Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adult eosinophilic esophagitis

Abstract

ObjectivesEsophageal microbiota and regulation of adaptive immunity are increasingly being investigated in eosinophilic esophagitis (EoE). Toll-like receptors (TLRs) play a central role in the initiation and maintenance of innate immune activity. Our objective was to characterize the esophageal and duodenal innate immune response in EoE and its modulation by dietary therapy.MethodsEsophageal and duodenal biopsy samples were collected from 10 adults with untreated EoE, before and after effective treatment with a six-food elimination diet (SFED), and 10 controls with normal esophagus. In all cases, bacterial load (by mRNA expression of 16S), TLRs, mucins, transcription factors, interleukins, components of the NKG2D system, and innate immunity effectors were assessed by qPCR. Protein expression of TLRs were also determined by immunofluorescence.ResultsBacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed on biopsies with active EoE compared with controls. Muc1 and Muc5B genes were downregulated while Muc4 was overexpressed. Upregulation of MyD88 and NFκB was found together with IL-1β, IL-6, IL-8, and IL-10 mediators and PER-1, iNOS, and GRZA effectors. NG-K2D components (KLRK1, IL-15, MICB) were also upregulated. In all cases, changes in active EoE were normalized following SFED and mucosal healing. Duodenal samples also showed increased expressions of TLR-1, TLR-2, and TLR-4, but not 16S or any other mediators nor effectors of inflammation.ConclusionsEsophageal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease.

Toll‐like receptor 2 stimulation augments esophageal barrier integrity

“…We do not observe gene expression differences in the PRRs on primary epithelial cells from EoE and control patients. In contrast, Arias et al have recently published gene expression data from whole biopsy tissue of adults with EoE demonstrating significant upregulation of TLR1, TLR2, TLR4, and TLR9 when compared to control patient biopsy tissue . The overexpression of these TLR improved with six‐food elimination diet .…”

“…In contrast, Arias et al have recently published gene expression data from whole biopsy tissue of adults with EoE demonstrating significant upregulation of TLR1, TLR2, TLR4, and TLR9 when compared to control patient biopsy tissue. 46 The overexpression of these TLR improved with six-food elimination diet. 46 Our current study used isolated cells between passages 2 and 4, which may have allowed for some normalization of expression between the In the ALI model, we have tested whether stimulation of TLR2 and TLR3 can improve barrier function.…”

“…46 The overexpression of these TLR improved with six-food elimination diet. 46 Our current study used isolated cells between passages 2 and 4, which may have allowed for some normalization of expression between the In the ALI model, we have tested whether stimulation of TLR2 and TLR3 can improve barrier function. Our data show that recognition of lipoprotein agonists by TLR2 is a mechanism that increases epithelial barrier integrity (Figure 2), with a modest increase in ALI TEER following stimulation with TLR2 ligands zymosan, peptidoglycan, and Pam2CSK4.…”

Epidemiology and implications of concurrent diagnosis of eosinophilic oesophagitis and IBD based on a prospective population-based analysis

“…Aberrant responses to alterations in the gastrointestinal microbiota is another potential shared mechanism between EoO and IBD 24 28. Both EoO and IBD pathogenesis involve upregulation of toll-like receptors (TLRs) in the oesophageal29 and intestinal mucosa,30 respectively. TLRs activate the innate immune response to pathogen-associated molecular patterns of gastrointestinal tract microbes.…”

Toll-like receptor 2 stimulation augments esophageal epithelial barrier integrity

“…TLRs, including TLR2 and TLR1 are upregulated in the mucosa of patients with EoE and downregulated following treatment with six-food elimination diet (36). TLR2 single nucleotide polymorphisms (SNP) have been associated with asthma in Puerto Rican, Norwegian, Danish and Caucasian African populations (37)(38)(39)(40)(41)(42)(43), as well as development of severe atopic dermatitis in Italian and German populations (44,45).…”