Suppression of MyD88 disturbs gut microbiota and activates the NLR pathway and hence fails to ameliorate DSS-induced colitis

Abstract

Background Myeloid differentiation factor 88 (MyD88) is the core adaptor for TLRs defending against microbial invasion and initiating downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of IBD is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism. Methods MyD88 knockout (MyD88−/−) mice and the MyD88 inhibitor (TJ-M2010-5) were used to investigate the impact of MyD88 on acute dextran sodium sulfate (DSS)-induced colitis. Disease activity index, colon length, histological score, and inflammatory cytokines were examined to evaluate the severity of colitis. The RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism. Results In the acute DSS-colitis model, the severity of colitis was not alleviated in MyD88−/− mice and TJ5-treated mice, despite significantly lower levels of NF-κB activation exhibited compared to control mice. Meanwhile, the 16S rDNA sequencing and RNA transcriptome analysis revealed a higher abundance of intestinal Proteobacteria and an up-regulation of the NOD-like receptors (NLRs) signaling pathway in colitis mice following MyD88 suppression. Further blockade of the NLR signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ5 ameliorated the disease severity, which was not improved solely by MyD88 inhibition. After treatment with broad-spectrum antibiotics, the downregulation of the NLR signaling pathway was observed. Conclusion Our study suggests that the suppression of MyD88 might be associated with unfavorable changes in the composition of gut microbiota, leading to NLR-mediated immune activation and intestinal inflammation.