Little is known about the pathogenesis of metabolic syndrome, although Toll-like receptor 4 (TLR4) has been implicated. We investigated whether TLR4 in the intestinal epithelium regulates metabolic syndrome by coordinating interactions between the luminal microbiota and host genes that regulate metabolism. Mice lacking TLR4 in the intestinal epithelium (TLR4^ΔIEC), but not mice lacking TLR4 in myeloid cells nor mice lacking TLR4 globally, developed metabolic syndrome; these features were not observed in TLR4^ΔIEC mice given antibiotics. Metagenomic analysis of the fecal microbiota revealed differences between TLR4^ΔIEC and wild-type mice, while meta-transcriptome analysis of the microbiota showed that intestinal TLR4 affected the expression of microbial genes involved in the metabolism of lipids, amino acids, and nucleotides. Genes regulated by peroxisome proliferator-activated receptors (PPARs) and the antimicrobial peptide lysozyme were significantly downregulated in TLR4^ΔIEC mice, suggesting a mechanism by which intestinal TLR4 could exert its effects on the microbiota and metabolic syndrome. Supportingly, antibiotics prevented both downregulation of PPAR genes and the development of metabolic syndrome, while PPAR agonists prevented development of metabolic syndrome in TLR4^ΔIEC mice. Thus, intestinal epithelial TLR4 regulates metabolic syndrome through altered host-bacterial signaling, suggesting that microbial or PPAR-based strategies might have therapeutic potential for this disease.

中文翻译：

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肠上皮 Toll 样受体 4 通过调节小鼠微生物和肠上皮细胞之间的相互作用来预防代谢综合征。

尽管 Toll 样受体 4 (TLR4) 与此有关，但人们对代谢综合征的发病机制知之甚少。我们研究了肠上皮细胞中的 TLR4 是否通过协调管腔微生物群与调节代谢的宿主基因之间的相互作用来调节代谢综合征。肠上皮细胞中缺乏 TLR4 的小鼠 (TLR4 ^ΔIEC )，而不是骨髓细胞中缺乏 TLR4 的小鼠，也不是全身缺乏 TLR4 的小鼠，会发展为代谢综合征；在给予抗生素的 TLR4 ^ΔIEC小鼠中未观察到这些特征。粪便微生物群的宏基因组分析揭示了 TLR4 ^{ΔIEC之间的差异}和野生型小鼠，而微生物群的元转录组分析表明，肠道 TLR4 影响参与脂质、氨基酸和核苷酸代谢的微生物基因的表达。受过氧化物酶体增殖物激活受体 (PPAR) 和抗菌肽溶菌酶调节的基因在 TLR4 ^ΔIEC小鼠中显着下调，表明肠道 TLR4 可以对微生物群和代谢综合征发挥作用的机制。支持性地，抗生素阻止了 PPAR 基因的下调和代谢综合征的发展，而 PPAR 激动剂阻止了 TLR4 ^{ΔIEC中代谢综合征的发展}老鼠。因此，肠上皮 TLR4 通过改变宿主-细菌信号传导调节代谢综合征，表明微生物或基于 PPAR 的策略可能具有治疗这种疾病的潜力。