Abstract
The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1-TIRAP (AA-CT; P: 2,8 × 10–17) and MyD88-TIRAP-IL1RL1 (AA-CT-AA; P: 1,4 × 10–8) – but not MyD88 alone—act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1—both associated with anti-inflammatory activity—and low levels of the pro-inflammatory molecules IL-1β, TNF-α, COX-2, and IL-6.
Highlights
The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP)
The present study shows that MyD88, TIRAP and IL1RL1—all members of the same p athway[13] and the first two physically associated14—confer resistance against H. pylori infection acting in concert
MyD88 and TIRAP interact against H. pylori
Summary
The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. NMR identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Pathogen eradication with antibiotics can alter the gut microbiome and foster obesity or type 2 d iabetes[8] These findings indicate the importance of knowing risks and advantages associated with H. pylori eradication. The superfamily includes interleukin 1 receptor-like 1 (IL1RL1) ( known as ST2), the Toll like receptors (TLRs), the adaptor molecule myeloid differentiation primary-response protein 88 (MyD88) and the MyD88 adaptor-like TIRAP ( known as MAL). IL1RL1 exerts its inhibitory activity sequestering the adaptor molecules MyD88 and TIRAP through the TIR d omain[11]
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