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Toll-like receptor 4 and myeloid differentiation factor 88 are required for gastric bypass-induced metabolic effects
Journal article   Open access   Peer reviewed

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

Marwa Abu El-Haija, Yuanchao Ye, Yi Chu, Hussein Herz, Benjamin Linden, Shailesh K Shahi, Kasra Zarei, Ashutosh K Mangalam, Steven J Mcelroy and Mohamad Mokadem
Surgery for obesity and related diseases, Vol.17(12), pp.1996-2006
08/02/2021
DOI: 10.1016/j.soard.2021.07.019
PMCID: PMC9083208
PMID: 34462225
url
https://doi.org/10.1016/j.soard.2021.07.019View
Published (Version of record) Open Access

Abstract

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. 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. Animal- based study. 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. We demonstrate that RYGB reduces TLR4 expression explicitly in the small and large intestine of C57Blc/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 naïve recipients fails to induce a metabolic phenotype similar to that of the donors, as it does in wild-type recipients. TLR4 and MyD88 are required for RYGB-induced metabolic response that is likely mediated by gut microbiome. •Roux-en-Y Gastric bypass decrease the expression of Toll-like receptor 4 (TLR4) in the small and large intestine.•Gastric bypass requires a functional TLR4 signaling for ample regulation of glucose metabolism.•MyD88 deficient mice fail to respond to all the metabolic benefits of gastric bypass surgery.•Microbiome-induced metabolic changes from gastric bypass donors require functional TLR4 and MyD88 molecules.
 Gastric bypass Gut microbiome Metabolic regulation MyD88 TLR4

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