Toll-like receptor 4 and myeloid differentiation factor 88 are required for gastric bypass-induced metabolic effects

Background: Toll-like receptor 4 (TLR4) has been suggested as one of the forefront cross-communicators between the intestinal bacteria and the host to regulate inflammatory signals and energy homeostasis. High-fat diet-induced inflammation is mediated by changes in gut microbiota and requires a functional TLR-4, the deficiency of which renders mice resistant to diet-induced obesity and its associated metabolic dysfunction. Furthermore, gut microbiota was suggested to play a key role in the beneficial effects of Roux-en-Y gastric bypass (RYGB), a commonly performed bariatric procedure. Objectives: To explore whether TLR4, myeloid differentiation factor 8 (MyD88; 1 of its key downstream signaling regulators) and gut microbiota play an integrative role in RYGB-induced metabolic outcomes. Setting: Animal- based study. Method: We performed RYGB in TLR4 and MyD88 knock-out (KO) mice and used fecal microbiota transplant (FMT) from RYGB-operated animals to these genetic mouse models to address our questions. Results: We demonstrate that RYGB reduces TLR4 expression explicitly in the small and large intestine of C57B1c/6J mice. We also show that TLR4 KO mice have an attenuated glucoregulatory response to RYGB. In addition, we reveal that MyD88 KO mice fail to respond to all RYGB-induced metabolic effects. Finally, fecal microbiota transplant from RYGB-operated mice into TLR4 KO and MyD88 KO naive recipients fails to induce a metabolic phenotype similar to that of the donors, as it does in wild-type recipients. Conclusion: TLR4 and MyD88 are required for RYGB-induced metabolic response that is likely mediated by gut microbiome. Published by Elsevier Inc. on behalf of American Society for Bariatric Surgery.

Automated summary

Toll-like receptor 4 (TLR4) and myeloid differentiation factor 8 (MyD88) play important roles in the metabolic response induced by Roux-en-Y gastric bypass surgery (RYGB), mainly mediated by gut microbiota. TLR4 knockout mice show attenuated glucose regulatory response to RYGB, while MyD88 knockout mice do not respond to the metabolic effects induced by RYGB. Fecal microbiota transplant from RYGB-operated mice fails to induce a metabolic phenotype similar to that of the donors in TLR4 and MyD88 KO mice, but is successful in wild-type recipients.