They have discovered that microbiota per se alters the intestinal gene expression in colonised mice in comparison to germfree counterparts.
Toll-Like Receptors (TLRs) are a group of PRRs which detect a wide range of stimuli. All TLRs except TLR3 function via MyD88. To address the question on the mechanism of transcriptional effect of microbiota on the in-testinal cells, Larsson et al conducted the mi-croarray experiment in MyD88-/- mice. If the microbiota effect was largely mediated by TLR signalling, it was expected to discover similar expression patterns in germfree and MyD88-/- mice. However, interestingly germ-free mice demonstrate a distinct gene expres-sion pattern compared to MyD88-/- mice. This finding is suggestive of a MyD88-indepen-dent mechanism of host-microbiota interaction in the normal intestine. MyD88 is the downstream effector of all TLRs except TLR3. However, the alternative MyD88-inde-pendent pathway is functional downstream of not only TLR3, but also TLR1/2, 2/6, 4, and 5 (2-4). It is noteworthy that a distinctive host response to microbiota is observed through activation of different downstream effectors in the TLR pathway; (5,6) the implication of which in the intestinal homeostasis and tumo-urigenesis is still unknown. In addition, other members of PRRs namely, NOD-like recep-tors and RIG-I-like receptors are potentially implicated in the physiologic host-microbiota interaction.
TRIF is the main adaptor of the MyD88-in-dependent TLR signalling. MyD88 -/- TRIF-/- mice are completely unresponsive to TLR stimulation (7). In other words, MyD88 and TRIF exhibit non-redundant effects in TLR signalling. Larsson et al have demonstrated that under physiologic condition, the MyD88-independent pathway is an important mechan-ism of intestinal homeostasis maintenance (1). In order to fully understand the role of TLR signalling in the normal intestinal homeostasis, it is essential to study the TRIF-dependent pathway in a similar experiment in TRIF-/- vs. TRIF+/+ mice. It is conceivable that the bal-ance between MyD88-dependent vs.–inde-pendent pathways can fine-tune the TLR sig-nalling in response to normal and altered mi-crobiota in health and disease.