High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway
By Kyung-Ah Kim, Wan Gu, In-Ah Lee, E. Joh, Dong-Hyun Kim. PLoS ONE, 2012
1,085 citations recorded by the source corpus.
Background & Aims While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet. Methods C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks. Results HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice. Conclusions HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.
Subfields: Epidemiology, Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/9454b2c4524de394cc550b0b3ec3bc50e66d8bbe
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Citations in the corpus
- Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders (2015, background): “In the second study increased levels of Enterobacteriaceae and Alistipes were observed.”
- Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? (2018, background): “By affecting gut microbiota, high-fat diet increases intestinal permeability and induces metabolic endotoxaemia, leading to chronic inflammation in the post-prandial phases.(167,168) Therefore, glucagon-like peptide-2 may drive improved gut permeability in obese mice.”
- What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases (2019, background): “In addition, the higher abundance of Ruminococcaceae and Rikenellaceae in mice fed a high-fat diet is not only dependent on the ingested diet but is also closely linked with obesity and type 2 diabetes [85].”
- Stress & the gut-brain axis: Regulation by the microbiome (2017, neutral): “…evidence that high-fat diet feeding promotes a “ leaky gut ” (i.e., increased intestinal permeability (Cani et al., 2008; Hildebrandt et al., 2009; Kim et al., 2012)), similar to the effect of chronic stress alone (Gareau et al., 2008; Maes and Leunis, 2008; Ait-Belgnaoui et al., 2014), and…”
- Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages (2018, positive): “Targeted LC-MS/MS experiments confirmed the impact of the HFD on cecum, serum, and liver FFA profiles, in good agreement with previous reports on similar HFD models (Kim et al., 2012; Pang et al., 2016).”