AJMB Avicenna Journal of Medical Biotechnology 2008-2835 2008-4625 Avicenna Research Institute AJMB-4-210 Letter to the Editor Host-Microbiota Interaction is MyD88-Independent in the Intestinal Tract under Physiologic Condition Moossavi Shirin 1 Rezaei Nima 2 3 4 * Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran Molecular Immunology Research Center, Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Department of Infection and Immunity, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK Corresponding author: Nima Rezaei, M.D., Ph.D., Children's Medical Centre Hospital, Tehran 14194, Iran. Tel: +98 21 66929234 Fax: +98 21 66929235. E-mails: rezaei_nima@tums.ac.ir; shirin.moossavi@gmail.com October-December 2012 4 4 210 211 05 08 2012 30 08 2012 Copyright © 2012 Avicenna Research Institute 2012

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The role of microbiota in health and disease is the subject of rigorous investigation. Several studies have demonstrated that microbiota and the pattern-recognition receptors contribute to intestinal tumourigenesis; the exact mechanism of which is still obscure. MyD88 is the downstream effector of all Toll-like receptors (TLRs) except TLR3. However, the alternative MyD88-independent pathway is functional downstream of not only TLR3, but also TLR1/2, 2/6, 4, and 5. TLR4 stimulation with intraperitoneal lipopolysaccharide exerts distinct functional effect on the intestinal motility via MyD88-dependent and-independent pathways.

 Host-microbiota interaction Intestinal tract Toll-like receptors <p>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 <italic>et al</italic> (<xref ref-type="bibr" rid="CIT0001">1</xref>). The role of microbiota in health and disease is the subject of rigorous investigation. Several studies have demonstrated that microbiota and the Pattern-Recognition Receptors (PRRs) contribute to intestinal tumourigenesis; the exact mechanism of which is still obscure. Larsson <italic>et al</italic> have studied the effect of microbiota on the intestinal epithelial cell gene expression through a systematically microarray experiment in germfree <italic>vs</italic>. colonised mice. They have discovered that microbiota <italic>per se</italic> alters the intestinal gene expression in colonised mice in comparison to germfree counterparts.</p> <p>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 intestinal cells, Larsson <italic>et al</italic> conducted the microarray experiment in MyD88<sup>-/-</sup> mice. If the microbiota effect was largely mediated by TLR signalling, it was expected to discover similar expression patterns in germfree and MyD88<sup>-/-</sup> mice. However, interestingly germ-free mice demonstrate a distinct gene expression pattern compared to MyD88<sup>-/-</sup> 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-independent pathway is functional downstream of not only TLR3, but also TLR1/2, 2/6, 4, and 5 (<xref ref-type="bibr" rid="CIT0002">2</xref>–<xref ref-type="bibr" rid="CIT0004">4</xref>). It is noteworthy that a distinctive host response to microbiota is observed through activation of different downstream effectors in the TLR pathway; (<xref ref-type="bibr" rid="CIT0005">5</xref>, <xref ref-type="bibr" rid="CIT0006">6</xref>) the implication of which in the intestinal homeostasis and tumo-urigenesis is still unknown. In addition, other members of PRRs namely, NOD-like receptors and RIG-I-like receptors are potentially implicated in the physiologic host-microbiota interaction.</p> <p>TRIF is the main adaptor of the MyD88-independent TLR signalling. MyD88 <sup>-/-</sup> TRIF<sup>-/-</sup> mice are completely unresponsive to TLR stimulation (<xref ref-type="bibr" rid="CIT0007">7</xref>). In other words, MyD88 and TRIF exhibit non-redundant effects in TLR signalling. Larsson <italic>et al</italic> have demonstrated that under physiologic condition, the MyD88-independent pathway is an important mechanism of intestinal homeostasis maintenance (<xref ref-type="bibr" rid="CIT0001">1</xref>). 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<sup>-/-</sup> <italic>vs</italic>. TRIF<sup>+/ +</sup> mice. It is conceivable that the balance between MyD88-dependent <italic>vs</italic>.–independent pathways can fine-tune the TLR signalling in response to normal and altered microbiota in health and disease.</p> </sec> </body> <back> <ref-list> <title>References Larsson E Tremaroli V Lee YS Koren O Nookaew I Fricker A Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88 Gut 2012 61 8 1124 1131 Gao Q Qi L Wu T Wang J Clostridium butyricum activates TLR2-mediated MyD88-independent signaling pathway in HT-29 cells Mol Cell Biochem 2012 361 1-2 31 37 Biswas SK Bist P Dhillon MK Kajiji T Del Fresno C Yamamoto M Role for MyD88-independent, TRIF pathway in lipid A/TLR4-induced endotoxin tolerance J Immunol 2007 179 6 4083 4092 Choi YJ Im E Chung HK Pothoulakis C Rhee SH TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells J Biol Chem 2010 285 48 37570 37578 Zughaier SM Zimmer SM Datta A Carlson RW Stephens DS Differential induction of the toll-like receptor 4-MyD88-dependent and -independent signaling pathways by endotoxins Infec Immun 2005 73 5 2940 2950 Buchholz BM Billiar TR Bauer AJ Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus Am J Physiol Gas-trointest Liver Physiol 2010 299 2 G531 G538 Gavin AL Hoebe K Duong B Ota T Martin C Beutler B Adjuvant-enhanced antibody responses occur without toll-like receptor signaling Science 2006 314 5807 1936 1938